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Co-delivery of tumor-derived exosomes with alpha-galactosylceramide on dendritic cell-based immunotherapy for glioblastoma.
Sep. 2017 | Liu, Hongyu; Chen, Ling; Liu, Jialin; Meng, Hengxing; Zhang, Rong; Ma, Lin; Wu, Liangliang; Yu, Songyan; Shi, Fei; Li, Ying; Zhang, Lijun; Wang, Lingxiong; Feng, Shiyu; Zhang, Qi; Peng, Yaojun; Wu, Qiyan; Liu, Chunxi; Chang, Xin; Yang, Lin; Uemura, Yasushi; Yu, Xinguang; Liu, Tianyi
Dendritic cell (DC) vaccine-based immunotherapy for glioblastoma multiforme (GBM) has shown apparent benefit in animal experiments and early-phase clinical trials, but the survival benefit is variable. In this work, we analyzed the mechanism of the potent antitumor immune response induced in vivo by tumor-associated antigen (TAA)-specific DCs with an invariant natural killer T (iNKT) cell adjuvant in orthotopic glioblastoma-bearing rats vaccinated with tumor-derived exosomes and α-galactosylceramide (α-GalCer) -pulsed DCs. Compared with traditional tumor lysate, exosomes were utilized as a more potent antigen to load DCs. iNKT cells, as an effective cellular adjuvant activated by α-GalCer, strengthened TAA presentation through their interaction with DCs. Co-delivery of tumor-derived exosomes with α-GalCer on a DC-based vaccine showed powerful effects in glioblastoma immunotherapy. This vaccine induced strong activation and proliferation of tumor-specific cytotoxic T lymphocytes, synergistically breaking the immune tolerance and improving the immunosuppressive environment. PMID 28947140

Prospect of Immunotherapy for Glioblastoma: Tumor Vaccine, Immune Checkpoint Inhibitors and Combination Therapy.
Mai 2017 | Ishikawa, Eiichi; Yamamoto, Tetsuya; Matsumura, Akira
To date, clinical trials of various vaccine therapies using autologous tumor antigens or tumor-associated/specific antigen peptide with adjuvants have been performed to treat patients with high-grade gliomas (HGG). Furthermore, immune checkpoint pathway-targeted therapies including anti- programmed cell death 1 (PD-1) antibody have been remarkably effective in other neoplasms, and various clinical trials with anti-PD-1 antibody in patients with HGG have started to date. It is possible that up-regulation of immune checkpoint molecules in tumor tissues after vaccine therapy may be one of the mechanisms of vaccine failure. Multiple preclinical studies indicate that combination therapy with vaccination and immune checkpoint blockade is effective for the treatment of malignant tumors including HGG. Thus, immunotherapy, especially combination therapy with vaccine and immune checkpoint inhibitors, may be a promising strategy for treatment of patients with HGG. PMID 28539528

A phase II trial of autologous dendritic cell vaccination and radiochemotherapy following fluorescence-guided surgery in newly diagnosed glioblastoma patients.
Mai 2017 | Inogés, Susana; Tejada, Sonia; de Cerio, Ascensión López-Díaz; Gállego Pérez-Larraya, Jaime; Espinós, Jaime; Idoate, Miguel Angel; Domínguez, Pablo Daniel; de Eulate, Reyes García; Aristu, Javier; Bendandi, Maurizio; Pastor, Fernando; Alonso, Marta; Andreu, Enrique; Cardoso, Felipe Prósper; Valle, Ricardo Díez
Prognosis of patients with glioblastoma multiforme (GBM) remains dismal, with median overall survival (OS) of about 15 months. It is therefore crucial to search alternative strategies that improve these results obtained with conventional treatments. In this context, immunotherapy seems to be a promising therapeutic option. We hypothesized that the addition of tumor lysate-pulsed autologous dendritic cells (DCs) vaccination to maximal safe resection followed by radiotherapy and concomitant and adjuvant temozolomide could improve patients' survival. PMID 28499389

Vaccine-based immunotherapeutic approaches to gliomas and beyond.
Mai 2017 | Weller, Michael; Roth, Patrick; Preusser, Matthias; Wick, Wolfgang; Reardon, David A; Platten, Michael; Sampson, John H
Astrocytic and oligodendroglial gliomas are intrinsic brain tumours characterized by infiltrative growth and resistance to classic cancer therapies, which renders them inevitably lethal. Glioblastoma, the most common type of glioma, also exhibits neoangiogenesis and profound immunosuppressive properties. Accordingly, strategies to revert glioma-associated immunosuppression and promote tumour-directed immune responses have been extensively explored in rodent models and in large clinical trials of tumour immunotherapy. This Review describes vaccination approaches investigated for the treatment of glioma. Several strategies have reached phase III clinical trials, including vaccines targeting epidermal growth factor receptor variant III, and the use of either immunogenic peptides or tumour lysates to stimulate autologous dendritic cells. Other approaches in early phases of clinical development employ multipeptide vaccines such as IMA-950, cytomegalovirus-derived peptides, or tumour-derived peptides such as heat shock protein-96 peptide complexes and the Arg132His mutant form of isocitrate dehydrogenase. However, some preclinical trial data suggest that addition of immunomodulatory reagents such as immune checkpoint inhibitors, transforming growth factor-β inhibitors, signal transducer and activator of transcription 3 inhibitors, or modifiers of tryptophan metabolism could augment the therapeutic activity of vaccination and overcome glioma-associated immunosuppression. PMID 28497804

Targeting the PD-1 pathway in pediatric solid tumors and brain tumors.
Apr. 2017 | Wagner, Lars M; Adams, Val R
While remarkable advances have been made in the treatment of pediatric leukemia over the past decades, new therapies are needed for children with advanced solid tumors and high-grade brain tumors who fail standard chemotherapy regimens. Immunotherapy with immune checkpoint inhibitors acting through the programmed cell death-1 (PD-1) pathway has shown efficacy in some chemotherapy-resistant adult cancers, generating interest that these agents may also be helpful to treat certain refractory pediatric malignancies. In this manuscript we review current strategies for targeting the PD-1 pathway, highlighting putative biomarkers and the rationale for investigation of these drugs to treat common pediatric tumors such as sarcoma, neuroblastoma, and high-grade glioma. We summarize the completed and ongoing clinical trial data available, and suggest potential applications for further study. PMID 28442918

Assessing Response of High-Grade Gliomas to Immune Checkpoint Inhibitors.
Apr. 2017 | Sahebjam, Solmaz; Stallworth, Dexter G; Mokhtari, Sepideh; Tran, Nam D; Arrington, John A
Immunotherapeutic agents, especially checkpoint inhibitors, have emerged as the mainstay of therapy for several solid and hematological malignancies. These therapies are under investigation for the treatment of high-grade gliomas and brain metastases. PMID 28441372

Dendritic cell based vaccination strategy: an evolving paradigm.
Apr. 2017 | Filley, Anna C; Dey, Mahua
Malignant gliomas (MG), tumors of glial origin, are the most commonly diagnosed primary intracranial malignancies in adults. Currently available treatments have provided only modest improvements in overall survival and remain limited by inevitable local recurrence, necessitating exploration of novel therapies. Among approaches being investigated, one of the leading contenders is immunotherapy, which aims to modulate immune pathways to stimulate the selective destruction of malignant cells. Dendritic cells (DCs) are potent initiators of adaptive immune responses and therefore crucial players in the development and success of immunotherapy. Clinical trials of various DC-based vaccinations have demonstrated the induction of anti-tumor immune responses and prolonged survival in the setting of many cancers. In this review, we summarize current literature regarding DCs and their role in the tumor microenvironment, their application and current clinical use in immunotherapy, current challenges limiting their efficacy in anti-cancer therapy, and future avenues for developing successful anti-tumor DC-based vaccines. PMID 28434112

Long-term Survival in Glioblastoma with Cytomegalovirus pp65-Targeted Vaccination.
Apr. 2017 | Batich, Kristen A; Reap, Elizabeth A; Archer, Gary E; Sanchez-Perez, Luis; Nair, Smita K; Schmittling, Robert J; Norberg, Pam; Xie, Weihua; Herndon, James E; Healy, Patrick; McLendon, Roger E; Friedman, Allan H; Friedman, Henry S; Bigner, Darell; Vlahovic, Gordana; Mitchell, Duane A; Sampson, John H
Purpose: Patients with glioblastoma have less than 15-month median survival despite surgical resection, high-dose radiation, and chemotherapy with temozolomide. We previously demonstrated that targeting cytomegalovirus pp65 using dendritic cells (DC) can extend survival and, in a separate study, that dose-intensified temozolomide (DI-TMZ) and adjuvant granulocyte macrophage colony-stimulating factor (GM-CSF) potentiate tumor-specific immune responses in patients with glioblastoma. Here, we evaluated pp65-specific cellular responses following DI-TMZ with pp65-DCs and determined the effects on long-term progression-free survival (PFS) and overall survival (OS).Experimental Design: Following standard-of-care, 11 patients with newly diagnosed glioblastoma received DI-TMZ (100 mg/m(2)/d × 21 days per cycle) with at least three vaccines of pp65 lysosome-associated membrane glycoprotein mRNA-pulsed DCs admixed with GM-CSF on day 23 ± 1 of each cycle. Thereafter, monthly DI-TMZ cycles and pp65-DCs were continued if patients had not progressed.Results: Following DI-TMZ cycle 1 and three doses of pp65-DCs, pp65 cellular responses significantly increased. After DI-TMZ, both the proportion and proliferation of regulatory T cells (Tregs) increased and remained elevated with serial DI-TMZ cycles. Median PFS and OS were 25.3 months [95% confidence interval (CI), 11.0-∞] and 41.1 months (95% CI, 21.6-∞), exceeding survival using recursive partitioning analysis and matched historical controls. Four patients remained progression-free at 59 to 64 months from diagnosis. No known prognostic factors [age, Karnofsky performance status (KPS), IDH-1/2 mutation, and MGMT promoter methylation] predicted more favorable outcomes for the patients in this cohort.Conclusions: Despite increased Treg proportions following DI-TMZ, patients receiving pp65-DCs showed long-term PFS and OS, confirming prior studies targeting cytomegalovirus in glioblastoma. Clin Cancer Res; 23(8); 1898-909. ©2017 AACR. PMID 28411277

Immune and viral therapies for malignant primary brain tumors.
März 2017 | Gardeck, Andrew M; Sheehan, Jordan; Low, Walter C
Glioblastoma multiforme (GBM) is a primary brain tumor with great lethality. Current standard of care with surgery, radiation therapy, and chemotherapy are ineffective in curing this disease. Recent advancements in biological therapies show promise in treating brain tumors. Areas covered: This article provides a review of: the peripheral activation of antigen presenting cells such as dendritic cells to stimulate T cells to recognize and destroy tumor cells within the brain; the ex vivo expansion and transfer of dendritic cells, T cells, and engineered T cells expressing chimeric antigen receptors to target cells bearing specific tumor antigens as well as monoclonal antibodies as immune check point inhibitors. Gene therapy approaches have also been utilized to employ viral vectors in transducing cells to express cytokines for activating immune responses to brain tumors. Finally, the article reviews engineering of viruses for oncolytic targeting and destruction of malignant tumors within the brain. Expert opinion: The ultimate goal of immune and viral approaches for treating malignant brain tumors is to cure this disease. Preclinical and clinical studies utilizing these biological therapeutic approaches for treating brain tumors have the potential to augment the current standard of care to provide potential curative therapies. PMID 28274139

Immunosuppressive tumor-infiltrating myeloid cells mediate adaptive immune resistance via a PD-1/PD-L1 mechanism in glioblastoma.
Jan. 2017 | Antonios, Joseph P; Soto, Horacio; Everson, Richard G; Moughon, Diana; Orpilla, Joey R; Shin, Namjo P; Sedighim, Shaina; Treger, Janet; Odesa, Sylvia; Tucker, Alexander; Yong, William H; Li, Gang; Cloughesy, Timothy F; Liau, Linda M; Prins, Robert M
Adaptive immune resistance in the tumor microenvironment appears to attenuate the immunotherapeutic targeting of glioblastoma (GBM). In this study, we identified a tumor-infiltrating myeloid cell (TIM) population that expands in response to dendritic cell (DC) vaccine treatment. The aim of this study was to understand how this programmed death ligand 1 (PD-L1)-expressing population restricts activation and tumor-cytolytic function of vaccine-induced tumor-infiltrating lymphocytes (TILs). PMID 28115578

Novel vaccines for glioblastoma: clinical update and perspective.
Dez. 2016 | Winograd, Evan K; Ciesielski, Michael J; Fenstermaker, Robert A
Glioblastoma is the most common primary brain cancer. Aggressive treatment with surgery, radiation therapy and chemotherapy provides limited overall survival benefit. Glioblastomas have a formidable tumor microenvironment that is hostile to immunological effector cells and these cancers produce profound systemic immunosuppression. However, surgical resection of these tumors creates conditions that favor the use of immunotherapeutic strategies. Therefore, extensive surgical resection, when feasible, will remain part of the equation to provide an environment in which active specific immunotherapy has the greatest chance of working. Toward that end, a number of vaccination protocols are under investigation. Vaccines studied to date have produced cellular and humoral antitumor responses, but unequivocal clinical efficacy has yet to be demonstrated. In addition, focus is shifting toward the prospect of therapies involving vaccines in combination with immune checkpoint inhibitors and other immunomodulatory agents so that effector cells remain active against their targets systemically and within the tumor microenvironment. PMID 27993092

Mesenchymal stem cells enhance the oncolytic effect of Newcastle disease virus in glioma cells and glioma stem cells via the secretion of TRAIL.
Okt. 2016 | Kazimirsky, Gila; Jiang, Wei; Slavin, Shimon; Ziv-Av, Amotz; Brodie, Chaya
Newcastle disease virus (NDV) is an avian paramyxovirus, which selectively exerts oncolytic effects in cancer cells. Mesenchymal stem cells (MSCs) have been reported to affect tumor growth and deliver anti-tumor agents to experimental glioblastoma (GBM). Here, we explored the effects of NDV-infected MSCs derived from different sources, on glioma cells and glioma stem cells (GSCs) and the mechanisms involved in their effects. PMID 27724977

Phase I/II trial of combination of temozolomide chemotherapy and immunotherapy with fusions of dendritic and glioma cells in patients with glioblastoma.
Sep. 2016 | Akasaki, Yasuharu; Kikuchi, Tetsuro; Homma, Sadamu; Koido, Shigeo; Ohkusa, Toshifumi; Tasaki, Tetsunori; Hayashi, Kazumi; Komita, Hideo; Watanabe, Nobuyuki; Suzuki, Yuta; Yamamoto, Yohei; Mori, Ryosuke; Arai, Takao; Tanaka, Toshihide; Joki, Tatsuhiro; Yanagisawa, Takaaki; Murayama, Yuichi
This trial was designed to evaluate the safety and clinical responses to a combination of temozolomide (TMZ) chemotherapy and immunotherapy with fusions of DCs and glioma cells in patients with glioblastoma (GBM). PMID 27688162

PD-1 blockade enhances the vaccination-induced immune response in glioma.
Juli 2016 | Antonios, Joseph P; Soto, Horacio; Everson, Richard G; Orpilla, Joey; Moughon, Diana; Shin, Namjo; Sedighim, Shaina; Yong, William H; Li, Gang; Cloughesy, Timothy F; Liau, Linda M; Prins, Robert M
DC vaccination with autologous tumor lysate has demonstrated promising results for the treatment of glioblastoma (GBM) in preclinical and clinical studies. While the vaccine appears capable of inducing T cell infiltration into tumors, the effectiveness of active vaccination in progressively growing tumors is less profound. In parallel, a number of studies have identified negative costimulatory pathways, such as programmed death 1/programmed death ligand 1 (PD-1/PD-L1), as relevant mediators of the intratumoral immune responses. Clinical responses to PD-1 pathway inhibition, however, have also been varied. To evaluate the relevance to established glioma, the effects of PD-1 blockade following DC vaccination were tested in intracranial (i.c.) glioma tumor- bearing mice. Treatment with both DC vaccination and PD-1 mAb blockade resulted in long-term survival, while neither agent alone induced a survival benefit in animals with larger, established tumors. This survival benefit was completely dependent on CD8(+) T cells. Additionally, DC vaccine plus PD-1 mAb blockade resulted in the upregulation of integrin homing and immunologic memory markers on tumor-infiltrating lymphocytes (TILs). In clinical samples, DC vaccination in GBM patients was associated with upregulation of PD-1 expression in vivo, while ex vivo blockade of PD-1 on freshly isolated TILs dramatically enhanced autologous tumor cell cytolysis. These findings strongly suggest that the PD-1/PD-L1 pathway plays an important role in the adaptive immune resistance of established GBM in response to antitumor active vaccination and provide us with a rationale for the clinical translation of this combination therapy. PMID 27453950

Immunological Aspects of Malignant Gliomas.
Juni 2016 | Cohen-Inbar, Or; Zaaroor, Menashe
Glioblastoma Multiforme (GBM) is the most common malignant primary brain neoplasm having a mean survival time of <24 months. This figure remains constant, despite significant progress in medical research and treatment. The lack of an efficient anti-tumor immune response and the micro-invasive nature of the glioma malignant cells have been explained by a multitude of immune-suppressive mechanisms, proven in different models. These immune-resistant capabilities of the tumor result in a complex interplay this tumor shares with the immune system. We present a short review on the immunology of GBM, discussing the different unique pathological and molecular features of GBM, current treatment modalities, the principles of cancer immunotherapy and the link between GBM and melanoma. Current knowledge on immunological features of GBM, as well as immunotherapy past and current clinical trials, is discussed in an attempt to broadly present the complex and formidable challenges posed by GBM. PMID 27324313

Irradiation of necrotic cancer cells, employed for pulsing dendritic cells (DCs), potentiates DC vaccine-induced antitumor immunity against high-grade glioma.
Apr. 2016 | Vandenberk, Lien; Garg, Abhishek D; Verschuere, Tina; Koks, Carolien; Belmans, Jochen; Beullens, Monique; Agostinis, Patrizia; De Vleeschouwer, Steven; Van Gool, Stefaan W
Dendritic cell (DC)-based immunotherapy has yielded promising results against high-grade glioma (HGG). However, the efficacy of DC vaccines is abated by HGG-induced immunosuppression and lack of attention toward the immunogenicity of the tumor lysate/cells used for pulsing DCs. A literature analysis of DC vaccination clinical trials in HGG patients delineated the following two most predominantly applied methods for tumor lysate preparation: freeze-thaw (FT)-induced necrosis or FT-necrosis followed by X-ray irradiation. However, from the available clinical evidence, it is unclear which of both methodologies has superior immunogenic potential. Using an orthotopic HGG murine model (GL261-C57BL/6), we observed that prophylactic vaccination with DCs pulsed with irradiated FT-necrotic cells (compared to FT-necrotic cells only) prolonged overall survival by increasing tumor rejection in glioma-challenged mice. This was associated, both in prophylactic and curative vaccination setups, with an increase in brain-infiltrating Th1 cells and cytotoxic T lymphocytes (CTL), paralleled by a reduced accumulation of regulatory T cells, tumor-associated macrophages (TAM) and myeloid-derived suppressor cells (MDSC). Further analysis showed that irradiation treatment of FT-necrotic cells considerably increased the levels of carbonylated proteins - a surrogate-marker of oxidation-associated molecular patterns (OAMPs). Through further application of antioxidants and hydrogen peroxide, we found a striking correlation between the amount of lysate-associated protein carbonylation/OAMPs and DC vaccine-mediated tumor rejection capacity thereby suggesting for the first time a role for protein carbonylation/OAMPs in at least partially mediating antitumor immunity. Together, these data strongly advocate the use of protein oxidation-inducing modalities like irradiation for increasing the immunogenicity of tumor lysate/cells used for pulsing DC vaccines. PMID 27057467

Dendritic cell vaccines based on immunogenic cell death elicit danger signals and T cell-driven rejection of high-grade glioma.
März 2016 | Garg, Abhishek D; Vandenberk, Lien; Koks, Carolien; Verschuere, Tina; Boon, Louis; Van Gool, Stefaan W; Agostinis, Patrizia
The promise of dendritic cell (DC)-based immunotherapy has been established by two decades of translational research. Of the four malignancies most targeted with clinical DC immunotherapy, high-grade glioma (HGG) has shown the highest susceptibility. HGG-induced immunosuppression is a roadblock to immunotherapy, but may be overcome by the application of T helper 1 (TH1) immunity-biased, next-generation, DC immunotherapy. To this end, we combined DC immunotherapy with immunogenic cell death (ICD; a modality shown to induce TH1 immunity) induced by hypericin-based photodynamic therapy. In an orthotopic HGG mouse model involving prophylactic/curative setups, both biologically and clinically relevant versions of ICD-based DC vaccines provided strong anti-HGG survival benefit. We found that the ability of DC vaccines to elicit HGG rejection was significantly blunted if cancer cell-associated reactive oxygen species and emanating danger signals were blocked either singly or concomitantly, showing hierarchical effect on immunogenicity, or if DCs, DC-associated MyD88 signal, or the adaptive immune system (especially CD8(+) T cells) were depleted. In a curative setting, ICD-based DC vaccines synergized with standard-of-care chemotherapy (temozolomide) to increase survival of HGG-bearing mice by ~300%, resulting in ~50% long-term survivors. Additionally, DC vaccines also induced an immunostimulatory shift in the brain immune contexture from regulatory T cells to TH1/cytotoxic T lymphocyte/TH17 cells. Analysis of the The Cancer Genome Atlas glioblastoma cohort confirmed that increased intratumor prevalence of TH1/cytotoxic T lymphocyte/TH17 cells linked genetic signatures was associated with good patient prognosis. Therefore, pending final preclinical checks, ICD-based vaccines can be clinically translated for glioma treatment. PMID 26936504

Electro-hyperthermia inhibits glioma tumorigenicity through the induction of E2F1-mediated apoptosis.
Okt. 2015 | Cha, Jihye; Jeon, Tae-Won; Lee, Chang Geol; Oh, Sang Taek; Yang, Hee-Beom; Choi, Kyung-Ju; Seo, Daekwan; Yun, Ina; Baik, In Hye; Park, Kyung Ran; Park, Young Nyun; Lee, Yun-Han
Modulated electro-hyperthermia (mEHT), also known as oncothermia, shows remarkable treatment efficacies for various types of tumours, including glioma. The aim of the present study was to investigate the molecular mechanism underlying phenotypic changes in oncothermic cancer cells. PMID 26367194

Ex vivo generation of dendritic cells from cryopreserved, post-induction chemotherapy, mobilized leukapheresis from pediatric patients with medulloblastoma.
Okt. 2015 | Nair, Smita K; Driscoll, Timothy; Boczkowski, David; Schmittling, Robert; Reynolds, Renee; Johnson, Laura A; Grant, Gerald; Fuchs, Herbert; Bigner, Darell D; Sampson, John H; Gururangan, Sridharan; Mitchell, Duane A
Generation of patient-derived, autologous dendritic cells (DCs) is a critical component of cancer immunotherapy with ex vivo-generated, tumor antigen-loaded DCs. An important factor in the ability to generate DCs is the potential impact of prior therapies on DC phenotype and function. We investigated the ability to generate DCs using cells harvested from pediatric patients with medulloblastoma for potential evaluation of DC-RNA based vaccination approach in this patient population. Cells harvested from medulloblastoma patient leukapheresis following induction chemotherapy and granulocyte colony stimulating factor mobilization were cryopreserved prior to use in DC generation. DCs were generated from the adherent CD14+ monocytes using standard procedures and analyzed for cell recovery, phenotype and function. To summarize, 4 out of 5 patients (80 %) had sufficient monocyte recovery to permit DC generation, and we were able to generate DCs from 3 out of these 4 patient samples (75 %). Overall, we successfully generated DCs that met phenotypic requisites for DC-based cancer therapy from 3 out of 5 (60 %) patient samples and met both phenotypic and functional requisites from 2 out of 5 (40 %) patient samples. This study highlights the potential to generate functional DCs for further clinical treatments from refractory patients that have been heavily pretreated with myelosuppressive chemotherapy. Here we demonstrate the utility of evaluating the effect of the currently employed standard-of-care therapies on the ex vivo generation of DCs for DC-based clinical studies in cancer patients. PMID 26311248

Dendritic cell-based immunotherapy targeting Wilms' tumor 1 in patients with recurrent malignant glioma.
Okt. 2015 | Sakai, Keiichi; Shimodaira, Shigetaka; Maejima, Shinya; Udagawa, Nobuyuki; Sano, Kenji; Higuchi, Yumiko; Koya, Terutsugu; Ochiai, Takanaga; Koide, Masanori; Uehara, Shunsuke; Nakamura, Midori; Sugiyama, Haruo; Yonemitsu, Yoshikazu; Okamoto, Masato; Hongo, Kazuhiro
OBJECT Dendritic cell (DC)-based vaccination is considered a potentially effective therapy against advanced cancer. The authors conducted a Phase I study to investigate the safety and immunomonitoring of Wilms' tumor 1 (WT1)-pulsed DC vaccination therapy for patients with relapsed malignant glioma. METHODS WT1-pulsed and/or autologous tumor lysate-pulsed DC vaccination therapy was performed in patients with relapsed malignant gliomas. Approximately 1 × 10(7) to 2 × 10(7) pulsed DCs loaded with WT1 peptide antigen and/or tumor lysate were intradermally injected into the axillary areas with OK-432, a streptococcal preparation, at 2-week intervals for at least 5-7 sessions (1 course) during an individual chemotherapy regimen. RESULTS Ten patients (3 men, 7 women; age range 24-64 years [median 39 years]) with the following tumors were enrolled: glioblastoma (6), anaplastic astrocytoma (2), anaplastic oligoastrocytoma (1), and anaplastic oligodendroglioma (1). Modified WT1 peptide-pulsed DC vaccine was administered to 7 patients, tumor lysate-pulsed DC vaccine to 2 patients, and both tumor lysate-pulsed and WT1-pulsed DC vaccine to 1 patient. The clinical response was stable disease in 5 patients with WT1-pulsed DC vaccination. In 2 of 5 patients with stable disease, neurological findings improved, and MR images showed tumor shrinkage. No serious adverse events occurred except Grade 1-2 erythema at the injection sites. WT1 tetramer analysis detected WT1-reactive cytotoxic T cells after vaccination in patients treated with WT1-pulsed therapy. Positivity for skin reaction at the injection sites was 80% (8 of 10 patients) after the first session, and positivity remained for these 8 patients after the final session. CONCLUSIONS This study of WT1-pulsed DC vaccination therapy demonstrated safety, immunogenicity, and feasibility in the management of relapsed malignant gliomas. PMID 26252465

Tumour Relapse Prediction Using Multiparametric MR Data Recorded during Follow-Up of GBM Patients.
Sep. 2015 | Ion-Margineanu, Adrian; Van Cauter, Sofie; Sima, Diana M; Maes, Frederik; Van Gool, Stefaan W; Sunaert, Stefan; Himmelreich, Uwe; Van Huffel, Sabine
Purpose. We have focused on finding a classifier that best discriminates between tumour progression and regression based on multiparametric MR data retrieved from follow-up GBM patients. Materials and Methods. Multiparametric MR data consisting of conventional and advanced MRI (perfusion, diffusion, and spectroscopy) were acquired from 29 GBM patients treated with adjuvant therapy after surgery over a period of several months. A 27-feature vector was built for each time point, although not all features could be obtained at all time points due to missing data or quality issues. We tested classifiers using LOPO method on complete and imputed data. We measure the performance by computing BER for each time point and wBER for all time points. Results. If we train random forests, LogitBoost, or RobustBoost on data with complete features, we can differentiate between tumour progression and regression with 100% accuracy, one time point (i.e., about 1 month) earlier than the date when doctors had put a label (progressive or responsive) according to established radiological criteria. We obtain the same result when training the same classifiers solely on complete perfusion data. Conclusions. Our findings suggest that ensemble classifiers (i.e., random forests and boost classifiers) show promising results in predicting tumour progression earlier than established radiological criteria and should be further investigated. PMID 26413548

Re-irradiation or re-operation followed by dendritic cell vaccination? Comparison of two different salvage strategies for relapsed high-grade gliomas by means of a new prognostic model.
Sep. 2015 | Müller, Klaus; Henke, Guido; Pietschmann, Sophie; van Gool, Stefaan; De Vleeschouwer, Steven; von Bueren, André O; Compter, Inge; Friedrich, Carsten; Matuschek, Christiane; Klautke, Gunther; Kortmann, Rolf-Dieter; Hundsberger, Thomas; Baumert, Brigitta G
We aimed to compare two different salvage treatment strategies for relapsed high-grade glioma (HGG) patients by means of a new prognostic model. A simplified version of the so-called HGG-Immuno RPA model estimates the prognosis of relapsed HGG patients and distinguishes three different prognostic classes (I = good, II = intermediate, III = poor). The model has been constructed with a cohort of 117 patients whose salvage treatment consisted of re-operation followed by dendritic cell vaccination (ReOP + DCV). However, using only the predictors histology, age and performance status, the simplified HGG-Immuno RPA model is basically independent from treatment. In the present study we applied the simplified model to the cohort used to construct the original HGG-Immuno RPA model and another cohort of 165 patients who underwent re-irradiation (ReRT) at relapse. Then, we compared the outcomes achieved by the two different salvage treatments in each prognostic class. The model predicted good, intermediate and poor prognosis for 11, 31 and 75 patients of the ReOP + DCV cohort and for 20, 39 and 106 patients of the ReRT cohort, respectively. Neither of the two strategies was superior to the other. In the groups with good, intermediate and poor prognosis 12-months survival rates were 73, 59 and 25 % after ReOP + DCV and 72, 36 and 23 % after ReRT, respectively. Being easy to handle and independent from treatment, the aforementioned model is useful for therapeutic decisions. ReRT and ReOP + DVC seem to be equally effective. The choice of salvage treatment should be based on the expected side effects. PMID 26070556

Brain Tumor Immunotherapy: What have We Learned so Far?
Juli 2015 | Van Gool, Stefaan Willy
High grade glioma is a rare brain cancer, incurable in spite of modern neurosurgery, radiotherapy, and chemotherapy. Novel approaches are in research, and immunotherapy emerges as a promising strategy. Clinical experiences with active specific immunotherapy demonstrate feasibility, safety and most importantly, but incompletely understood, prolonged long-term survival in a fraction of the patients. In relapsed patients, we developed an immunotherapy schedule and we categorized patients into clinically defined risk profiles. We learned how to combine immunotherapy with standard multimodal treatment strategies for newly diagnosed glioblastoma multiforme patients. The developmental program allows further improvements related to newest scientific insights. Finally, we developed a mode of care within academic centers to organize cell-based therapies for experimental clinical trials in a large number of patients. PMID 26137448

Dendritic Cell-Based Vaccines that Utilize Myeloid Rather than Plasmacytoid Cells Offer a Superior Survival Advantage in Malignant Glioma.
Juni 2015 | Dey, Mahua; Chang, Alan L; Miska, Jason; Wainwright, Derek A; Ahmed, Atique U; Balyasnikova, Irina V; Pytel, Peter; Han, Yu; Tobias, Alex; Zhang, Lingjiao; Qiao, Jian; Lesniak, Maciej S
Dendritic cells (DCs) are professional APCs that are traditionally divided into two distinct subsets, myeloid DC (mDCs) and plasmacytoid DC (pDCs). pDCs are known for their ability to secrete large amounts of IFN-α. Apart from IFN-α production, pDCs can also process Ag and induce T cell immunity or tolerance. In several solid tumors, pDCs have been shown to play a critical role in promoting tumor immunosuppression. We investigated the role of pDCs in the process of glioma progression in the syngeneic murine model of glioma. We show that glioma-infiltrating pDCs are the major APC in glioma and are deficient in IFN-α secretion (p < 0.05). pDC depletion leads to increased survival of the mice bearing intracranial tumor by decreasing the number of regulatory T cells (Tregs) and by decreasing the suppressive capabilities of Tregs. We subsequently compared the ability of mDCs and pDCs to generate effective antiglioma immunity in a GL261-OVA mouse model of glioma. Our data suggest that mature pDCs and mDCs isolated from naive mice can be effectively activated and loaded with SIINFEKL Ag in vitro. Upon intradermal injection in the hindleg, a fraction of both types of DCs migrate to the brain and lymph nodes. Compared to mice vaccinated with pDC or control mice, mice vaccinated with mDCs generate a robust Th1 type immune response, characterized by high frequency of CD4(+)T-bet(+) T cells and CD8(+)SIINFEKEL(+) T cells. This robust antitumor T cell response results in tumor eradication and long-term survival in 60% of the animals (p < 0.001). PMID 26026061

Hyperthermia Sensitizes Glioma Stem-like Cells to Radiation by Inhibiting AKT Signaling.
Apr. 2015 | Man, Jianghong; Shoemake, Jocelyn D; Ma, Tuopu; Rizzo, Anthony E; Godley, Andrew R; Wu, Qiulian; Mohammadi, Alireza M; Bao, Shideng; Rich, Jeremy N; Yu, Jennifer S
Glioma stem-like cells (GSC) are a subpopulation of cells in tumors that are believed to mediate self-renewal and relapse in glioblastoma (GBM), the most deadly form of primary brain cancer. In radiation oncology, hyperthermia is known to radiosensitize cells, and it is reemerging as a treatment option for patients with GBM. In this study, we investigated the mechanisms of hyperthermic radiosensitization in GSCs by a phospho-kinase array that revealed the survival kinase AKT as a critical sensitization determinant. GSCs treated with radiation alone exhibited increased AKT activation, but the addition of hyperthermia before radiotherapy reduced AKT activation and impaired GSC proliferation. Introduction of constitutively active AKT in GSCs compromised hyperthermic radiosensitization. Pharmacologic inhibition of PI3K further enhanced the radiosensitizing effects of hyperthermia. In a preclinical orthotopic transplant model of human GBM, thermoradiotherapy reduced pS6 levels, delayed tumor growth, and extended animal survival. Together, our results offer a preclinical proof-of-concept for further evaluation of combined hyperthermia and radiation for GBM treatment. PMID 25712125

Immune Suppression during Oncolytic Virotherapy for High-Grade Glioma; Yes or No?
Feb. 2015 | Koks, Carolien A E; De Vleeschouwer, Steven; Graf, Norbert; Van Gool, Stefaan W
Oncolytic viruses have been seriously considered for glioma therapy over the last 20 years. The oncolytic activity of several oncolytic strains has been demonstrated against human glioma cell lines and in in vivo xenotransplant models. So far, four of these stains have additionally completed the first phase I/II trials in relapsed glioma patients. Though safety and feasibility have been demonstrated, therapeutic efficacy in these initial trials, when described, was only minor. The role of the immune system in oncolytic virotherapy for glioma remained much less studied until recent years. When investigated, the immune system, adept at controlling viral infections, is often hypothesized to be a strong hurdle to successful oncolytic virotherapy. Several preclinical studies have therefore aimed to improve oncolytic virotherapy efficacy by combining it with immune suppression or evasion strategies. More recently however, a new paradigm has developed in the oncolytic virotherapy field stating that oncolytic virus-mediated tumor cell death can be accompanied by elicitation of potent activation of innate and adaptive anti-tumor immunity that greatly improves the efficacy of certain oncolytic strains. Therefore, it seems the three-way interaction between oncolytic virus, tumor and immune system is critical to the outcome of antitumor therapy. In this review we discuss the studies which have investigated how the immune system and oncolytic viruses interact in models of glioma. The novel insights generated here hold important implications for future research and should be incorporated into the design of novel clinical trials. PMID 25663937

Newcastle disease virotherapy induces long-term survival and tumor-specific immune memory in orthotopic glioma through the induction of immunogenic cell death.
Dez. 2014 | Koks, Carolien A; Garg, Abhishek D; Ehrhardt, Michael; Riva, Matteo; Vandenberk, Lien; Boon, Louis; De Vleeschouwer, Steven; Agostinis, Patrizia; Graf, Norbert; Van Gool, Stefaan W
The oncolytic features of several naturally oncolytic viruses have been shown on Glioblastoma Multiforme cell lines and in xenotransplant models. However, orthotopic glioma studies in immunocompetent animals are lacking. Here we investigated Newcastle disease virus (NDV) in the orthotopic, syngeneic murine GL261 model. Seven days after tumor induction, mice received NDV intratumorally. Treatment significantly prolonged median survival and 50% of animals showed long-term survival. We demonstrated immunogenic cell death (ICD) induction in GL261 cells after NDV infection, comprising calreticulin surface exposure, release of HMGB1 and increased PMEL17 cancer antigen expression. Uniquely, we found absence of secreted ATP. NDV-induced ICD occurred independently of caspase signaling and was blocked by Necrostatin-1, suggesting the contribution of necroptosis. Autophagy induction following NDV infection of GL261 cells was demonstrated as well. In vivo, elevated infiltration of IFN-γ(+) T cells was observed in NDV-treated tumors, along with reduced accumulation of myeloid derived suppressor cells. The importance of a functional adaptive immune system in this paradigm was demonstrated in immunodeficient Rag2(-/-) mice and in CD8(+) T cell depleted animals, where NDV slightly prolonged survival, but failed to induce long-term cure. Secondary tumor induction with GL261 cells or LLC cells in mice surviving long-term after NDV treatment, demonstrated the induction of a long-term, tumor-specific immunological memory response by ND virotherapy. For the first time, we describe the therapeutic activity of NDV against GL261 tumors, evidenced in an orthotopic mouse model. The therapeutic effect relies on the induction of ICD in the tumor cells, which primes adaptive antitumor immunity. PMID 25208916

Enhancing dendritic cell-based vaccination for highly aggressive glioblastoma.
Dez. 2014 | Batich, Kristen A; Swartz, Adam M; Sampson, John H
Patients with primary glioblastoma (GBM) have a dismal prognosis despite standard therapy, which can induce potentially deleterious side effects. Arming the immune system is an alternative therapeutic approach, as its cellular effectors and inherent capacity for memory can be utilized to specifically target invasive tumor cells, while sparing collateral damage to otherwise healthy brain parenchyma. PMID 25327832

Immunotherapy for malignant gliomas.
Dez. 2014 | Bloch, Orin
Cancer immunotherapy aims to harness the innate ability of the immune system to recognize and destroy malignant cells. Immunotherapy for malignant gliomas is an emerging field that promises the possibility of highly specific and less toxic treatment compared to conventional chemotherapy. In addition, immunotherapy has the added benefit of sustained efficacy once immunologic memory is induced. Although there are numerous therapeutic agents that boost general immune function and facilitate improved antitumor immunity, to date, immunotherapy for gliomas has focused primarily on active vaccination against tumor-specific antigens. The results of numerous early phase clinical trials demonstrate promising results for vaccine therapy, but no therapy has yet proven to improve survival in a randomized, controlled trial. The major barrier to immunotherapy in malignant gliomas is tumor-induced immunosuppression. The mechanisms of immunosuppression are only now being elucidated, but clearly involve a combination of factors including regulatory T cells, tumor-associated PD-L1 expression, and CTLA-4 signaling. Immunomodulatory agents have been developed to combat these immunosuppressive factors and have demonstrated efficacy in other cancers. The future of glioma immunotherapy likely lies in a combination of active vaccination and immune checkpoint inhibition. PMID 25468230

Emerging treatment strategies for glioblastoma multiforme.
Nov. 2014 | Carlsson, Steven K; Brothers, Shaun P; Wahlestedt, Claes
Glioblastoma multiforme (GBM) is the deadliest form of brain tumor with a more than 90% 5-year mortality. GBM has a paltry median survival of 12.6 months attributed to the unique treatment limitations such as the high average age of onset, tumor location, and poor current understandings of the tumor pathophysiology. The resection techniques, chemotherapic strategies, and radiation therapy currently used to treat GBM have slowly evolved, but the improvements have not translated to marked increases in patient survival. Here, we will discuss the recent progress in our understanding of GBM pathophysiology, and the diagnostic techniques and treatment options. The discussion will include biomarkers, tumor imaging, novel therapies such as monoclonal antibodies and small-molecule inhibitors, and the heterogeneity resulting from the GBM cancer stem cell population. PMID 25312641

Dendritic cell-based vaccine for the treatment of malignant glioma: a systematic review.
Okt. 2014 | Wang, Xuan; Zhao, Hong-Yang; Zhang, Fang-Cheng; Sun, Yun; Xiong, Zhi-Yong; Jiang, Xiao-Bing
Glioblastoma multiforme (GBM) has a poor prognosis. The purpose of this systematic review and meta-analysis was to analyze the outcomes of clinical trials which compared immunotherapy with conventional therapy for the treatment of malignant gliomas. PMID 25259676

Perspectives for immunotherapy in glioblastoma treatment.
Okt. 2014 | Finocchiaro, Gaetano; Pellegatta, Serena
Avoiding immune destruction is one emerging hallmark of cancer, including glioblastoma. The number of immunotherapy approaches to fight glioblastoma is growing. Here, we review the recent progress in four main areas: dendritic cell immunotherapy, peptide vaccination, chimeric antigen receptors and immune checkpoints. PMID 25210870

Newcastle disease virus interaction in targeted therapy against proliferation and invasion pathways of glioblastoma multiforme.
Sep. 2014 | Abdullah, Jafri Malin; Mustafa, Zulkifli; Ideris, Aini
Glioblastoma multiforme (GBM), or grade IV glioma, is one of the most lethal forms of human brain cancer. Current bioscience has begun to depict more clearly the signalling pathways that are responsible for high-grade glioma initiation, migration, and invasion, opening the door for molecular-based targeted therapy. As such, the application of viruses such as Newcastle disease virus (NDV) as a novel biological bullet to specifically target aberrant signalling in GBM has brought new hope. The abnormal proliferation and aggressive invasion behaviour of GBM is reported to be associated with aberrant Rac1 protein signalling. NDV interacts with Rac1 upon viral entry, syncytium induction, and actin reorganization of the infected cell as part of the replication process. Ultimately, intracellular stress leads the infected glioma cell to undergo cell death. In this review, we describe the characteristics of malignant glioma and the aberrant genetics that drive its aggressive phenotype, and we focus on the use of oncolytic NDV in GBM-targeted therapy and the interaction of NDV in GBM signalling that leads to inhibition of GBM proliferation and invasion, and subsequently, cell death. PMID 25243137

Dendritic cell immunotherapy for glioblastoma.
Juni 2014 | Polyzoidis, Stavros; Ashkan, Keyoumars
Dendritic cell immunotherapy is emerging as a promising addition to the multimodal treatment of patients with glioblastoma multiform. Initial Phase I and II trials have demonstrated favorable outcomes with minimal toxicity. In this editorial, the current status and the future challenges of this therapy are discussed. PMID 24850137

Immunotherapy for high-grade glioma.
Juni 2014 | Dixit, Sanjay
4th Quadrennial Meeting of the World Federation of Neuro-Oncology in conjunction with the 18th Annual Meeting of the Society for Neuro-Oncology, San Francisco, CA, USA, 21-24 November 2013. Aside from temozolomide, there has been no major breakthrough for decades to improve outcome for high-grade glioma. Bevacizumab failed to show a survival advantage in two large studies - AVaglio and RTOG-0825 - and no other novel chemotherapy agents seem to be appearing on the horizon for this universally fatal disease. Consequently, the neuro-oncology fraternity is turning to immunotherapy. This became apparent in this meeting, considering a number of delegates focused their attention to presentations on immunotherapy. The ReACT study demonstrated the safety and efficacy of the combination of a promising peptide vaccine, rindopepimut, and bevacizumab with longer survival seen in patients with a higher antibody titer. Several presentations reassured that dendritic cell-based immunotherapy is safe and can generate a lasting immune response. Employing gene therapy, increased intratumor 5-fluorouracil chemotherapy concentration can be achieved using TOCA 511, and temozolomide-resistant transgenic lymphocytes could be produced through retroviral coding. Blocking immune checkpoints PDL-01, CTLA-4 and indoleamine 2,3-dioxygenase through monoclonal antibodies appears promising. PMID 24941977

Cytokine responsiveness of CD8(+) T cells is a reproducible biomarker for the clinical efficacy of dendritic cell vaccination in glioblastoma patients.
Juni 2014 | Everson, Richard G; Jin, Richard M; Wang, Xiaoyan; Safaee, Michael; Scharnweber, Rudi; Lisiero, Dominique N; Soto, Horacio; Liau, Linda M; Prins, Robert M
Immunotherapeutic approaches, such as dendritic cell (DC) vaccination, have emerged as promising strategies in the treatment of glioblastoma. Despite their promise, however, the absence of objective biomarkers and/or immunological monitoring techniques to assess the clinical efficacy of immunotherapy still remains a primary limitation. To address this, we sought to identify a functional biomarker for anti-tumor immune responsiveness associated with extended survival in glioblastoma patients undergoing DC vaccination. PMID 24883189

Vaccination with dendritic cells loaded with allogeneic brain tumor cells for recurrent malignant brain tumors induces a CD4(+)IL17(+) response.
Mai 2014 | Olin, Michael R; Low, Walter; McKenna, David H; Haines, Stephen J; Dahlheimer, Tambra; Nascene, David; Gustafson, Michael P; Dietz, Allan B; Clark, H Brent; Chen, Wei; Blazar, Bruce; Ohlfest, John R; Moertel, Christopher
We tested the hypothesis that a novel vaccine developed from autologous dendritic cells (DC) loaded with cells from a unique allogeneic brain tumor cell line (GBM6-AD) would be well-tolerated and would generate an immune response. PMID 24829761

Current vaccine trials in glioblastoma: a review.
Mai 2014 | Xu, Linda W; Chow, Kevin K H; Lim, Michael; Li, Gordon
Glioblastoma (GBM) is the most common primary brain tumor, and despite aggressive therapy with surgery, radiation, and chemotherapy, average survival remains at about 1.5 years. The highly infiltrative and invasive nature of GBM requires that alternative treatments for this disease be widespread and targeted to tumor cells. Immunotherapy in the form of tumor vaccines has the potential to meet this need. Vaccines against GBM hold the promise of triggering specific and systemic antitumor immune responses that may be the key to eradicating this unrelenting cancer. In this review, we will discuss past and present clinical trials of various GBM vaccines and their potential impact on the future care of GBM patients. There have been many promising phase I and phase II GBM vaccine studies that have led to ongoing and upcoming phase III trials. If the results of these randomized trials show a survival benefit, immunotherapy will become a standard part of the treatment of this devastating disease. PMID 24804271

Novel approaches and mechanisms of immunotherapy for glioblastoma.
März 2014 | Hegde, Meenakshi; Bielamowicz, Kevin J; Ahmed, Nabil
Glioblastoma (GBM) is the most aggressive primary brain tumor. Combination therapy with surgery, radiation, and chemotherapy is not curative at present and carries a significant risk of toxicity. Advancements in the knowledge of tumor biology and tumor microenvironment have led to the development of novel targeted therapies for glioblastoma. In the past 15 years, a vast amount of pre-clinical data has been generated for glioblastoma immunotherapy. Translating these promising results into the clinic is, however, still an evolving process. Early clinical trials have demonstrated the feasibility and safety of several such approaches in patients with recurrent as well as newly diagnosed glioblastoma. Both passive as well as active immunotherapeutic modalities have also shown potential clinical benefit in at least a subset of these patients. This brief review discusses 'why' and 'how' various types of immunotherapies are being employed to treat glioblastoma. PMID 24641957

Fighting fire with fire: the revival of thermotherapy for gliomas.
Feb. 2014 | Lee Titsworth, William; Murad, Greg J A; Hoh, Brian L; Rahman, Maryam
In 1891, an orthopedic surgeon in New York noted the disappearance of an inoperable sarcoma in a patient after a febrile illness. This observation resulted in experiments assessing the utility of heat therapy or thermotherapy for the treatment of cancer. While it initially fell from favor, thermotherapy has recently made a resurgence, sparking investigations into its anticancer properties. This therapy is especially attractive for glioblastoma multiforme (GBM) which is difficult to target due to the blood-brain barrier and recalcitrant to treatment. Here we briefly review the history of thermotherapy and then more methodically present the current literature as it relates to central nervous system malignancies. Recent developments show that heat is preferentially cytotoxic to tumor cells and induces cellular pathways which result in apoptotic and non-apoptotic death. Techniques to induce hyperthermia include regional hyperthermia by water bath, focused ultrasound, radiofrequency microwaves, laser-induced interstitial thermotherapy, and magnetic energy. The recent revival of these therapeutic approaches and their preliminary outcomes in the treatment of GBM is reviewed. From bacterial toxins to infusion of magnetic nanoparticles, hyperthermia has the potential to be an effective and easy-to-execute adjuvant therapy for GBM. Hyperthermia for GBM is a promising therapy as part of a growing armamentarium for malignant glioma treatment. PMID 24510985

Dendritic cell-based immunotherapy for glioma: multiple regimens and implications in clinical trials.
Nov. 2013 | Mineharu, Yohei; Castro, Maria G; Lowenstein, Pedro R; Sakai, Nobuyuki; Miyamoto, Susumu
High grade glioma is a highly invasive brain tumor and recurrence is almost inevitable, even after radical resection of the tumor mass. Cytotoxic immune responses and immunological memory induced by immunotherapy might prevent tumor recurrence. Dendritic cells (DCs) are professional antigen-presenting cells of the innate immune system with the potential to generate robust antigen-specific T cell immune responses. DC-based immunotherapeutic strategies have been intensively studied in both preclinical and clinical settings. Although advances have been made in the experimental use of DCs, there are still considerable challenges that need to be addressed for clinical translation. In this review, we describe the variability of regimens currently available for DC-based immunotherapy and then review strategies to optimize DC therapeutic efficacy against glioma. PMID 24140772

Myeloid-derived suppressor cells in glioma.
Nov. 2013 | Mirghorbani, Masoud; Van Gool, Stefaan; Rezaei, Nima
Glioblastoma is the most prevalent form of gliomas with high aggressive nature and high recurrence. Despite aggressive therapy, including surgery, chemotherapy and radiotherapy, median patient survival is only about 15 months. Hence, developing novel and efficient therapies seem urgent. Many fields have begun their work in preclinical studies but gained limited success in clinical phases. One of the most notable reasons is tumor-induced immunosuppression. In recent decade, efforts to dissect this immunosuppressive network have been done vastly. In a number of malignancies such as glioma, myeloid-derived suppressor cells (MDSCs) have been shown to infiltrate malignant tissues having critical role in the network. Many studies, most of them on lab models, were conducted to understand how MDSCs take part in immunosuppression. Here, we reviewed MDSC relations with other immunocellular components like T cell and natural killer cell. PMID 24215283

Formulations for Intranasal Delivery of Pharmacological Agents to Combat Brain Disease: A New Opportunity to Tackle GBM?
Nov. 2013 | van Woensel, Matthias; Wauthoz, Nathalie; Rosière, Rémi; Amighi, Karim; Mathieu, Véronique; Lefranc, Florence; van Gool, Stefaan W; de Vleeschouwer, Steven
Despite recent advances in tumor imaging and chemoradiotherapy, the median overall survival of patients diagnosed with glioblastoma multiforme does not exceed 15 months. Infiltration of glioma cells into the brain parenchyma, and the blood-brain barrier are important hurdles to further increase the efficacy of classic therapeutic tools. Local administration methods of therapeutic agents, such as convection enhanced delivery and intracerebral injections, are often associated with adverse events. The intranasal pathway has been proposed as a non-invasive alternative route to deliver therapeutics to the brain. This route will bypass the blood-brain barrier and limit systemic side effects. Upon presentation at the nasal cavity, pharmacological agents reach the brain via the olfactory and trigeminal nerves. Recently, formulations have been developed to further enhance this nose-to-brain transport, mainly with the use of nanoparticles. In this review, the focus will be on formulations of pharmacological agents, which increase the nasal permeation of hydrophilic agents to the brain, improve delivery at a constant and slow release rate, protect therapeutics from degradation along the pathway, increase mucoadhesion, and facilitate overall nasal transport. A mounting body of evidence is accumulating that the underexplored intranasal delivery route might represent a major breakthrough to combat glioblastoma. PMID 24202332

Immunotherapy for high-grade glioma: how to go beyond Phase I/II clinical trials.
Okt. 2013 | van Gool, Stefaan
Evaluation of: Lasky JL 3rd, Panosyan EH, Plant A et al. Autologous tumor lysate-pulsed dendritic cell immunotherapy for pediatric patients with newly diagnosed or recurrent high-grade gliomas. Anticancer Res. 33, 2047-2056 (2013). Immunotherapy for children and adults with high-grade glioma (HGG) is an emerging innovative treatment approach, which aims at stimulating the body's own immune system against HGG by using autologous dendritic cells pulsed with autologous tumor lysate as a therapeutic vaccine. This is the third report on immunotherapy for HGG in children, bringing additional knowledge and experience to the scientific community. However, at the same time, this and other manuscripts urge for the next step in treatment development. PMID 24138559

Dendritic cell vaccine for recurrent high-grade gliomas in pediatric and adult subjects: clinical trial protocol.
Okt. 2013 | Shah, Ashish H; Bregy, Amade; Heros, Deborah O; Komotar, Ricardo J; Goldberg, John
Although there have been significant advances in understanding the basic pathogenesis of glioblastoma multiforme, the median survival of patients has changed little in the past 25 years. Recent studies have suggested that immune modulation through dendritic cell (DC) vaccines may stimulate the immune system against tumor antigens and potentially increase survival. PMID 23867302

Active immunotherapy using dendritic cells in the treatment of glioblastoma multiforme.
Sep. 2013 | Bregy, Amade; Wong, Theresa M; Shah, Ashish H; Goldberg, John M; Komotar, Ricardo J
Glioblastoma multiforme, the most common malignant brain tumor still has a dismal prognosis with conventional treatment. Therefore, it is necessary to explore new and/or adjuvant treatment options to improve patient outcomes. Active immunotherapy is a new area of research that may be a successful treatment option. The focus is on vaccines that consist of antigen presenting cells (APCs) loaded with tumor antigen. We have conducted a systematic review of prospective studies, case reports and clinical trials. The goal of this study was to examine the efficacy and safety in terms of complications, median overall survival (OS), progression free survival (PFS) and quality of life. PMID 23790634

Therapeutic vaccination against autologous cancer stem cells with mRNA-transfected dendritic cells in patients with glioblastoma.
Aug. 2013 | Vik-Mo, Einar Osland; Nyakas, Marta; Mikkelsen, Birthe Viftrup; Moe, Morten Carstens; Due-Tønnesen, Paulina; Suso, Else Marit Inderberg; Sæbøe-Larssen, Stein; Sandberg, Cecilie; Brinchmann, Jan E; Helseth, Eirik; Rasmussen, Anne-Marie; Lote, Knut; Aamdal, Steinar; Gaudernack, Gustav; Kvalheim, Gunnar; Langmoen, Iver A
The growth and recurrence of several cancers appear to be driven by a population of cancer stem cells (CSCs). Glioblastoma, the most common primary brain tumor, is invariably fatal, with a median survival of approximately 1 year. Although experimental data have suggested the importance of CSCs, few data exist regarding the potential relevance and importance of these cells in a clinical setting. PMID 23817721

Vaccine strategies for glioblastoma: progress and future directions.
Feb. 2013 | Jackson, Christopher; Ruzevick, Jacob; Brem, Henry; Lim, Michael
Recent advances in glioblastoma therapy have led to optimism that more effective therapies will improve outcomes. Immunotherapy is a promising approach that has demonstrated the potential to eradicate cancer cells with cellular-level accuracy while minimizing damage to surrounding healthy tissue. Several vaccination strategies have been evaluated for activity against glioblastoma in clinical trials. These include peptide vaccines, polyvalent dendritic cell vaccines, heat shock protein vaccines and adoptive immunotherapy. In this review, we highlight clinical trials representative of each of these approaches and discuss strategies for integrating these therapies into routine patient care. PMID 23413907

Comparison of glioma-associated antigen peptide-loaded versus autologous tumor lysate-loaded dendritic cell vaccination in malignant glioma patients.
Feb. 2013 | Prins, Robert M; Wang, Xiaoyan; Soto, Horacio; Young, Emma; Lisiero, Dominique N; Fong, Brendan; Everson, Richard; Yong, William H; Lai, Albert; Li, Gang; Cloughesy, Timothy F; Liau, Linda M
Dendritic cell (DC) vaccination is emerging as a promising therapeutic option for malignant glioma patients. However, the optimal antigen formulation for loading these cells has yet to be established. The objective of this study was to compare the safety, feasibility, and immune responses of malignant glioma patients on 2 different DC vaccination protocols. Twenty-eight patients were treated with autologous tumor lysate (ATL)-pulsed DC vaccination, whereas 6 patients were treated with glioma-associated antigen (GAA) peptide-pulsed DCs. Safety, toxicity, feasibility, and correlative immune monitoring assay results were compared between patients on each trial. Because of HLA subtype restrictions on the GAA-DC trial, 6/15 screened patients were eligible for treatment, whereas 28/32 patients passed eligibility screening for the ATL-DC trial. Elevated frequencies of activated natural killer cells were observed in the peripheral blood from GAA-DC patients compared with the ATL-DC patients. In addition, a significant correlation was observed between decreased regulatory T lymphocyte (Treg) ratios (postvaccination/prevaccination) and overall survival (P = 0.004) in patients on both trials. In fact, Treg ratios were independently prognostic for overall survival in these patients, whereas tumor pathology was not in multivariate analyses. In conclusion, these results suggest that ATL-DC vaccination is associated with wider patient eligibility compared with GAA-DC vaccination. Decreased postvaccination/prevaccination Treg ratios and decreased frequencies of activated natural killer cells were associated with prolonged survival in patients from both trials, suggesting that these lymphocyte subsets may be relevant immune monitoring endpoints for immunotherapy protocols in malignant glioma patients. PMID 23377664

α-type-1 polarized dendritic cell-based vaccination in recurrent high-grade glioma: a phase I clinical trial.
Jan. 2013 | Akiyama, Yasuto; Oshita, Chie; Kume, Akiko; Iizuka, Akira; Miyata, Haruo; Komiyama, Masaru; Ashizawa, Tadashi; Yagoto, Mika; Abe, Yoshiaki; Mitsuya, Koichi; Watanabe, Reiko; Sugino, Takashi; Yamaguchi, Ken; Nakasu, Yoko
High-grade gliomas including glioblastoma multiforme (GBM) are among the most malignant and aggressive of tumors, and have a very poor prognosis despite a temozolomide-based intensive treatment. Therefore, a novel therapeutic approach to controlling recurrence is needed. In the present study, we investigated the effect of activated dendritic cell (DC) (α-type-1 polarized DC)-based immunotherapy on high-grade glioma patients with the HLA-A2 or A24 genotype. PMID 23270484

Immunotherapy with tumor vaccines for the treatment of malignant gliomas.
Dez. 2012 | Ajay, Divya; Sanchez-Perez, Luis; Choi, Bryan D; De Leon, Gabriel; Sampson, John H
With an average life expectancy of 14 months, Glioblastoma multiforme (GBM), is the most aggressive primary brain tumor. Our growing understanding of the immune system and its role in oncogenesis has helped develop cancer vaccines as a promising treatment modality against this disease. What follows is a comprehensive discussion on the history of immunotherapy and the various vaccine based therapies being developed and utilized for the treatment of malignant gliomas. PMID 22339070

Integration of autologous dendritic cell-based immunotherapy in the standard of care treatment for patients with newly diagnosed glioblastoma: results of the HGG-2006 phase I/II trial.
Nov. 2012 | Ardon, Hilko; Van Gool, Stefaan W; Verschuere, Tina; Maes, Wim; Fieuws, Steffen; Sciot, Raf; Wilms, Guido; Demaerel, Philippe; Goffin, Jan; Van Calenbergh, Frank; Menten, Johan; Clement, Paul; Debiec-Rychter, Maria; De Vleeschouwer, Steven
Dendritic cell (DC)-based tumor vaccination has rendered promising results in relapsed high-grade glioma patients. In the HGG-2006 trial (EudraCT 2006-002881-20), feasibility, toxicity, and clinical efficacy of the full integration of DC-based tumor vaccination into standard postoperative radiochemotherapy are studied in 77 patients with newly diagnosed glioblastoma. PMID 22527250

Newcastle disease virus triggers autophagy in U251 glioma cells to enhance virus replication.
Mai 2012 | Meng, Chunchun; Zhou, Zhizhi; Jiang, Ke; Yu, Shengqing; Jia, Lijun; Wu, Yantao; Liu, Yanqing; Meng, Songshu; Ding, Chan
Newcastle disease virus (NDV) can replicate in tumor cells and induce apoptosis in late stages of infection. However, the interaction between NDV and cells in early stages of infection is not well understood. Here, we report that, shortly after infection, NDV triggers the formation of autophagosomes in U251 glioma cells, as demonstrated by an increased number of double-membrane vesicles, GFP-microtubule-associated protein 1 light chain 3 (GFP-LC3) a dot formations, and elevated production of LC3II. Moreover, modulation of NDV-induced autophagy by rapamycin, chloroquine or small interfering RNAs targeting the genes critical for autophagosome formation (Atg5 and Beclin-1) affects virus production, indicating that autophagy may be utilized by NDV to facilitate its own production. Furthermore, the class III phosphatidylinositol 3-kinase (PI3K)/Beclin-1 pathway plays a role in NDV-induced autophagy and virus production. Collectively, our data provide a unique example of a paramyxovirus that uses autophagy to enhance its production. PMID 22398914

Monitoring of regulatory T cell frequencies and expression of CTLA-4 on T cells, before and after DC vaccination, can predict survival in GBM patients.
Apr. 2012 | Fong, Brendan; Jin, Richard; Wang, Xiaoyan; Safaee, Michael; Lisiero, Dominique N; Yang, Isaac; Li, Gang; Liau, Linda M; Prins, Robert M
Dendritic cell (DC) vaccines have recently emerged as an innovative therapeutic option for glioblastoma patients. To identify novel surrogates of anti-tumor immune responsiveness, we studied the dynamic expression of activation and inhibitory markers on peripheral blood lymphocyte (PBL) subsets in glioblastoma patients treated with DC vaccination at UCLA. PMID 22485134

Clinical application of a dendritic cell vaccine raised against heat-shocked glioblastoma.
Jan. 2012 | Jie, X; Hua, L; Jiang, W; Feng, F; Feng, G; Hua, Z
Establishment of a detection platform for glioblastoma-dendritic cell (DC) vaccine preparation and to determine the efficacy of the vaccine in a clinical trial. Autologous glioblastoma-DC vaccine was prepared from a glioblast specimen procured from surgical resection. The specimen was used to enrich the vaccine with peripherally blood-derived DCs after heat-shock induced, glioblastoma apoptosis. The control group received conventional treatment of surgery and radio-chemotherapy post-operation. The therapeutic group received a combination of glioblastoma-DC vaccine and conventional therapy. A comparison of the functional immune parameters, including tumor control, rate live time, Karnofsky scores, and complications occurring in each group were observed and recorded. The proportions of peripheral CD3(+), CD3(+)CD4(+), CD4(+)/CD8(+), and NK cells were significantly higher after DC vaccination than the control group (P < 0.05). Serum levels of IL-2, IL-12, and IFN-γ were significantly higher after DC vaccination than in the control group (P < 0.05). Nine months after vaccination, tumor control rate is significantly improved in the DC group compared with the control group (P < 0.05); survival rate was significantly higher in DC group than in control group (P < 0.05) and the time to relapse was significantly longer in DC group than that in control group (P < 0.05). Karnofsky scores were better in DC vaccination group 6 and 9 months post-treatment compared with the control group (P < 0.05). The combination of glioma DC vaccine and radiotherapy/chemotherapy post-operatively enhances the immune function of patients, increases the tumor control rate, prolongs the survival time and relapse duration, improves the quality of life, and therefore provides a more effective intervention of treating glioblastoma. PMID 21909820

Therapeutical doses of temozolomide do not impair the function of dendritic cells and CD8+ T cells.
Jan. 2012 | Xu, Xun; Stockhammer, Florian; Schmitt, Anita; Casalegno-Garduno, Rosaely; Enders, Anne; Mani, Jiju; Classen, Carl Friedrich; Linnebacher, Michael; Freund, Mathias; Schmitt, Michael
The median survival of patients with glioblastoma multiforme (GBM) remains poor. Innovative immunotherapies with dendritic cell (DC) vaccination might be combined with standard temozolomide (TMZ) treatment. Here, we evaluated the influence of TMZ on the phenotype and function of DCs and CD8+ T cells. DCs were generated from the peripheral blood of healthy volunteers (HVs) and GBM patients. DCs were analyzed by light microscopy and flow cytometry. Phagocytic activity was tested by FITC-dextran engulfment. Mixed lymphocyte peptide cultures were followed by enzyme-linked immunospot (ELISPOT) and flow cytometry assays. TMZ was added to DC and T cell cultures at concentrations up to 500 µM. Mature DCs were generated from HVs and GBM patients. Cells displayed a typical DC morphology and a mature DC phenotype. Expression of CD209 was even higher in DCs generated from patients under therapy than from HVs (75.2 vs. 51.1%). In contrast, CD40 (1.1 vs. 13.5%) and BDCA4 (26.5 vs. 52.9%) were lower expressed in GBM patients at time of diagnosis. Immature DCs showed high phagocytic activity. Addition of TMZ at concentrations up to 50 µM did neither impair the phenotype nor the function of DCs. In ELISPOT and flow cytometry assays, no impairment of CD8+ T cell responses to viral antigens could be observed. Taken together, TMZ does not impair the function of either DCs or the CD8+ T cells. PMID 22134728

New perspectives in glioma immunotherapy.
Nov. 2011 | Daga, Antonio; Bottino, Cristina; Castriconi, Roberta; Gangemi, Rosaria; Ferrini, Silvano
Glioblastoma (GBM) is a deadly tumor, which in spite of surgery and radio/chemotherapy frequently undergoes relapses related to the infiltration of the normal parenchyma and to resistance to cytotoxic and radiation therapy. Immunotherapy may represent a promising approach, which may complement existing therapies with the aim of eliminating residual tumor cells, through their selective targeting by immune effector cells or antibodies. This goal can be achieved through different approaches, based either on the induction of an immune response of the host, or by the injection of in vitro generated effector cells or monoclonal antibodies. Recent advances in the immunobiology of GBM and of its stem cell compartment will help in the development of more effective immunotherapy protocols. To this aim, the identification of antigens and receptors involved in GBM/immune cell interactions and of GBM immune escape mechanisms will provide new targets and tools. In this review we will discuss active immunotherapy approaches, including molecular-defined, GBM cell-based and dendritic-cell based vaccines. In addition, cytokines such as interferons and several interleukins can be used to enhance the immune response, both as recombinant molecules and by gene transfer technologies. Monoclonal antibodies or other ligands specific for GBM- or neovasculature-associated targets are now available in different genetically modified formats and can be used as such or for the targeted delivery of active compounds. Finally the in vitro activation and expansion of specific or innate immunity effector cells endowed with anti-GBM properties may provide an additional weapon for adoptive imunotherapy approaches. PMID 21827420

Immunotherapy for glioma: getting closer to the clinical arena?
Nov. 2011 | Finocchiaro, Gaetano; Pellegatta, Serena
During recent years different approaches have been explored to raise effective antitumor responses against brain tumors and particularly glioblastomas (GBMs). In most cases, cancer vaccines were based on autologous dendritic cells loaded with GBM peptides or whole tumor lysates. Many phase I-II studies showed that such strategy is feasible and nontoxic but failed to provide convincing evidence of its efficacy. This was due to study design and other biological issues: local immune suppression and insufficient characterization of appropriate epitopes appear as particularly relevant. PMID 22027543

Immunotherapy in human glioblastoma.
Sep. 2011 | Szabo, A T; Carpentier, A F
Glioblastoma patients spontaneously develop anti-tumour immune responses. However, the tumour itself develops several mechanisms that allow the tumor to escape the immune system. Clinical trials using infusion of activated autologous immune cells, or active immunotherapy with tumor antigens and dendritic cells have successfully induced anti-tumour immunity and some radiological responses. More recently, approaches targeting the mechanisms of tolerance have shown promising data in melanoma, and are currently under investigations in gliomas. However, large randomised trials are still needed to prove the usefulness of cancer vaccines in brain tumors. PMID 21885075

Treatment of high-grade glioma in children and adolescents.
Sep. 2011 | MacDonald, T J; Aguilera, D; Kramm, C M
Pediatric high-grade gliomas (HGGs)--including glioblastoma multiforme, anaplastic astrocytoma, and diffuse intrinsic pontine glioma--are difficult to treat and are associated with an extremely poor prognosis. There are no effective chemotherapeutic regimens for the treatment of pediatric HGG, but many new treatment options are in active investigation. There are crucial molecular differences between adult and pediatric HGG such that results from adult clinical trials cannot simply be extrapolated to children. Molecular markers overexpressed in pediatric HGG include PDGFRα and P53. Amplification of EGFR is observed, but to a lesser degree than in adult HGG. Potential molecular targets and new therapies in development for pediatric HGG are described in this review. Research into bevacizumab in pediatric HGG indicates that its activity is less than that observed in adult HGG. Similarly, tipifarnib was found to have minimal activity in pediatric HGG, whereas gefitinib has shown greater effects. After promising phase I findings in children with primary CNS tumors, the integrin inhibitor cilengitide is being investigated in a phase II trial in pediatric HGG. Studies are also ongoing in pediatric HGG with 2 EGFR inhibitors: cetuximab and nimotuzumab. Other novel treatment modalities under investigation include dendritic cell-based vaccinations, boron neutron capture therapy, and telomerase inhibition. While the results of these trials are keenly awaited, the current belief is that multimodal therapy holds the greatest promise. Research efforts should be directed toward building multitherapeutic regimens that are well tolerated and that offer the greatest antitumor activity in the setting of pediatric HGG. PMID 21784756

Improvement of dendritic cell therapy in glioblastoma multiforme WHO 4 by Newcastle disease virus
Sep. 2011 | Nesselhut, J

2011 ASCO Annual Meeting; Oral Abstract Session, Developmental Therapeutics - Clinical Pharmacology and Immunotherapy

Background: Glioblastoma multiforme (GBM, WHO grade 4 glioma) is an aggressive disease with an unfavorable prognosis. The current first line treatment comprises radical operation and radiotherapy combined with temozolomide chemotherapy. The reported median overall survival time after primary diagnosis is less than 15 months. After failure of first-line therapy there is currently no effective therapy, and side effects from further treatments may potentially impair quality of life. We report that immunotherapy with monocyte-derived dendritic cells (MoDC) combined with oncolytic Newcastle Disease Virus (NDV) can improve the efficacy of dendritic cell based immune therapy for relapsed GBM. Methods: After isolating monocytes from peripheral blood of n=37 patients with stage IV GBM who failed first-line radio-chemotherapy (PFI: 8 months), MoDC were generated using standard protocols. In 19 patients, NDV was added to the MoDC on day 5. These patients were also pretreated with an infusion with NDV one day before vaccination. The MoDC were harvested on day 7 of culture and administered to the patients intradermally. Results: Improvement of the clinical response was observed in patients, who received combination of NDV with MoDC vs. MoDC alone (47% vs. 11%). The median survival after onset of DC-therapy was 3 months with MoDC alone and 10 months (23 months after primary diagnosis) in combination with NDV. The 1- year-survival rates after onset of DC therapy were 6% and 32%, respectively. The therapy was well tolerated without any major side effects. IFN-gamma Elispot analyses from patients who received NDV injections and NDV-primed MoDC show that MoDC primed with NDV can induce a specific CD4 and CD8 T-cell response against NDV whereas healthy donors show no specific T-cell response. Conclusions: The efficacy of dendritic-cell based therapy for GBM can be improved by combination with NDV and may prolong overall survival of patients after failure of first-line therapy. For a first time we demonstrate that NDV primed MoDC induces a NDV specific T-cell response in humans, which may lead to in-vivo lysis of NDV-infected tumor cells.

A phase I/II clinical trial investigating the adverse and therapeutic effects of a postoperative autologous dendritic cell tumor vaccine in patients with malignant glioma.
Juli 2011 | Chang, Chen-Nen; Huang, Yin-Cheng; Yang, Den-Mei; Kikuta, Kenichiro; Wei, Kuo-Jen; Kubota, Toshihiko; Yang, Wen-Kuang
Previous clinical trials of dendritic cell (DC)-based immunotherapy in patients with glioblastoma multiforme (GBM) have reported induction of systemic immune responses and prolonged survival. From 2003 to 2005, we performed a clinical trial in which patients with malignant glioma underwent surgery for maximal cytoreduction followed by a 6-month 10-injection course of autologous DC-tumor vaccine therapy, each injection containing 1-6×10(7) DC. Of the 17 treated patients (16 with World Health Organization grade IV and one with grade III glioma), eight (47.1%) had an initial transient elevation in aspartate aminotransferase (AST)/alanine aminotransferase (ALT). Vaccination caused some tumor shrinkage and increased concentration of tumor-infiltrating CD8(+) lymphocytes. Median survival and 5-year survival were 525 days and 18.8%, respectively, for 16 patients with grade IV glioma (381 days and 12.5% for eight newly diagnosed; 966 days and 25% for eight relapsed patients) compared to 380 days and 0% for 63 historical control patients. We concluded that autologous DC-tumor immunotherapy benefits patients with malignant glioma but may cause transient but reversible elevation of serum AST/ALT levels. PMID 21715171

Engineering the brain tumor microenvironment enhances the efficacy of dendritic cell vaccination: implications for clinical trial design.
Juli 2011 | Mineharu, Yohei; King, Gwendalyn D; Muhammad, A K M G; Bannykh, Serguei; Kroeger, Kurt M; Liu, Chunyan; Lowenstein, Pedro R; Castro, Maria G
Glioblastoma multiforme (GBM) is a deadly primary brain tumor. Clinical trials for GBM using dendritic cell (DC) vaccination resulted in antitumor immune responses. Herein, we tested the hypothesis that combining in situ (intratumoral) Ad-Flt3L/Ad-TK-mediated gene therapy with DC vaccination would increase therapeutic efficacy and antitumor immunity. PMID 21632862

Immune response in patients with newly diagnosed glioblastoma multiforme treated with intranodal autologous tumor lysate-dendritic cell vaccination after radiation chemotherapy.
Apr. 2011 | Fadul, Camilo E; Fisher, Jan L; Hampton, Thomas H; Lallana, Enrico C; Li, Zhongze; Gui, Jiang; Szczepiorkowski, Zbigniew M; Tosteson, Tor D; Rhodes, C Harker; Wishart, Heather A; Lewis, Lionel D; Ernstoff, Marc S
Patients with glioblastoma multiforme (GBM) are profoundly immunosuppressed and may benefit from restoration of an antitumor immune response in combination with conventional radiation therapy and temozolomide (TMZ). The optimal strategies to evaluate clinically relevant immune responses to treatment have yet to be determined. The primary objective of our study was to determine immunologic response to cervical intranodal vaccination with autologous tumor lysate-loaded dendritic cells (DCs) in patients with GBM after radiation therapy and TMZ. We used a novel hierarchical clustering analysis of immune parameters measured before and after vaccination. Secondary objectives were to assess treatment feasibility and to correlate immune response with progression-free survival (PFS) and overall survival. Ten eligible patients received vaccination. Tumor-specific cytotoxic T-cell response measured after vaccination was enhanced for the precursor frequency of CD4+ T and CD4+ interferon γ-producing cells. Hierarchical clustering analysis of multiple functional outcomes discerned 2 groups of patients according to their immune response, and additionally showed that patients in the top quintile for at least one immune function parameter had improved survival. There were no serious adverse events related to DC vaccination. All patients were alive at 6 months after diagnosis and the 6-month PFS was 90%. The median PFS was 9.5 months and overall survival was 28 months. In patients with GBM, immune therapy with DC vaccination after radiation and TMZ resulted in tumor-specific immune responses that were associated with prolonged survival. Our data suggest that DC vaccination in combination with radiation and chemotherapy in patients with GBM is feasible, safe, and may induce tumor-specific immune responses. PMID 21499132

Gene expression profile correlates with T-cell infiltration and relative survival in glioblastoma patients vaccinated with dendritic cell immunotherapy.
März 2011 | Prins, Robert M; Soto, Horacio; Konkankit, Vera; Odesa, Sylvia K; Eskin, Ascia; Yong, William H; Nelson, Stanley F; Liau, Linda M
To assess the feasibility, safety, and toxicity of autologous tumor lysate-pulsed dendritic cell (DC) vaccination and toll-like receptor (TLR) agonists in patients with newly diagnosed and recurrent glioblastoma. Clinical and immune responses were monitored and correlated with tumor gene expression profiles. PMID 21135147

Induction of CD8+ T-cell responses against novel glioma-associated antigen peptides and clinical activity by vaccinations with {alpha}-type 1 polarized dendritic cells and polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose in patients with recurrent malignant glioma.
Jan. 2011 | Okada, Hideho; Kalinski, Pawel; Ueda, Ryo; Hoji, Aki; Kohanbash, Gary; Donegan, Teresa E; Mintz, Arlan H; Engh, Johnathan A; Bartlett, David L; Brown, Charles K; Zeh, Herbert; Holtzman, Matthew P; Reinhart, Todd A; Whiteside, Theresa L; Butterfield, Lisa H; Hamilton, Ronald L; Potter, Douglas M; Pollack, Ian F; Salazar, Andres M; Lieberman, Frank S
A phase I/II trial was performed to evaluate the safety and immunogenicity of a novel vaccination with α-type 1 polarized dendritic cells (αDC1) loaded with synthetic peptides for glioma-associated antigen (GAA) epitopes and administration of polyinosinic-polycytidylic acid [poly(I:C)] stabilized by lysine and carboxymethylcellulose (poly-ICLC) in HLA-A2(+) patients with recurrent malignant gliomas. GAAs for these peptides are EphA2, interleukin (IL)-13 receptor-α2, YKL-40, and gp100. PMID 21149657

Transcranial electro-hyperthermia combined with alkylating chemotherapy in patients with relapsed high-grade gliomas: phase I clinical results.
Juni 2010 | Wismeth, Caecilia; Dudel, Christine; Pascher, Christina; Ramm, Paul; Pietsch, Torsten; Hirschmann, Birgit; Reinert, Christiane; Proescholdt, Martin; Rümmele, Petra; Schuierer, Gerhard; Bogdahn, Ulrich; Hau, Peter
Non-invasive loco-regional electro-hyperthermia (EHT) plus alkylating chemotherapy is occasionally used as salvage treatment in the relapse of patients with high-grade gliomas. Experimental data and retrospective studies suggest potential effects. However, no prospective clinical results are available. We performed a single-center prospective non-controlled single-arm Phase I trial. Main inclusion criteria were recurrent high-grade glioma WHO Grade III or IV, age 18-70, and Karnofsky performance score > or = 70. Primary endpoints were dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) with the combined regimen. Groups of 3 or 4 patients were treated 2-5 times a week in a dose-escalation scheme with EHT. Alkylating chemotherapy (ACNU, nimustin) was administered at a dose of 90 mg/m(2) on day 1 of 42 days for up to six cycles or until tumor progression (PD) or DLT occurred. Fifteen patients with high-grade gliomas were included. Relevant toxicities were local pain and increased focal neurological signs or intracranial pressure. No DLT occurred. In some patients, the administration of mannitol during EHT or long-term use of corticosteroids was necessary to resolve symptoms. Although some patients showed responses in their primarily treated sites, the pattern of response was not well defined. EHT plus alkylating chemotherapy is tolerable in patients with relapse of high-grade gliomas. Episodes of intracranial pressure were, at least, possibly attributed to EHT but did not cause DLTs. A Phase II trial targeting treatment effects is warranted on the basis of the results raised in this trial. PMID 20033471

Adjuvant dendritic cell-based tumour vaccination for children with malignant brain tumours.
Feb. 2010 | Ardon, Hilko; De Vleeschouwer, Steven; Van Calenbergh, Frank; Claes, Laurence; Kramm, Christof M; Rutkowski, Stefan; Wolff, Johannes E A; Van Gool, Stefaan W
A large experience with dendritic cell (DC)-based vaccination for malignant brain tumours has been gained in adults. Here we focus on the results obtained in children with relapsed malignant brain tumours. PMID 19852061

Technical advancement in regulatory T cell isolation and characterization using CD127 expression in patients with malignant glioma treated with autologous dendritic cell vaccination.
Jan. 2010 | Ardon, H; Verbinnen, B; Maes, W; Beez, T; Van Gool, S; De Vleeschouwer, S
We have successfully treated over two hundred high-grade glioma (HGG) patients with immunotherapy consisting of vaccination with autologous dendritic cells (DCs) loaded with autologous tumour lysate. It has been documented that regulatory T cells (Treg) can counteract anti-tumour immune responses. Therefore, monitoring of Treg in these patients is essential. Up till now, Treg have been characterized based on the expression of the transcription factor Foxp3. Here, we validated IL-7 receptor alpha subunit (CD127)dim expression as a marker for human Treg within HGG patients, as a less laborious assay for routine use in tumour vaccination trials. We noted a strong positive correlation between Foxp3 expression and CD127dim expression in CD4+CD25+ and CD4+ cells. The suppressive function of CD4+CD127dim cells was assessed in an allogeneic mixed lymphocyte reaction (MLR). We conclude that CD127 staining is a fast, well-suited and reproducible Treg monitoring tool in HGG patients treated with immunotherapy. PMID 19874827

Clinical applications of a peptide-based vaccine for glioblastoma.
Nov. 2009 | Kanaly, Charles W; Ding, Dale; Heimberger, Amy B; Sampson, John H
Glioblastoma multiforme is a malignant, relentless brain cancer with no known cure, and standard therapies leave significant room for the development of better, more effective treatments. Immunotherapy is a promising approach to the treatment of solid tumors that directs the patient's own immune system to destroy tumor cells. The most successful immunologically based cancer therapy to date involves the passive administration of monoclonal antibodies, but significant antitumor responses have also been generated with active vaccination strategies and cell-transfer therapies. This article summarizes the important components of the immune system, discusses the specific difficulty of immunologic privilege in the central nervous system, and reviews treatment approaches that are being attempted, with an emphasis on active immunotherapy using peptide vaccines. PMID 19944970

Dendritic cell vaccines for brain tumors.
Nov. 2009 | Kim, Won; Liau, Linda M
Over the past decade, dendritic cell-based immunotherapy for central nervous system tumors has progressed from preclinical rodent models and safety assessments to phase I/II clinical trials in over 200 patients, which have produced measurable immunologic responses and some prolonged survival rates. Many questions regarding the methods and molecular mechanisms behind this new treatment option, however, remain unanswered. Results from currently ongoing and future studies will help to elucidate which dendritic cell preparations, treatment protocols, and adjuvant therapeutic regimens will optimize the efficacy of dendritic cell vaccination. As clinical studies continue to report results on dendritic cell-mediated immunotherapy, it will be critical to continue refining treatment methods and developing new ways to augment this promising form of glioma treatment. PMID 19944973

Heat shock proteins in glioblastomas.
Nov. 2009 | Yang, Isaac; Fang, Shanna; Parsa, Andrew T
Glioblastoma multiforme is the most common primary central nervous system tumor. The prognosis for these malignant brain tumors is poor, with a median survival of 14 months and a 5-year survival rate below 2%. Development of novel treatments is essential to improving survival and quality of life for these patients. Endogenous heat shock proteins have been implicated in mediation of both adaptive and innate immunity, and there is a rising interest in the use of this safe and multifaceted heat shock protein vaccine therapy as a promising treatment for human cancers, including glioblastoma multiforme. PMID 19944971

Monitoring immune responses after glioma vaccine immunotherapy.
Nov. 2009 | Jian, Brian; Yang, Isaac; Parsa, Andrew T
Immunotherapy provides the ideal candidate of therapeutic attack against malignant gliomas because it allows for targeting of cancer cells without the potential for nonspecific toxicity. This is important when glial tumor cells spread far through normal brain tissue. Current vaccine therapies are in clinical trials and are showing beneficial responses. Given that the inflammatory response may make serial radiographic imaging more difficult to interpret, newer methodologies of immunomonitoring must be developed to assess the biologic efficacy of these immunotherapies. This article reviews methods of monitoring the immune system after vaccination against malignant gliomas. Improvements in immunomonitoring should lead to an increase in the efficiency of identifying viable avenues of therapeutic research, and assess the efficacy of those currently employed. PMID 19944978

Heat-shock protein vaccines as active immunotherapy against human gliomas.
Nov. 2009 | Yang, Isaac; Han, Seunggu; Parsa, Andrew T
Modern advances in cancer immunotherapy have led to the development of active immunotherapy that utilizes tumor-associated antigens to induce a specific immune response against the tumor. Current methods of immunotherapy implementation are based on the principle that tumor-associated antigens are capable of being processed by antigen-presenting cells and inducing an activated cytotoxic T-lymphocyte-specific immune response that targets the tumor cells. Antigen internalization and processing by antigen-presenting cells, such as dendritic cells, or macrophages results in their surface association with MHC class I molecules, which can be recognized by an antigen-specific cytotoxic T-lymphocyte adaptive immune response. With the aim of augmenting current immunotherapeutic modalities, much effort has been directed towards enhancing antigen-presenting cell activation and optimizing the processing of tumor-associated antigens and major histocompatibility molecules. The goal of these immunotherapy modifications is to ultimately improve the adaptive specific immune response in killing of tumor cells while sparing normal tissues. Immunotherapy has been actively studied and applied in glioblastomas. Preclinical animal models have shown the feasibility of an active immunotherapy approach through the utilization of tumor vaccines, and recently several clinical studies have also been initiated. Recently, endogenous heat-shock proteins have been implicated in the mediation of both the adaptive and innate immune responses. They are now being investigated as a potential modality and adjuvant to immunotherapy, and they represent a promising novel treatment for human glioblastomas. PMID 19895242

An epidermal growth factor receptor variant III-targeted vaccine is safe and immunogenic in patients with glioblastoma multiforme.
Okt. 2009 | Sampson, John H; Archer, Gary E; Mitchell, Duane A; Heimberger, Amy B; Herndon, James E; Lally-Goss, Denise; McGehee-Norman, Sharon; Paolino, Alison; Reardon, David A; Friedman, Allan H; Friedman, Henry S; Bigner, Darell D
Conventional therapies for glioblastoma multiforme (GBM) fail to target tumor cells exclusively, such that their efficacy is ultimately limited by nonspecific toxicity. Immunologic targeting of tumor-specific gene mutations, however, may allow more precise eradication of neoplastic cells. The epidermal growth factor receptor variant III (EGFRvIII) is a consistent and tumor-specific mutation widely expressed in GBMs and other neoplasms. The safety and immunogenicity of a dendritic cell (DC)-based vaccine targeting the EGFRvIII antigen was evaluated in this study. Adults with newly diagnosed GBM, who had undergone gross-total resection and standard conformal external beam radiotherapy, received three consecutive intradermal vaccinations with autologous mature DCs pulsed with an EGFRvIII-specific peptide conjugated to keyhole limpet hemocyanin. The dose of DCs was escalated in cohorts of three patients. Patients were monitored for toxicity, immune response, radiographic and clinical progression, and death. No allergic reactions or serious adverse events were seen. Adverse events were limited to grade 2 toxicities. The maximum feasible dose of antigen-pulsed mature DCs was reached at 5.7 x 10(7) +/- 2.9 x 10(7) SD without dose-limiting toxicity. EGFRvIII-specific immune responses were evident in most patients. The mean time from histologic diagnosis to vaccination was 3.6 +/- 0.6 SD months. Median time to progression from vaccination was 6.8 months [95% confidence interval (C.I.(95)), 2.5-8.8], and median survival time from vaccination was 18.7 months (C.I.(95), 14.5-25.6). Overall median survival from time of histologic diagnosis was 22.8 months (C.I.(95), 17.5-29). This study establishes the EGFRvIII mutation as a safe and immunogenic tumor-specific target for immunotherapy. PMID 19825799

Brain tumor immunotherapy with type-1 polarizing strategies.
Sep. 2009 | Okada, Hideho
Although the safety of vaccine approaches for central nervous system (CNS) malignancies has been established in early phase clinical trials, the success of a vaccine strategy will depend critically on the ability of effector T cells to home in to CNS tumors and durably exert antitumor effects. Based on our recent studies, efficient CNS tumor homing is a characteristic of cytotoxic T lymphocytes (CTLs) with a type 1 phenotype (Tc1), and this appears to be related to the Tc1 response to the type 1 CXC chemokine ligand (CXCL) 10 [also known as interferon (IFN)-inducible protein (IP)-10] and expression of an integrin receptor very late antigen (VLA)-4 on Tc1. In addition, we have previously shown that direct intratumoral delivery of dendritic cells (DCs) ex vivo engineered to secrete IFN-alpha further enhances Tc1 homing via upregulation of CXCL10/IP-10 in the tumor microenvironment. As a means to induce IFN-alpha and CXCL10/IP-10 in the CNS tumor microenvironment in a clinically feasible manner, we used administration of polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose (poly-ICLC), a ligand for toll-like receptor 3 and melanoma differentiation-associated gene 5 (MDA5) in combination with vaccinations targeting CTL epitopes derived from glioma-associated antigens (GAAs). The combination of subcutaneous vaccination and i.m. poly-ICLC administration remarkably promoted systemic induction of antigen GAA-specific Tc1s expressing VLA-4 in the CNS tumors and improved the survival of tumor-bearing mice in the absence of detectable autoimmunity. Based on these data, we have implemented a phase I/II vaccination study using type 1 polarizing DCs loaded with GAA peptides in combination with poly-ICLC in patients with recurrent malignant glioma. PMID 19769732

Immunotherapy of diffuse gliomas: biological background, current status and future developments.
Sep. 2009 | Grauer, Oliver M; Wesseling, Pieter; Adema, Gosse J
Despite aggressive multimodal treatment approaches, the prognosis for patients with diffuse gliomas remains disappointing. Glioma cells often extensively infiltrate in the surrounding brain parenchyma, a phenomenon that helps them to escape surgical removal, radiation exposure and chemotherapy. Moreover, conventional therapy is often associated with considerable local and systemic side effects. Therefore, the development of novel therapeutic approaches is essential to improve the outcome of these patients. Immunotherapy offers the opportunity to specifically target residual radio-and chemoresistant tumor cells without damaging healthy neighboring brain tissue. Significant progress has been made in recent years both in understanding the mechanisms of immune regulation in the central nervous system (CNS) as well as tumor-induced and host-mediated immunosuppression elicited by gliomas. In this review, after discussing the special requirements needed for the initiation and control of immune responses in the CNS, we focus on immunological phenomena observed in glioma patients, discuss different immunological approaches to attack glioma-associated target structures and touch on further strategies to improve the efficacy of immunotherapy of gliomas. PMID 19744040

Dendritic cell therapy of high-grade gliomas.
Sep. 2009 | Van Gool, Stefaan; Maes, Wim; Ardon, Hilko; Verschuere, Tina; Van Cauter, Sofie; De Vleeschouwer, Steven
The prognosis of patients with malignant glioma is poor in spite of multimodal treatment approaches consisting of neurosurgery, radiochemotherapy and maintenance chemotherapy. Among innovative treatment strategies like targeted therapy, antiangiogenesis and gene therapy approaches, immunotherapy emerges as a meaningful and feasible treatment approach for inducing long-term survival in at least a subpopulation of these patients. Setting up immunotherapy for an inherent immunosuppressive tumor located in an immune-privileged environment requires integration of a lot of scientific input and knowledge of both tumor immunology and neuro-oncology. The field of immunotherapy is moving into the direction of active specific immunotherapy using autologous dendritic cells (DCs) as vehicle for immunization. In the translational research program of the authors, the whole cascade from bench to bed to bench of active specific immunotherapy for malignant glioma is covered, including proof of principle experiments to demonstrate immunogenicity of patient-derived mature DCs loaded with autologous tumor lysate, preclinical in vivo experiments in a murine orthotopic glioma model, early phase I/II clinical trials for relapsing patients, a phase II trial for patients with newly diagnosed glioblastoma (GBM) for whom immunotherapy is integrated in the current multimodal treatment, and laboratory analyses of patient samples. The strategies and results of this program are discussed in the light of the internationally available scientific literature in this fast-moving field of basic science and translational clinical research. PMID 19744041

Antigen-specific T-cell response from dendritic cell vaccination using cancer stem-like cell-associated antigens.
Sep. 2009 | Xu, Qijin; Liu, Gentao; Yuan, Xiangpeng; Xu, Minlin; Wang, Hongqiang; Ji, Jianfei; Konda, Bindu; Black, Keith L; Yu, John S
Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor, with current treatment remaining palliative. Immunotherapies harness the body's own immune system to target cancers and could overcome the limitations of conventional treatments. One active immunotherapy strategy uses dendritic cell (DC)-based vaccination to initiate T-cell-mediated antitumor immunity. It has been proposed that cancer stem-like cells (CSCs) may play a key role in cancer initiation, progression, and resistance to current treatments. However, whether using human CSC antigens may improve the antitumor effect of DC vaccination against human cancer is unclear. In this study, we explored the suitability of CSCs as sources of antigens for DC vaccination again human GBM, with the aim of achieving CSC-targeting and enhanced antitumor immunity. We found that CSCs express high levels of tumor-associated antigens as well as major histocompatibility complex molecules. Furthermore, DC vaccination using CSC antigens elicited antigen-specific T-cell responses against CSCs. DC vaccination-induced interferon-gamma production is positively correlated with the number of antigen-specific T cells generated. Finally, using a 9L CSC brain tumor model, we demonstrate that vaccination with DCs loaded with 9L CSCs, but not daughter cells or conventionally cultured 9L cells, induced cytotoxic T lymphocytes (CTLs) against CSCs, and prolonged survival in animals bearing 9L CSC tumors. Understanding how immunization with CSCs generates superior antitumor immunity may accelerate development of CSC-specific immunotherapies and cancer vaccines. PMID 19536809

Dendritic-cell- and peptide-based vaccination strategies for glioma.
Juni 2009 | Yamanaka, Ryuya
Despite advances in radiation and chemotherapy along with surgical resectioning, the prognosis of patients with malignant glioma is poor. Therefore, the development of a new treatment modality is extremely important. There are increasing reports demonstrating that systemic immunotherapy using dendritic cells and peptide is capable of inducing an antiglioma response. This review highlights dendritic-cell- and peptide-based immunotherapy for glioma patients. Dendritic-cell- and peptide-based immunotherapy strategies appear promising as an approach to successfully induce an antitumor immune response and increase survival in patients with glioma. Dendritic cell- and peptide-based therapy of glioma seems to be safe and without major side effects. There are several types of glioma; so to achieve effective therapy, it may be necessary to evaluate the molecular genetic abnormalities in individual patient tumors and design novel immunotherapeutic strategies based on the pharmacogenomic findings. Here, in this review, recent advances in dendritic-cell- and peptide-based immunotherapy approaches for patients with gliomas are discussed. PMID 19214609

DCVax-Brain and DC vaccines in the treatment of GBM.
Apr. 2009 | Wheeler, Christopher J; Black, Keith L
DCVax-Brain (Northwest Biotherapeutics, Inc., Bethesda, MD, USA) is a personalized treatment for brain tumors. Its approach of administering autologous tumor antigen-bearing dendritic cells (DCs) has garnered hope for more effective and less toxic therapy for patients with malignant brain tumors including glioblastoma multiforme (GBM). DCVax-Brain composition and efficacy are not fully disclosed, although sponsors claim it is poised to critically test clinical DC vaccine efficacy in GBM patients. PMID 19335279

Tumour vaccine approaches for CNS malignancies: progress to date.
März 2009 | Ebben, Johnathan D; Rocque, Brandon G; Kuo, John S
Despite the many overall advances in understanding cancer biology and therapeutic development in the last 50 years, most CNS malignancies are still clinically difficult, incurable diseases. Current combinations of aggressive surgical resection, radiation therapy and chemotherapy regimens do not significantly improve long-term patient survival for these cancers. Cancer immunotherapy is a potentially promising new therapeutic strategy that primes a patient's immune system to attack neoplastic cells. We review the preclinical and clinical progress in developing vaccination-based therapy for CNS malignancies to date, including peptide-based vaccinations, dendritic cell-based vaccinations and other potential modalities. Some of the challenges for developing an effective vaccination strategy, such as abnormal immune molecules on glioma cells and abnormal lymphocyte populations within a glioma, are also discussed. PMID 19275269

Newcastle diseases virus strain V4UPM displayed oncolytic ability against experimental human malignant glioma.
Feb. 2009 | Zulkifli, M M; Ibrahim, R; Ali, A M; Aini, I; Jaafar, H; Hilda, S S; Alitheen, N B; Abdullah, J M
Newcastle disease virus (NDV) is a virus of paramyxovirus family and lately has been studied for the treatment of cancer in human. In this study, we successfully determined the oncolysis potential of NDV vaccine, V4UPM tested on the human glioblastoma multiform cell line (DBTRG.05MG) and human glioblastoma astrocytoma cell line (U-87MG) in vitro and in vivo. The V4UPM strain is a modified V4 strain developed as thermostable feed pellet vaccine for poultry. PMID 18937888

Therapeutic efficacy of antitumor dendritic cell vaccinations correlates with persistent Th1 responses, high intratumor CD8+ T cell recruitment and low relative regulatory T cell infiltration.
Sep. 2008 | Driessens, Gregory; Gordower, Laurence; Nuttin, Lise; Stordeur, Patrick; Blocklet, Didier; Egrise, Dominique; Velu, Thierry; Bruyns, Catherine
Despite the increasing number of immunotherapeutic strategies for the treatment of cancer, most approaches have failed to correlate the induction of an anti-tumor immune response with therapeutic efficacy. We therefore took advantage of a successful vaccination strategy-combining dendritic cells and irradiated GM-CSF secreting tumor cells-to compare the immune response induced against 9L gliosarcoma tumors in cured rats versus those with progressively growing tumors. At the systemic level, the tumor specific cytotoxic responses were quite heterogeneous in uncured vaccinated rats, and were surprisingly often high in animals with rapidly-growing tumors. IFN-gamma secretion by activated splenic T cells was more discriminative as the CD4+ T cell-mediated production was weak in uncured rats whereas high in cured ones. At the tumor level, regressing tumors were strongly infiltrated by CD8+ T cells, which demonstrated lytic capacities as high as their splenic counterparts. In contrast, progressing tumors were weakly infiltrated by T cells showing impaired cytotoxic activities. Proportionately to the T cell infiltrate, the expression of Foxp3 was increased in progressive tumors suggesting inhibition by regulatory T cells. In conclusion, the main difference between cured and uncured vaccinated animals does not depend directly upon the induction of systemic cytotoxic responses. Rather the persistence of higher CD4+ Th1 responses, a high intratumoral recruitment of functional CD8+ T cells, and a low proportion of regulatory T cells correlate with tumor rejection. PMID 18369621

Vaccination elicits correlated immune and clinical responses in glioblastoma multiforme patients.
Juli 2008 | Wheeler, Christopher J; Black, Keith L; Liu, Gentao; Mazer, Mia; Zhang, Xiao-xue; Pepkowitz, Samuel; Goldfinger, Dennis; Ng, Hiushan; Irvin, Dwain; Yu, John S
Cancer vaccine trials have failed to yield robust immune-correlated clinical improvements as observed in animal models, fueling controversy over the utility of human cancer vaccines. Therapeutic vaccination represents an intriguing additional therapy for glioblastoma multiforme (GBM; grade 4 glioma), which has a dismal prognosis and treatment response, but only early phase I vaccine trial results have been reported. Immune and clinical responses from a phase II GBM vaccine trial are reported here. IFN-gamma responsiveness was quantified in peripheral blood of 32 GBM patients given therapeutic dendritic cell vaccines. Posttreatment times to tumor progression (TTP) and survival (TTS) were compared in vaccine responders and nonresponders and were correlated with immune response magnitudes. GBM patients (53%) exhibited >or=1.5-fold vaccine-enhanced cytokine responses. Endogenous antitumor responses of similar magnitude occurred in 22% of GBM patients before vaccination. Vaccine responders exhibited significantly longer TTS and TTP relative to nonresponders. Immune enhancement in vaccine responders correlated logarithmically with TTS and TTP spanning postvaccine chemotherapy, but not with initial TTP spanning vaccination alone. This is the first report of a progressive correlation between cancer clinical outcome and T-cell responsiveness after therapeutic vaccination in humans and the first tracing of such correlation to therapeutically exploitable tumor alteration. As such, our findings offer unique opportunities to identify cellular and molecular components of clinically meaningful antitumor immunity in humans. PMID 18632651

Postoperative adjuvant dendritic cell-based immunotherapy in patients with relapsed glioblastoma multiforme.
Mai 2008 | De Vleeschouwer, Steven; Fieuws, Steffen; Rutkowski, Stefan; Van Calenbergh, Frank; Van Loon, Johannes; Goffin, Jan; Sciot, Raf; Wilms, Guido; Demaerel, Philippe; Warmuth-Metz, Monika; Soerensen, Niels; Wolff, Johannes E A; Wagner, Sabine; Kaempgen, Eckhart; Van Gool, Stefaan W
To investigate the therapeutic role of adjuvant vaccination with autologous mature dendritic cells (DC) loaded with tumor lysates derived from autologous, resected glioblastoma multiforme (GBM) at time of relapse. PMID 18483377

Dendritic cell immunotherapy for malignant gliomas.
Mai 2008 | Luptrawan, Anne; Liu, Gentao; Yu, John S
The prognosis for patients with malignant gliomas remains poor despite advances in surgical technique, chemotherapy and radiation therapy. Median survival for glioblastoma multiforme, the most aggressive and deadliest form of brain cancer, remains only fifteen months even after optimal treatment with surgical resection followed by chemoradiation therapy. The grim prognosis can be attributed to the infiltrative nature of the disease, a central nervous system microenvironment that can escape immune surveillance and resistance of the tumor to chemotherapy. In recent trials, dendritic cells have demonstrated an ability to promote an effective anti-tumor immune response and sensitize glioma cells to chemotherapy. This review will discuss the results of dendritic-cell based immunotherapy clinical trials for the treatment of malignant gliomas and explore the future strategies of DC vaccines for glioma immunotherapy. PMID 18474011

Cell- and peptide-based immunotherapeutic approaches for glioma.
Mai 2008 | Yamanaka, Ryuya
Glioblastoma multiforme (GBM) is the most common and lethal primary malignant brain tumor. Although considerable progress has been made in surgical and radiation treatment for glioma patients, the impact of these advances on clinical outcome has been disappointing. Therefore, the development of novel therapeutic approaches is essential. Recent reports demonstrate that systemic immunotherapy using dendritic cells (DCs) or peptide vaccines is capable of inducing an antiglioma response. These approaches successfully induce an antitumor immune response and prolong survival in patients with glioma without major side effects. There are several types of glioma, so to achieve effective therapy, it might be necessary to evaluate the molecular genetic abnormalities in individual patient tumors and design novel immunotherapeutic strategies based on the pharmacogenomic findings. Here, we review recent advances in DC- and peptide-based immunotherapy approaches for patients with gliomas. PMID 18403264

Autologous glioma cell vaccine admixed with interleukin-4 gene transfected fibroblasts in the treatment of patients with malignant gliomas.
Feb. 2008 | Okada, Hideho; Lieberman, Frank S; Walter, Kevin A; Lunsford, L Dade; Kondziolka, Douglas S; Bejjani, Ghassan K; Hamilton, Ronald L; Torres-Trejo, Alejandro; Kalinski, Pawel; Cai, Quan; Mabold, Jennifer L; Edington, Howard D; Butterfield, Lisa H; Whiteside, Theresa L; Potter, Douglas M; Schold, S Clifford; Pollack, Ian F
The prognosis for malignant gliomas remains dismal. We addressed the safety, feasibility and preliminary clinical activity of the vaccinations using autologous glioma cells and interleukin (IL)-4 gene transfected fibroblasts. PMID 18093335

Elimination of regulatory T cells is essential for an effective vaccination with tumor lysate-pulsed dendritic cells in a murine glioma model.
Feb. 2008 | Grauer, Oliver M; Sutmuller, Roger P M; van Maren, Wendy; Jacobs, Joannes F M; Bennink, Erik; Toonen, Liza W J; Nierkens, Stefan; Adema, Gosse J
Both melanoma and glioma cells are of neuroectodermal origin and share common tumor associated antigens. In this article, we report that the melanocyte differentiation antigen TRP2 (tyrosinase-related protein 2) is not predominantly involved in the tumor rejection of a syngeneic murine glioma. Although GL261 glioma cells endogenously expressed TRP2 and were lysed by TRP2 specific cytotoxic T cells (CTLs) in vitro, vaccinations with TRP2 peptide-pulsed dendritic cells (DCs) could only induce minor antiglioma responses in a prophylactic setting and failed to work in a stringent setting where vaccine and tumor were administered on the same day. Further analysis revealed that TRP2 is not recognized by bulk CTLs after depletion of regulatory T cells which results in tumor rejections in vivo. In contrast to TRP2 peptide-pulsed DC, tumor lysate-pulsed DCs were more potent as a vaccine and completely protected mice from tumor outgrowth in a prophylactic setting. However, the vaccine efficacy of tumor lysate-pulsed DC was not sufficient to prevent the tumor outgrowth when tumors were inoculated the same day. In this case, Treg depletion before vaccination was essential to boost antiglioma immune responses leading to the rejection of 80% of the mice and long-term immunity. Therefore, we conclude that counteracting the immunosuppressive glioma tumor environment via depletion of regulatory T cells is a prerequisite for successful eradication of gliomas after targeting multiple tumor antigens by using tumor lysate-pulsed DCs as a vaccine in a more stringent setting. PMID 18076066

Dendritic cell-based immunotherapy for malignant glioma.
Feb. 2008 | Gu, Jin-Hai; Li, Gang
The immunotherapy for malignant glioma faces unique difficult, due to some anatomical and immunological characteristics including the existence of blood brain barrier, the absence of lymphatic tissues and dendritic cells (DCs) in the central nervous system (CNS) parenchyma, and the presence of an immunosuppressive microenvironment. Therefore, immunotherapeutic approaches will not be beneficial unless the compromised immune status in malignant glioma patients is overcome. DC-based immunotherapy, vaccinating cancer patients with DCs pulsed with various tumor antigens, is one of the most promising immunotherapeutic approaches for treatment of malignant glioma because it seems able to overcome, at least partially, the immunosuppressive state associated with primary malignancies. The preparation of DCs, choice of antigen, and route and schedule of administration are improving and optimizing with rapid development of molecular biology and gene engineering technology. DC vaccination in humans, after a number of pre-clinical models and clinical trials, would increase the clinical benefits for malignant glioma immunotherapy. PMID 18273075

Use of interferon-alpha-induced dendritic cells in the therapy of patients with malignant brain gliomas.
Jan. 2008 | Leplina, O Yu; Stupak, V V; Kozlov, Yu P; Pendyurin, I V; Nikonov, S D; Tikhonova, M A; Sycheva, N V; Ostanin, A A; Chernykh, E R
Clinical and immunological analysis of the efficiency of combined immunotherapy with the use dendritic cells for the treatment of malignant glioma of the brain was carried out. Dendritic cells generated in the presence of granulocyte-macrophage CSF and IFN-alpha retain their functional characteristics in patients with gliomas, which suggests the possibility of their use for the treatment of malignant tumors (glioma) of the brain. Combined therapy using interferon-induced dendritic cells was associated with generation of antigen-specific immune response during vaccinations. The results indicate satisfactory tolerance of combined immunotherapy using dendritic cells and the absence of toxic side effects at the stage of adoptive immunotherapy and at the stage of vaccinations with dendritic cells. Clinical trials showed that vaccinations with dendritic cells included into combined immunotherapy improved the quality of life and survival of patients with malignant gliomas. PMID 18214316

Results of a phase I dendritic cell vaccine trial for malignant astrocytoma: potential interaction with adjuvant chemotherapy.
Dez. 2007 | Walker, David G; Laherty, Richard; Tomlinson, Frank H; Chuah, Teong; Schmidt, Chris
Dendritic cell vaccination has been applied to the treatment of a variety of cancers, including malignant astrocytoma. We have treated 13 patients with malignant astrocytoma using dendritic cell vaccination and have shown that this treatment is safe and is likely to be effective in combination with standard adjuvant therapy. Future studies should prospectively incorporate dendritic cell vaccination together with chemotherapy. Ideally, dendritic cell vaccination should be tested in a prospective fashion, in a coordinated trial involving multiple centres. PMID 18083572

Enhanced antitumour immunity by combined use of temozolomide and TAT-survivin pulsed dendritic cells in a murine glioma.
Nov. 2007 | Kim, Chang-Hyun; Woo, Sun-Je; Park, Jung-Sun; Kim, Hye-Sung; Park, Mi-Young; Park, Sung-Dong; Hong, Yong-Kil; Kim, Tai-Gyu
Although chemotherapy remains among the best treatment options for most cancers, adjuvant therapies such as dendritic cell (DC)-based immunotherapy have been added to treatment protocols to destroy residual tumour cells. Combination treatment with low-dose temozolomide (TMZ) chemotherapy followed by vaccination with TAT-survivin-pulsed DCs enhanced T-cell responses specific for survivin and improved survival rate, as compared with DC alone or TMZ alone. Moreover, antigen-specific immunity appears to be mediated by CD8(+) T cells, as determined by in vitro T-cell subset depletion. These studies demonstrated that a combination of low-dose TMZ chemotherapy and TAT-based DC immunotherapy may be a novel strategy for safe and effective treatment of malignant gliomas. PMID 17645496

Persistent IL-10 production is required for glioma growth suppressive activity by Th1-directed effector cells after stimulation with tumor lysate-loaded dendritic cells.
Juli 2007 | De Vleeschouwer, Steven; Spencer Lopes, Isabel; Ceuppens, Jan L; Van Gool, Stefaan W
Injection of dendritic cells (DC) pulsed with tumor antigens is a novel treatment strategy against malignancies, and aims to elicit anti-tumoral cell-mediated immune responses. We studied the in vitro proliferative responses and cytokine production in T cell cultures after 2 stimulations with autologous DC loaded with tumor lysates derived from glioblastoma multiforme (GBM) cells in the presence of recombinant interleukin (rIL)-6/rIL-12 in the first, and rIL-2/rIL-7 in the second stimulation. After the second stimulation, T cells were co-cultured with glioblastoma (GBM) cells and tumor growth suppression by T cells was assessed using a MTT assay. Although loaded DC induced a significant shift towards T helper cell type 1 (Th1) cytokine production as compared to unloaded DC, persistent interleukin (IL)-10 production by T cells both at the end of 2 stimulations with loaded DC and during the effector phase was also required for their tumor suppressive activity. A stronger glioma growth suppressive activity by T cells stimulated with tumor lysate-loaded DC than by control T cells, cultured with unloaded DC, was seen only if the relative IL-10 production after two stimulations with loaded DC was at least 40% of the IL-10 production after two stimulations with unloaded DC. If less than 40% IL-10 was produced in the experimental condition compared to the control condition, T cells also lost their tumor growth suppressive activity. Addition of rIL-10 during stimulation increased the suppressive activity on tumor cell viability and interferon (IFN)-gamma production by T cells that showed Th1 response upon stimulation with loaded DC. The data point towards the production of both IFN-gamma and IL-10 by responding effector T cells, and towards an immune modulatory rather than immune suppressive role of IL-10 to generate anti-tumoral effector T cells against GBM. PMID 17361330

Antitumor effects of vaccination with dendritic cells transfected with modified receptor for hyaluronan-mediated motility mRNA in a mouse glioma model.
Apr. 2007 | Amano, Takayuki; Kajiwara, Koji; Yoshikawa, Koichi; Morioka, Jun; Nomura, Sadahiro; Fujisawa, Hirosuke; Kato, Shoichi; Fujii, Masami; Fukui, Mikiko; Hinoda, Yuji; Suzuki, Michiyasu
The receptor for hyaluronan-mediated motility (RHAMM) is frequently overexpressed in brain tumors and was recently identified as an immunogenic antigen by using serological screening of cDNA expression libraries. In this study, which was conducted using a mouse glioma model, the authors tested the hypothesis that vaccination with dendritic cells transfected with RHAMM mRNA induces strong immunological antitumor effects. PMID 17432716

Mahaley Clinical Research Award: chemosensitization of glioma through dendritic cell vaccination.
März 2007 | Yu, John S; Luptrawan, Anne; Black, Keith L; Liu, Gentao
A major reason chemotherapy fails in cancer treatment is drug resistance. New targets against chemotherapy resistance have been developed with the identification of molecular pathways in drug resistance. These targets are proteins that are highly expressed in human gliomas and are known to be tumor antigens. The immune system produces specialized white blood cells called dendritic cells (DCs). DCs are the most potent antigen-presenting cell of the immune system. DCs have demonstrated the ability to stimulate antibodies and cell-mediated immune responses against tumor antigens. Immunotherapy has emerged as a novel treatment strategy for gliomas with tumor antigens serving as the driving force. Clinical immunotherapy trials for glioma patients using vaccinations made of tumor antigens combined with dendritic cells ex vivo have shown promising results. DC vaccinations may increase sensitivity to chemotherapy, as demonstrated by a significant increase in 2-year survival rates in patients with malignant gliomas who received chemotherapy after immunotherapy (51). The use of DC vaccinations to increase sensitivity of tumor cells to chemotherapy can be rationalized as a novel strategy. Hence, this review will focus on the recent advances in the identification of tumor-associated antigens in gliomas, as well as their biological function related to drug resistance. The current research status and the future direction of DC vaccines to treat glioma in animal models and clinical trials will also be discussed. PMID 17380773

Dendritic cell-based active specific immunotherapy for malignant glioma.
März 2007 | Parajuli, Prahlad; Mathupala, Saroj; Mittal, Sandeep; Sloan, Andrew E
Immunotherapy is an appealing therapeutic modality for malignant gliomas because of its potential to selectively target residual tumor cells that have invaded the normal brain. Most immunotherapeutic studies are designed to exploit the capacity of dendritic cells for inducing cell-mediated effects as well as immune memory responses for destroying residual tumor cells and preventing recurrence. Although initial clinical studies on dendritic cell-based immunotherapy resulted in very limited success, they have prompted many new studies on exploring strategies to induce a more robust antitumor immune response by using novel adjuvants for maturation and activation of dendritic cells. More studies have focused on the mechanisms of immune suppression by tumor cells and the role of regulatory T cells in tumor growth and progression. In this article, the authors review the evolution of dendritic cell-based immunotherapeutic strategies for adjuvant treatment of malignant gliomas. The authors also discuss how new knowledge on tumor-intrinsic mechanisms of tolerance induction and immunosuppression are likely to shape the future of immunotherapy for high-grade gliomas. PMID 17373896

p53-independent endoplasmic reticulum stress-mediated cytotoxicity of a Newcastle disease virus strain in tumor cell lines.
Feb. 2007 | Fábián, Zsolt; Csatary, Christine M; Szeberényi, József; Csatary, Laszlo K
While Newcastle disease virus (NDV) causes serious infections in birds, it is apparently nonpathogenic in mammalian species, including humans. Previous observations and small-scale clinical trials indicated that NDV exerts oncolytic effects. Isolates of NDV were found to have selective affinity to transformed cells. We previously showed that the attenuated NDV strain MTH-68/H causes apoptotic cell death in cultures of PC12 rat pheochromocytoma cells. The aim of the present study was to extend MTH-68/H cytotoxicity testing with human tumor cell lines and to analyze certain biochemical aspects of its oncolytic effect. MTH-68/H was found to be able to kill a wide range of transformed cells by apoptosis. While caspase-8 and caspase-9 are not involved in MTH-68/H-induced apoptosis, activation of caspase-3 and caspase-12 was detected in virus-infected PC12 cells. A human glioblastoma cell line with repressible expression of the p53 protein did not show any difference in MTH-68/H sensitivity in its p53-expressing and p53-depleted states, indicating that the apoptotic process induced by MTH-68/H does not depend on p53. Apoptosis was accompanied by virus replication in two tumor cell lines tested (PC12 cells and HeLa human cervical cells), and signs of endoplasmic reticulum stress (phosphorylation of protein kinase R-like endoplasmic reticulum kinase and eIF2alpha) were also detected in transformed cells. In contrast, proliferation of nontransformed mouse and rat fibroblast cell lines and human primary fibroblasts was not affected by MTH-68/H treatment. MTH-68/H thus selectively kills tumor cell cultures by inducing endoplasmic reticulum stress leading to p53-independent apoptotic cell death. PMID 17215292

Antigenic profiling of glioma cells to generate allogeneic vaccines or dendritic cell-based therapeutics.
Jan. 2007 | Zhang, Jian Gang; Eguchi, Junichi; Kruse, Carol A; Gomez, German G; Fakhrai, Habib; Schroter, Stephanie; Ma, Wenxue; Hoa, Neil; Minev, Boris; Delgado, Christina; Wepsic, H Terry; Okada, Hideho; Jadus, Martin R
Allogeneic glioma cell lines that are partially matched to the patient at class I human leukocyte antigen (HLA) loci and that display tumor-associated antigens (TAA) or antigenic precursors [tumor antigen precursor proteins (TAPP)] could be used for generating whole tumor cell vaccines or, alternatively, for extraction of TAA peptides to make autologous dendritic cell vaccines. PMID 17255279

Expression of nine tumour antigens in a series of human glioblastoma multiforme: interest of EGFRvIII, IL-13Ralpha2, gp100 and TRP-2 for immunotherapy.
Jan. 2007 | Saikali, Stéphan; Avril, Tony; Collet, Brigitte; Hamlat, Abderrahmane; Bansard, Jean-Yves; Drenou, Bernard; Guegan, Yvon; Quillien, Véronique
In this study, we investigated the mRNA and protein expression of nine tumour antigens in human glioblastoma multiforme with a view to their possible use in dendritic cell-based immunotherapy. Expression of ALK, EGFRvIII, GALT3, gp100, IL-13Ralpha2, MAGE-A3, NA17-A, TRP-2 and tyrosinase were studied by real-time RT-PCR on frozen tissues using a series of 47 tumour samples from patients with glioblastoma. Results were compared with non-neoplastic brain expression or glioblastoma samples with very low levels of expression near the limits of detection for EGFRvIII and MAGE-A3, as these latter two antigens were not detected in non-neoplastic brain. Tumour antigens showing a 5-fold increase in mRNA expression were considered as positive, and only antigens displaying an mRNA over-expression in a significant number of cases were analysed by immunohistochemistry on paraffin-embedded sections. Using real time RT-PCR, we found EGFRvIII, gp100, IL-13Ralpha2 and TRP-2 to be positive in 64, 38, 32 and 21% of cases, respectively. While we observed no over-expression for ALK, GALT3 and tyrosinase, 3 samples out of 47 were positive for MAGE-3 and 1 sample for NA17-A. More than 25% of tumour cells showed strong protein expression in 13, 34, 85 and 96% of GBM samples for gp100, TRP-2, EGFRvIII and IL-13Ralpha2, respectively. Interestingly, protein expression of at least 3 antigens was observed in 38% of cases. These results point out the importance of EGFRvIII, IL-13Ralpha2 and, to a less extent gp100 and TRP-2, for developing an immunotherapy strategy against glioblastoma. PMID 17004103

[Dendritic cells and gliomas: a hope in immunotherapy?].
Jan. 2007 | Jouanneau, E; Poujol, D; Caux, C; Belin, M-F; Blay, J-Y; Puisieux, I; ,
Immunotherapy has been explored for several decades to try to improve the prognosis of gliomas, but until recently no therapeutic benefit has been achieved. The discovery of dendritic cells, the most potent professional antigen presenting cells to initiate specific immune response, and the possibility of producing them ex vivo gave rise to new protocols of active immunotherapy. In oncology, promising experimental and clinical therapeutic results were obtained using these dendritic cells loaded with tumor antigen. Patients bearing gliomas have deficit antigen presentation making this approach rational. In several experimental glioma models, independent research teams have showed specific antitumor responses using these dendritic cells. Phase I/II clinical trials have demonstrated the feasibility and the tolerance of this immunotherapeutic approach. In neuro-oncology, the efficiency of such an approach remains to be established, similarly in oncology where positive phase III studies are missing. Nevertheless, dendritic cells comprise a complex network which is only partially understood and capable of generating either immunotolerance or immune response. Numerous parameters remain to be explored before any definitive conclusion about their utility as an anticancer weapon can be drawn. It seems however logical that immunotherapy with dendritic cells could prevent or delay tumor recurrence in patients with minor active disease. A review on glioma and dendritic cells is presented. PMID 17203907

A phase II clinical study on relapsed malignant gliomas treated with electro-hyperthermia.
Jan. 2007 | Fiorentini, Giammaria; Giovanis, Petros; Rossi, Susanna; Dentico, Patrizia; Paola, Raffaele; Turrisi, Gina; Bernardeschi, Paolo
The purpose of this study was to evaluate the activity and toxicity of electro-hyperthermia (ET) on relapsed malignant glioma patients. Twelve patients with histologically diagnosed malignant glioma entered the study. Eight patients had glioblastoma multiforme, two had anaplastic astrocytoma grade III and two had anaplastic oligodendroglioma. All patients were pre-treated with temozolamide-based chemotherapy and radiotherapy. Hyperthermia with short radiofrequency waves of 13.56 MHz was applied using a capacitive coupling technique keeping the skin surface at 20 degrees C. The applied power ranged between 40-150 Watts and the calculated average equivalent temperature in the tumours was above 40 degrees C for more than 90% of the treatment duration. One complete remission and 2 partial remission were achieved, with a response rate of 25%. The median duration of response was 10 months (range 4-32). The median survival of the entire patient population was 9 months, with 25% survival rate at 1 year. ET appears to have some effectiveness in adults with relapsed malignant glioma. PMID 17203754

Neurospheres enriched in cancer stem-like cells are highly effective in eliciting a dendritic cell-mediated immune response against malignant gliomas.
Nov. 2006 | Pellegatta, Serena; Poliani, Pietro Luigi; Corno, Daniela; Menghi, Francesca; Ghielmetti, Francesco; Suarez-Merino, Blanca; Caldera, Valentina; Nava, Sara; Ravanini, Maria; Facchetti, Fabio; Bruzzone, Maria Grazia; Finocchiaro, Gaetano
Cancer stem-like cells (CSC) could be a novel target for cancer therapy, including dendritic cell (DC) immunotherapy. To address this, we developed experiments aimed at DC targeting of neurospheres (NS) from GL261 glioma cells because neurospheres can be enriched in CSC. We obtained murine neurospheres by growing GL261 cells in epidermal growth factor/basic fibroblast growth factor without serum. GL261-NS recapitulated important features of glioblastoma CSC and expressed higher levels of radial glia stem cell markers than GL261 cells growing under standard conditions (GL261 adherent cells, GL261-AC), as assessed by DNA microarray and real-time PCR. GL261-NS brain gliomas were highly infiltrating and more rapidly lethal than GL261-AC, as evidenced by survival analysis (P < 0.0001), magnetic resonance imaging and histology. DC from the bone marrow of syngeneic mice were then used for immunotherapy of GL261-NS and GL261-AC tumors. Strikingly, DC loaded with GL261-NS (DC-NS) cured 80% and 60% of GL261-AC and GL261-NS tumors, respectively (P < 0.0001), whereas DC-AC cured only 50% of GL261-AC tumors (P = 0.0022) and none of the GL261-NS tumors. GL261-NS expressed higher levels of MHC and costimulatory molecules (CD80 and CD86) than GL261-AC; the JAM assay indicated that DC-NS splenocytes had higher lytic activity than DC-AC splenocytes on both GL261-NS and GL261-AC, and immunohistochemistry showed that DC-NS vaccination was associated with robust tumor infiltration by CD8+ and CD4+ T lymphocytes. These findings suggest that DC targeting of CSC provides a higher level of protection against GL261 gliomas, a finding with potential implications for the design of clinical trials based on DC vaccination. PMID 17079441

Induction of potent antitumor immunity by intratumoral injection of interleukin 23-transduced dendritic cells.
Sep. 2006 | Hu, Jinwei; Yuan, Xiangpeng; Belladonna, Maria L; Ong, John M; Wachsmann-Hogiu, Sebastian; Farkas, Daniel L; Black, Keith L; Yu, John S
Dendritic cells (DCs) are potent antigen-presenting cells that play a critical role in priming immune responses to tumor. Interleukin (IL)-23 can act directly on DC to promote immunogenic presentation of tumor peptide in vitro. Here, we evaluated the combination of bone marrow-derived DC and IL-23 on the induction of antitumor immunity in a mouse intracranial glioma model. DCs can be transduced by an adenoviral vector coding single-chain mouse IL-23 to express high levels of bioactive IL-23. Intratumoral implantation of IL-23-expressing DCs produced a protective effect on intracranial tumor-bearing mice. The mice consequently gained systemic immunity against the same tumor rechallenge. The protective effect of IL-23-expressing DCs was comparable with or even better than that of IL-12-expressing DCs. IL-23-transduced DC (DC-IL-23) treatment resulted in robust intratumoral CD8(+) and CD4(+) T-cell infiltration and induced a specific TH1-type response to the tumor in regional lymph nodes and spleen at levels greater than those of nontransduced DCs. Moreover, splenocytes from animals treated with DC-IL-23 showed heightened levels of specific CTL activity. In vivo lymphocyte depletion experiments showed that the antitumor immunity induced by DC-IL-23 was mainly dependent on CD8(+) T cells and that CD4(+) T cells and natural killer cells were also involved. In summary, i.t. injection of DC-IL-23 resulted in significant and effective systemic antitumor immunity in intracranial tumor-bearing mice. These findings suggest a new approach to induce potent tumor-specific immunity to intracranial tumors. This approach may have therapeutic potential for treating human glioma. PMID 16951206

Enhancement of anti-tumor immunity specific to murine glioma by vaccination with tumor cell lysate-pulsed dendritic cells engineered to produce interleukin-12.
Aug. 2006 | Kim, Chang-Hyun; Hong, Min-Jung; Park, Sung-Dong; Kim, Choong-Kwon; Park, Mi-Young; Sohn, Hyun-Jung; Cho, Hyun-Il; Kim, Tai-Gyu; Hong, Yong-Kil
The aim of this study was to develop an immunotherapy specific to a malignant glioma by examining the efficacy of glioma tumor-specific cytotoxic T lymphocytes (CTL) as well as the anti-tumor immunity by vaccination with dendritic cells (DC) engineered to express murine IL-12 using adenovirus-mediated gene transfer and pulsed with a GL26 glioma cell lysate (AdVIL-12/DC+GL26) was investigated. EXPERIMENT1: For measuring CTL activity, splenocytes were harvested from the mice immunized with AdVIL-12/DC+GL26 and restimulated with syngeneic GL26 for 7 days. The frequencies of antigen-specific cytokine-secreting T cell were determined with mIFN-gamma ELISPOT. The cytotoxicity of CTL was assessed in a standard 51Cr-release assay. For the protective study in the subcutaneous tumor model, the mice were vaccinated subcutaneously (s.c) with 1x10(6) AdVIL-12/DC+GL26 in the right flanks on day -21, -14 and -7. On day 7, the mice were challenged with 1x10(6) GL26 tumor cells in the shaved left flank. For a protective study in the intracranial tumor model, the mice were vaccinated with 1x10(6) AdVIL-12/DC+GL26 s.c in the right flanks on days -21, -14 and -7. Fresh 1x10(4) GL26 cells were inoculated into the brain on day 0. To prove a therapeutic benefit in established tumors, subcutaneous or intracranial GL26 tumor-bearing mice were vaccinated s.c with 1x10(6) AdVIL-12/DC+GL26 on day 5, 12 and 19 after tumor cell inoculation. PMID 16463038

Cellular immunity of patients with malignant glioma: prerequisites for dendritic cell vaccination immunotherapy.
Juli 2006 | Rapp, Marion; Ozcan, Zakir; Steiger, Hans-Jakob; Wernet, Peter; Sabel, Michael C; Sorg, Rüdiger V
Vaccination therapy that uses dendritic cells (DCs) is a promising immunotherapeutic approach. However, it relies on intact cellular immunity and efficient generation of mature DCs, both of which can be impaired in patients with glioma. Therefore, the immune status and ex vivo generation of DC in such patients were studied. PMID 16874889

Treatment of a patient by vaccination with autologous dendritic cells pulsed with allogeneic major histocompatibility complex class I-matched tumor peptides. Case Report.
Juli 2006 | Liau, L M; Black, K L; Martin, N A; Sykes, S N; Bronstein, J M; Jouben-Steele, L; Mischel, P S; Belldegrun, A; Cloughesy, T F
Dendritic cells (DCs) are antigen-presenting cells that play a central role in the initiation and modulation of antitumor immune responses. In this pilot study, we investigated the ability of autologous DCs pulsed ex vivo with allogeneic major histocompatibility complex class I-matched glioblastoma peptides to stimulate host antitumor immune responses when injected as a vaccine. A patient with recurrent brainstem glioblastoma multiforme (GBM) received a series of three intradermal immunizations of antigen-pulsed DCs on an outpatient basis following surgical debulking of her posterior fossa tumor. Dendritic cell vaccination was well tolerated, and no clinical signs of autoimmunity or experimental allergic encephalomyelitis were detected. She developed a measurable cellular immune response against the allogeneic glioblastoma peptides used in her vaccine preparation, as demonstrated by in vitro T-cell proliferation assays. In addition, increased T-cell infiltration was noted within the intracranial tumor site in the biopsy sample obtained following DC vaccination. An objective clinical response, however, was not evident, and this patient eventually died 21 months after her disease was diagnosed. To our knowledge, this is the first patient with brain cancer ever to be treated with DC-based immunotherapy. This case illustrates that vaccination with DCs pulsed with acid-eluted glioblastoma peptides is feasible and can induce systemic antigen-specific immunity in a patient with recurrent GBM. Additional studies are necessary to determine the optimum DC doses and antigen loading conditions that may translate into clinical effectiveness and survival benefit for patients with brain tumors. Phase I trials for malignant glioma are currently underway. PMID 16817691

Dendritic cells pulsed with glioma lysates induce immunity against syngeneic intracranial gliomas and increase survival of tumor-bearing mice.
Juni 2006 | Pellegatta, S; Poliani, P L; Corno, D; Grisoli, M; Cusimano, M; Ubiali, F; Baggi, F; Bruzzone, M G; Finocchiaro, G
In recent years, the use of dendritic cells (DC), the most powerful antigen presenting cells, has been proposed for the creation of vaccines against gliomas. This approach has been demonstrated to be safe and non-toxic in phase I or I-II trials (2, 3). Immunotherapy plays a central role in the search for new treatments for glioblastoma multiforme (GBM). In particular, several phase I studies have been performed using DC pulsed by GBM proteins as a vaccine for patients with relapsing GBM. The studies demonstrated that DC vaccination is safe and may produce a significant increase in overall survival. As the first step in the preparation of appropriate conditions for a clinical evaluation in Italy, we have performed pre-clinical experiments on immune-competent mice injected intra-cerebrally with syngeneic GL261GBM cells and treated subcutaneously and intra-tumorally with DC loaded with a GL261 homogenate. These results show that vaccination with DC pulsed with a tumor lysate increases considerably survival in mice bearing intracranial glioblastomas and supports the development of DC-based clinical trials for patients with glioblastomas that do not respond to standard therapies. PMID 16808884

Sensitization of malignant glioma to chemotherapy through dendritic cell vaccination.
Apr. 2006 | Liu, Gentao; Black, Keith L; Yu, John S
Drug resistance represents a major cause of chemotherapy failure in patients with cancer. The characterization of the molecular pathways involved in drug resistance has provided new targets to circumvent or reverse chemotherapy resistance. Many of these target proteins are often overexpressed in human glioma and have been identified as tumor antigens, which implicate the development of immunotherapy as a therapeutic strategy. Dendritic cells (DCs) are the most potent antigen-presenting cells of the immune system and have been demonstrated to stimulate antibody and cell-mediated immune responses against tumor-associated antigens. Ex vivo-generated and tumor antigen-loaded DCs have been successfully introduced to clinical vaccination protocols, which have proven to be feasible and effective in some glioma patients. Most importantly, immunotherapy followed by chemotherapy could significantly increase 2-year survival in malignant glioma patients, which obviously demonstrates that DC vaccination could increase the sensitivity of tumor cells to chemotherapy. This review focuses on recent advances in the identification of tumor-associated antigen in glioma, as well as novel insights into their biological function related to drug resistance. These insights may provide the rationale for a novel strategy of a DC cancer vaccine that sensitizes tumor cells to chemotherapy. In addition, the current research status and the future direction of a DC-based vaccine to treat glioma in animal models and clinical trials will also be discussed. PMID 16608423

Novel immunotherapeutic approaches to glioma.
März 2006 | Yamanaka, Ryuya
Despite advances in radiation, chemotherapy and surgical resectioning, the prognosis of patients with malignant glioma is poor. Therefore, the development of a new treatment modality is extremely important. There are an increasing number of reports that systemic immunotherapy using dendritic cells and peptides is capable of inducing an anti-glioma response. This review highlights progress in dendritic cell- and peptide-based immunotherapy for glioma patients. Dendritic cell- and peptide-based immunotherapy strategies appear promising as an approach to successfully induce an antitumor immune response and increase survival in patients with glioma; the therapy appears to be safe and without major side effects. Biotherapy for malignant glioma with dendritic cells and peptides represents a novel treatment paradigm. PMID 16506525

Harnessing the immune system against human glioma.
Feb. 2006 | Dhodapkar, Kavita M; Banerjee, Devi; Steinman, Ralph M
Our studies are directed toward immune resistance to glial tumors, particularly in children. Initial experiments indicate that it is possible to boost both innate natural killer T lymphocytes and adaptive CD4+ and CD8+ T cells by targeting the appropriate antigens to dendritic cells. Our hypothesis is that optimal vaccination approaches against cancer will need to recruit both innate and adaptive defense mechanisms. PMID 16461784

Phase I/II trial of intravenous NDV-HUJ oncolytic virus in recurrent glioblastoma multiforme.
Dez. 2005 | Freeman, Arnold I; Zakay-Rones, Zichria; Gomori, John M; Linetsky, Eduard; Rasooly, Linda; Greenbaum, Evgeniya; Rozenman-Yair, Shira; Panet, Amos; Libson, Eugene; Irving, Charles S; Galun, Eithan; Siegal, Tali
We undertook a Phase I/II trial in patients with apparent recurrent glioblastoma multiforme (GBM) based on imaging studies to determine the safety and tumor response of repetitive intravenous administration of NDV-HUJ, the oncolytic HUJ strain of Newcastle disease virus. The first part of the study utilized an accelerated intrapatient dose-escalation protocol with one-cycle dosage steps of 0.1, 0.32, 0.93, 5.9, and 11 billion infectious units (BIU) of NDV-HUJ (1 BIU = 1 x 10(9) EID(50) 50% egg infectious dose) followed by three cycles of 55 BIU. Virus was administered by intravenous infusion over 15 min. In the second part, patients received three cycles of 11 BIU. All patients without progressive disease were maintained with two doses of 11 BIU iv weekly. Eleven of the 14 enrolled patients (11-58 years, Karnofsky performance scale 50-90%) received treatment. Toxicity was minimal with Grade I/II constitutional fever being seen in 5 patients. Maximum tolerated dose was not achieved. Anti-NDV hemagglutinin antibodies appeared within 5-29 days. NDV-HUJ was recovered from blood, saliva, and urine samples and one tumor biopsy. One patient achieved a complete response. Intravenous NDV-HUJ is well tolerated. The findings of good tolerability and encouraging responses warrant the continued evaluation of NDV-HUJ in GBM, as well as other cancers. PMID 16257582

Dendritic cells pulsed with total tumor RNA for activation NK-like T cells against glioblastoma multiforme.
Nov. 2005 | Vichchatorn, Prachya; Wongkajornsilp, Adisak; Petvises, Sawang; Tangpradabkul, Sumalee; Pakakasama, Samart; Hongeng, Suradej
Dendritic cells (DCs) are potent antigen presenting cells and play critical role in T cell-mediated immunity. DCs have been shown to induce strong anti-tumor responses both in vitro and in vivo. Their efficacies in tumor therapy are being investigated in clinical trials. Previous evidence has shown that these DCs enhance the cytotoxicity of NK cells. We generated NK-like T cells (CD3(+)CD56(+)), a novel type of effector cells differentiated from normal lymphocyte, which is now being used for adoptive immunotherapy in clinical trials. This study aimed to elucidate the effects of NK-like T cells after co-culturing with DCs against tumor cells. The result revealed that tumor-derived RNA-pulsed DCs can enhance the immune responses of NK-like T cells against glioblastoma multiforme cell line but these effector cells did not appear to have the cytotoxic effect against normal cells (human umbilical vein endothelial cells (HUVEC) and fibroblasts) in vitro. This study may be beneficial for the development of new immunologic effector cells for using in adoptive immunotherapy for glioblastoma multiforme in the future. PMID 16234988

Active immunotherapy for advanced intracranial murine tumors by using dendritic cell-tumor cell fusion vaccines.
Aug. 2005 | Kjaergaard, Jorgen; Wang, Li-Xin; Kuriyama, Hideyuki; Shu, Suyu; Plautz, Gregory E
Immunotherapy for malignant brain tumors by active immunization or adoptive transfer of tumor antigen-specific T lymphocytes has the potential to make up for some of the limitations of current clinical therapy. In this study, the authors tested whether active immunotherapy is curative in mice bearing advanced, rapidly progressive intracranial tumors. PMID 16121986

Dendritic cell vaccination in glioblastoma patients induces systemic and intracranial T-cell responses modulated by the local central nervous system tumor microenvironment.
Aug. 2005 | Liau, Linda M; Prins, Robert M; Kiertscher, Sylvia M; Odesa, Sylvia K; Kremen, Thomas J; Giovannone, Adrian J; Lin, Jia-Wei; Chute, Dennis J; Mischel, Paul S; Cloughesy, Timothy F; Roth, Michael D
We previously reported that autologous dendritic cells pulsed with acid-eluted tumor peptides can stimulate T cell-mediated antitumor immune responses against brain tumors in animal models. As a next step in vaccine development, a phase I clinical trial was established to evaluate this strategy for its feasibility, safety, and induction of systemic and intracranial T-cell responses in patients with glioblastoma multiforme. PMID 16061868

Tumor lysate and IL-18 loaded dendritic cells elicits Th1 response, tumor-specific CD8+ cytotoxic T cells in patients with malignant glioma.
Mai 2005 | Yamanaka, Ryuya; Honma, Junpei; Tsuchiya, Naoto; Yajima, Naoki; Kobayashi, Tsutomu; Tanaka, Ryuichi
In this study, we demonstrate that tumor lysate-loaded dendritic cells can elicit a specific CD8+ cytotoxic T lymphocyte response against autologous tumor cells in patients with malignant glioma. CTL from three of five patients expressed strong cytolytic activity against autologous glioma cells, did not lyse autologous lymphoblasts and were variably cytotoxic against the LAK-sensitive cell line Daudi. Also, DCs pulsed normal brain lysate failed to induce cytolytic activity against autologous glioma cells, suggesting the lack of autoimmune response. Two of five patients CD8+ T cells expressed a modest cytotoxicity against autologous glioma cells. CD8+ T cells isolated during these ineffective primings secreted large amounts of IL-10, less amounts of IFN-gamma as detected by ELISA, Type 2 bias in the CD8+ T cell response accounts for the lack of cytotoxic effector function from these patients. Cytotoxicity against autologous glioma cells could be significantly inhibited by anti-HLA class I antibody. These data demonstrate that tumor lysate-loaded DC can be an effective tool in inducing glioma-specific CD8+ CTL able to kill autologous glioma cells in vitro. However, high levels of tumor specific tolerance in some patients may account for a significant barrier to therapeutic vaccination. Moreover, cytotoxic responses were augmented by transfecting DC with the gene for IL-18. For all five patients, CD8+T cells treated with IL18 transfected DC produced Th1 response. These results may have important implications for the treatment of malignant glioma patients with immunotherapy. DCs loaded with total tumor lysate and IL-18 may represent a method for inducing Th1 immunoresponses against the entire repertoire of glioma antigens. PMID 15925989

Vaccination of glioma patients with fusions of dendritic and glioma cells and recombinant human interleukin 12.
Nov. 2004 | Kikuchi, Tetsuro; Akasaki, Yasuharu; Abe, Toshiaki; Fukuda, Takahiro; Saotome, Hideo; Ryan, John L; Kufe, Donald W; Ohno, Tsuneya
Despite aggressive treatment, the median survival of patients with high-grade malignant astrocytoma is about 1 year. The authors investigated the safety and clinical response to immunotherapy using fusions of dendritic and glioma cells combined with recombinant human interleukin 12 (rhIL-12) for the treatment of malignant glioma. Fifteen patients with malignant glioma participated in this study. Dendritic cells were generated from peripheral blood. Cultured autologous glioma cells were established from surgical specimens in each case. Fusion cells were prepared from dendritic and glioma cells using polyethylene glycol. All patients received fusion cells intradermally on day 1. rhIL-12 was injected subcutaneously at the same site on days 3 and 7. Response to the treatment was evaluated by clinical observations and radiologic findings. No serious adverse effects were observed. In four patients, magnetic resonance imaging showed a greater than 50% reduction in tumor size. One patient had a mixed response. These results show that administration of fusion cells and rhIL-12 safely induces clinical antitumor effects in some patients with malignant glioma. PMID 15534489

Surgery and adjuvant dendritic cell-based tumour vaccination for patients with relapsed malignant glioma, a feasibility study.
Okt. 2004 | Rutkowski, S; De Vleeschouwer, S; Kaempgen, E; Wolff, J E A; Kühl, J; Demaerel, P; Warmuth-Metz, M; Flamen, P; Van Calenbergh, F; Plets, C; Sörensen, N; Opitz, A; Van Gool, S W
Patients with relapsed malignant glioma have a poor prognosis. We developed a strategy of vaccination using autologous mature dendritic cells loaded with autologous tumour homogenate. In total, 12 patients with a median age of 36 years (range: 11-78) were treated. All had relapsing malignant glioma. After surgery, vaccines were given at weeks 1 and 3, and later every 4 weeks. A median of 5 (range: 2-7) vaccines was given. There were no serious adverse events except in one patient with gross residual tumour prior to vaccination, who repetitively developed vaccine-related peritumoral oedema. Minor toxicities were recorded in four out of 12 patients. In six patients with postoperative residual tumour, vaccination induced one stable disease during 8 weeks, and one partial response. Two of six patients with complete resection are in CCR for 3 years. Tumour vaccination for patients with relapsed malignant glioma is feasible and likely beneficial for patients with minimal residual tumour burden. PMID 15477864

Antitumor vaccination of patients with glioblastoma multiforme: a pilot study to assess feasibility, safety, and clinical benefit.
Okt. 2004 | Steiner, Hans Herbert; Bonsanto, Matteo Mario; Beckhove, Philipp; Brysch, Michael; Geletneky, Karsten; Ahmadi, Rezvan; Schuele-Freyer, Rebecca; Kremer, Paul; Ranaie, Golamreza; Matejic, Dejana; Bauer, Harald; Kiessling, Marika; Kunze, Stefan; Schirrmacher, Volker; Herold-Mende, Christel
Prognosis of patients with glioblastoma is poor. Therefore, in glioblastoma patients, we analyzed whether antitumor vaccination with a virus-modified autologous tumor cell vaccine is feasible and safe. Also, we determined the influence on progression-free survival and overall survival and on vaccination-induced antitumor reactivity. PMID 15452186

Clinical responsiveness of glioblastoma multiforme to chemotherapy after vaccination.
Aug. 2004 | Wheeler, Christopher J; Das, Asha; Liu, Gentao; Yu, John S; Black, Keith L
Although the development of immune-based therapies for various cancers including malignant glioma has been heralded with much hope and optimism, objective clinical improvements in most vaccinated cancer patients have not been realized. To broaden the search for vaccine-induced benefits, we examined synergy of vaccines with conventional chemotherapy. PMID 15328167

Transient local response and persistent tumor control in a child with recurrent malignant glioma: treatment with combination therapy including dendritic cell therapy. Case report.
Aug. 2004 | De Vleeschouwer, Steven; Van Calenbergh, Frank; Demaerel, Philippe; Flamen, Patrick; Rutkowski, Stefan; Kaempgen, Eckhart; Wolff, Johannes E; Plets, Christian; Sciot, Raf; Van Gool, Stefaan W
Treatment of malignant glioma is difficult and discouraging. Even after resection and maximal adjuvant therapy, the prognosis remains poor. The authors sought a novel form of treatment, such as stimulating the patient's own immune response against the tumor, and developed a protocol of tumor vaccination in which autologous dendritic cells (DCs) were used in patients with recurrent malignant glioma. A 4-year-old girl was treated by means of biopsy sampling and radiotherapy for a rolandic low-grade glioma. Ten years later, a Grade III recurrence was discovered and treated with subtotal resection, interstitial radiation, six courses of oral temozolomide, and 12 courses of oral VP 16. At the end of the chemotherapy cycle, a new rapidly growing recurrence was diagnosed. A macroscopically complete resection was performed. Afterward, the girl was vaccinated with autologous DCs that had been pulsed ex vivo with the homogenate of the resection specimen. She received six vaccines in total. The efficacy of immunization was checked by a positive delayed-type hypersensitivity skin reaction after the second injection. After the fifth vaccine, a transient contrast enhancement without mass effect was visualized on magnetic resonance imaging. Simultaneously, positron emission tomography imaging revealed a transient increase of metabolic activity around the resection cavity, but the metabolic uptake ratio remained below 1.8. The patient's disease is still in complete remission 24 months after the last surgery. She is clinically well with minor and stable left hemiparesis. This case report illustrates the potential of vaccination with DCs loaded with crude tumor homogenate as adjuvant therapy to induce prolonged tumor control of malignant glioma and the objective noninvasively monitored immune response against infiltrating tumor cells. PMID 15287461

Vaccination with tumor lysate-pulsed dendritic cells elicits antigen-specific, cytotoxic T-cells in patients with malignant glioma.
Juli 2004 | Yu, John S; Liu, Gentao; Ying, Han; Yong, William H; Black, Keith L; Wheeler, Christopher J
The primary goal of this Phase I study was to assess the safety and bioactivity of tumor lysate-pulsed dendritic cell (DC) vaccination to treat patients with glioblastoma multiforme and anaplastic astrocytoma. Adverse events, survival, and cytotoxicity against autologous tumor and tumor-associated antigens were measured. Fourteen patients were thrice vaccinated 2 weeks apart with autologous DCs pulsed with tumor lysate. Peripheral blood mononuclear cells were differentiated into phenotypically and functionally confirmed DCs. Vaccination with tumor lysate-pulsed DCs was safe, and no evidence of autoimmune disease was noted. Ten patients were tested for the development of cytotoxicity through a quantitative PCR-based assay. Six of 10 patients demonstrated robust systemic cytotoxicity as demonstrated by IFN-gamma expression by peripheral blood mononuclear cells in response to tumor lysate after vaccination. Using HLA-restricted tetramer staining, we identified a significant expansion in CD8+ antigen-specific T-cell clones against one or more of tumor-associated antigens MAGE-1, gp100, and HER-2 after DC vaccination in four of nine patients. A significant CD8+ T-cell infiltrate was noted intratumorally in three of six patients who underwent reoperation. The median survival for patients with recurrent glioblastoma multiforme in this study (n = 8) was 133 weeks. This Phase I study demonstrated the feasibility, safety, and bioactivity of an autologous tumor lysate-pulsed DC vaccine for patients with malignant glioma. We demonstrate for the first time the ability of an active immunotherapy strategy to generate antigen-specific cytotoxicity in brain tumor patients. PMID 15256471

MTH-68/H oncolytic viral treatment in human high-grade gliomas.
Apr. 2004 | Csatary, L K; Gosztonyi, G; Szeberenyi, J; Fabian, Z; Liszka, V; Bodey, B; Csatary, C M
Application of virus therapy to treat human neoplasms has over a three decade history. MTH-68/H, a live attenuated oncolytic viral strain of the Newcastle disease virus, is one of the viruses used in the treatment of different malignancies. Here we report on the administration of MTH-68/H to patients with glioblastoma multiforme, the most common and most aggressive neuroectodermal neoplasm with a poor prognosis, averaging six months to a year. Four cases of advanced high-grade glioma were treated with MTH-68/H after the conventional modalities of anti-neoplastic therapies had failed. This treatment resulted in survival rates of 5-9 years, with each patient still living today. Against all odds, each patient resumed a lifestyle that resembles their previous daily routines and enjoys a good quality of life, Each of these patients has regularly received MTH-68/H as their sole form of onco-therapy for a number of years now without interruption. PMID 15072452

Vaccination of recurrent glioma patients with tumour lysate-pulsed dendritic cells elicits immune responses: results of a clinical phase I/II trial.
Okt. 2003 | Yamanaka, R; Abe, T; Yajima, N; Tsuchiya, N; Homma, J; Kobayashi, T; Narita, M; Takahashi, M; Tanaka, R
In this Phase I/II trial, the patient's peripheral blood dendritic cells were pulsed with an autologous tumour lysate of the glioma. Seven patients with glioblastoma and three patients with anaplastic glioma, ranging in age from 20 to 69 years, participated in this study. The mean numbers of vaccinations of tumour lysate-pulsed dendritic cells were 3.7 times intradermally close to a cervical lymph node, and 3.2 times intratumorally via an Ommaya reservoir. The percentage of CD56-positive cells in the peripheral blood lymphocytes increased after immunisation. There were two minor responses and four no-change cases evaluated by radiological findings. Dendritic cell vaccination elicited T-cell-mediated antitumour activity, as evaluated by the ELISPOT assay after vaccination in two of five tested patients. Three patients showed delayed-type hypersensitivity reactivity to the autologous tumour lysate, two of these had a minor clinical response, and two had an increased ELISPOT result. Intratumoral CD4+ and CD8+ T-cell infiltration was detected in two patients who underwent reoperation after vaccination. This study demonstrated the safety and antitumour effects of autologous tumour lysate-pulsed dendritic cell therapy for patients with malignant glioma. PMID 14520441

The history, evolution, and clinical use of dendritic cell-based immunization strategies in the therapy of brain tumors.
Sep. 2003 | Fecci, Peter E; Mitchell, Duane A; Archer, Gary E; Morse, Michael A; Lyerly, H Kim; Bigner, Darell D; Sampson, John H
Despite advancements in therapeutic regimens, the prognosis remains poor for patients with malignant gliomas. Specificity has been an elusive goal for current modalities, but immunotherapy has emerged as a potential means of designing more tumor-specific treatments. Dendritic cells (DC) are the specialized antigen presenting cells of the immune system and have served now as a platform for therapeutic immunizations against such cancers as lymphoma, multiple myeloma, melanoma, prostate cancer, renal cell carcinoma, non-small cell lung carcinoma, colon cancer, and even malignant gliomas. DC-based immunizations offer a number of advantages over traditional immunotherapeutic approaches to brain tumors, approaches that have proved promising despite concerns over central nervous system immune privilege and glioma-mediated immunosuppression. The future success of clinical trials will depend on the optimization and standardizing of procedures for DC generation, loading, and administration. PMID 12952297

Human tumor cell infection by Newcastle Disease Virus leads to upregulation of HLA and cell adhesion molecules and to induction of interferons, chemokines and finally apoptosis.
Juni 2002 | Washburn, B; Schirrmacher, V
In order to analyse immune-stimulatory effects of infection of human tumor cells with Newcastle Disease Virus (NDV), gamma-irradiated human breast carcinoma, colon-carcinoma or glioblastoma cells from defined cell lines were modified either by true infection with live virus or by cell surface adsorption of UV-inactivated replication deficient virus. Modification with live but not inactive NDV induced in all human tumor cells IFN-beta and the chemokines RANTES and IFN-gamma-inducible protein-10 (IP-10). In addition, infection by live NDV induced upregulation of HLA-ABC-molecules in all tumor lines tested and HLA-DR molecules in breast carcinoma lines. Two cell adhesion molecules, ICAM-I (CD54) and LFA-3 (CD58), were also upregulated on human tumor cells after infection with live NDV. When infection of MCF-7 breast carcinoma cells by NDV was performed in the presence of neutralizing anti-IFN-beta antibodies no upregulation of HLA molecules was observed suggesting an important role of IFN-beta in this process. Forty-eight to 72 hours after infection of the irradiated tumor cells with live NDV, many tumor cells were dead or in early or late stages of apoptosis. These results provide explanations for the function of the virus-modified autologous tumor vaccine ATV-NDV with which promising clinical results have already been obtained. PMID 12063554

Preliminary results of active specific immunization with modified tumor cell vaccine in glioblastoma multiforme.
Okt. 2001 | Schneider, T; Gerhards, R; Kirches, E; Firsching, R
Treatment for glioblastoma multiforme has failed to show any progress for decades. While specific immunization with tumor cells modified with Newcastle-Disease-Virus (NDV) has been reported successful in some extracerebral tumors, its effect on glioblastoma is unknown. We report on 11 patients, in whom this approach was analyzed. PMID 11678429

Results of a phase I clinical trial of vaccination of glioma patients with fusions of dendritic and glioma cells.
Okt. 2001 | Kikuchi, T; Akasaki, Y; Irie, M; Homma, S; Abe, T; Ohno, T
Several reports of clinical trials of immunotherapy using dendritic cells have been published to date. In this study, we investigated the safety and clinical response of immunotherapy with fusions of dendritic and glioma cells for the treatment of patients with malignant glioma. Eight patients with malignant glioma, ranging in age from 4 to 63 years old, participated in this study. Dendritic cells were generated from peripheral blood. Cultured autologous glioma cells were established from surgical specimens in each case. Fusion cells of dendritic and glioma cells were prepared with polyethylene glycol, and the fusion efficiency ranged from 9.2 to 35.3% (mean, 21.9%). All patients received the fusion cells every three weeks for a minimum of 3, and a maximum of 7, immunizations. Fusion cells were injected intradermally, close to a cervical lymph node. The percentage of CD16- and CD56-positive cells in peripheral blood lymphocytes slightly increased after immunization in 4 out of 5 cases investigated. Peripheral blood mononuclear cells were incubated with irradiated autologous glioma or U87MG cells and supernatants were harvested. In 6 cases analyzed, the concentration of interferon-gamma in the supernatant increased after immunization. Clinical results showed that there were no serious adverse effects and two partial responses. Although the results of the phase I clinical trial of fusion cells indicated that this treatment safely induced immune responses. we were unable to establish a statistically significant treatment-associated response rate, due to the limited sample population. Therefore, further evaluation of the role of adjuvant cytokines is necessary. PMID 11676393

Vaccination of malignant glioma patients with peptide-pulsed dendritic cells elicits systemic cytotoxicity and intracranial T-cell infiltration.
Feb. 2001 | Yu, J S; Wheeler, C J; Zeltzer, P M; Ying, H; Finger, D N; Lee, P K; Yong, W H; Incardona, F; Thompson, R C; Riedinger, M S; Zhang, W; Prins, R M; Black, K L
In this Phase I trial, patients' peripheral blood dendritic cells were pulsed with peptides eluted from the surface of autologous glioma cells. Three biweekly intradermal vaccinations of peptide-pulsed dendritic cells were administered to seven patients with glioblastoma multiforme and two patients with anaplastic astrocytoma. Dendritic cell vaccination elicited systemic cytotoxicity in four of seven tested patients. Robust intratumoral cytotoxic and memory T-cell infiltration was detected in two of four patients who underwent reoperation after vaccination. This Phase I study demonstrated the feasibility, safety, and bioactivity of an autologous peptide-pulsed dendritic cell vaccine for patients with malignant glioma. PMID 11221866

Treatment of malignant gliomas with interstitial irradiation and hyperthermia.
Dez. 1992 | Stea, B; Kittelson, J; Cassady, J R; Hamilton, A; Guthkelch, N; Lulu, B; Obbens, E; Rossman, K; Shapiro, W; Shetter, A
A Phase I study of interstitial thermoradiotherapy for high-grade supratentorial gliomas has been completed. The objective of this trial was to test the feasibility and toxicity of hyperthermia induced by ferromagnetic implants in the treatment of intracranial tumors. The patient population consisted of 16 males and 12 females, with a median age of 44 years and a median Karnofsky score of 90. Nine patients had anaplastic astrocytoma while 19 had glioblastoma multiforme. Twenty two patients were treated at the time of their initial diagnosis with a course of external beam radiotherapy (median dose 48.4 Gy) followed by an interstitial implant with Ir-192 (median dose 32.7 Gy). Six patients with recurrent tumors received only an interstitial implant (median dose 40 Gy). Median implant volume for all patients was 55.8 cc and median number of treatment catheters implanted per tumor was eighteen. A 60-minute hyperthermia treatment was given through these catheters just before and right after completion of brachytherapy. Time-averaged temperatures of all treatments were computed for sensors located within the core of (> 5 mm from edge of implant), and at the periphery of the implant (outer 5 mm). The percentage of sensors achieving an average temperature > 42 degrees C was 61% and 35%, respectively. Hyperthermia was generally well tolerated; however, there have been 11 minor toxicities, which resolved with conservative management, and one episode of massive edema resulting in the death of a patient. In addition, there were three major complications associated with the surgical implantation of the catheters. Preliminary survival analysis shows that 16 of the 28 patients have died, with a median survival of 20.6 months from diagnosis. We conclude that interstitial hyperthermia of brain tumors with ferromagnetic implants is feasible and carries significant but acceptable morbidity given the extremely poor prognosis of this patient population. PMID 1429088

[Radiofrequency hyperthermia in malignant brain tumors: clinical trials].
Juli 1988 | Tanaka, R
Local hyperthermia using 13.56-MHz radiofrequency (RF) capacitive heating was evaluated in 19 patients with malignant brain tumor. Intraoperative heating was performed in 4 patients. RF applicators were placed on the cerebral convexity and medial surface with the tumor between them. RF power was controlled so as to maintain the brain temperature below 40 degrees C. Under these conditions, the highest temperature of each tumor varied from 44 to 52 degrees C. After heating alone for about 60 min, 3 tumors showed regression on CT scan. Extracranial heating was performed in 15 patients with cerebral glioblastoma. RF applicators were placed on the scalp and applied to diametrically opposite sides of the tumor after bilateral craniectomy not smaller than the size of the applicator. The heating was performed for about 60 min at each session and repeated twice a week for a total of 4 to 10 times in combination with radiation and ACNU-chemotherapy. The brain temperatures were maintained below 42 degrees C. The highest temperatures of the tumor varied from 42 to 46 degrees C. Seven of 13 evaluable tumors on CT scan showed regression after the treatment. Low-density lesions appeared transiently in the brains of 2 patients, located in the RF field. In conclusion, RF capacitive heating can be applied to human malignant cerebral tumors. PMID 3289497

[Local hyperthermia of malignant brain tumors].
Aug. 1987 | Heppner, F; Schuy, S; Ascher, P W; Holzer, P; Wiesspeiner, G
In glioblastoma multiforme and high-grade astrocytomas the following procedure has been implemented to try and prevent recurrence: after extirpation of the tumour its bed is lined with metal powder and the patient's head is exposed to a high-frequency magnetic field every 4 weeks. As a result the temperature is raised by induction to +45 degrees C at the boundary between metal and brain tissue. This ought to be sufficient to prevent tumour recurrence. Varied results were achieved using this technique in 103 patients. PMID 3039746

Combination radiofrequency hyperthermia and chemotherapy (BCNU) for brain malignancy. Animal experience and two case reports.
Okt. 1984 | Silberman, A W; Morgan, D F; Storm, F K; Rand, R W; Benz, M; Drury, B; Morton, D L
Patients with high-grade primary and metastatic brain malignancies have a median survival time of 3-8 months, regardless of therapy. Because MagnetrodeTM hyperthermia provides safe, deep internal heating without normal-tissue injury, we studied its effects first on the brain and surrounding tissues of rabbits. The normal rabbit brain (n = 26) could be heated to potentially tumoricidal temperatures (42-43 degrees C) without apparent histopathologic or clinical damage to the brain, skull, external eye, subcutaneous tissue or skin. Intracranial pressure did not rise significantly. Using transplanted VX-2 carcinoma, we showed both the safety and potential efficacy of thermochemotherapy (IV BCNU: 14 mg/kg) in the presence of a solid brain tumor. The average maximum brain temperature achieved was 43.06 degrees C. Mean survival from the time of tumor implantation in the treated group (n = 16) was 18.56 days, compared to 9.3 days for untreated controls (n = 30) (p less than .0001). Two patients have been treated with localized brain hyperthermia combined with intravenous BCNU (80 mg/m2) for a total of eight treatments. Maximum normal brain temperature achieved was 40.0 degrees C in Patient #1 and 41.5 degrees C in Patient #2. A tumor temperature of 42.9 degrees C was achieved in Patient #2. Intracranial pressure remained within the upper limits of normal. Swan-Ganz monitoring in Patient #1 revealed a stable cardiac index and mean pulmonary artery pressure with mild fluctuations in the CVP, PAD, and PCW. No increase in chemotherapy toxicity was observed and no normal tissue injury occurred in either patient. We conclude that non-invasive localized radiofrequency hyperthermia to the brain is feasible and can be performed safely in the presence of a solid brain tumor. PMID 6470758

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