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A novel allogeneic off-the-shelf dendritic cell vaccine for post-remission treatment of elderly patients with acute myeloid leukemia.
Juli 2018 | van de Loosdrecht, Arjan A; van Wetering, Sandra; Santegoets, Saskia J A M; Singh, Satwinder Kaur; Eeltink, Corien M; den Hartog, Yvonne; Koppes, Malika; Kaspers, Jorn; Ossenkoppele, Gert J; Kruisbeek, Ada M; de Gruijl, Tanja D
In elderly acute myeloid leukemia (AML) patients post-remission treatment options are associated with high comorbidity rates and poor survival. Dendritic cell (DC)-based immunotherapy is a promising alternative treatment strategy. A novel allogeneic DC vaccine, DCP-001, was developed from an AML-derived cell line that uniquely combines the positive features of allogeneic DC vaccines and expression of multi-leukemia-associated antigens. Here, we present data from a phase I study conducted with DCP-001 in 12 advanced-stage elderly AML patients. Patients enrolled were in complete remission (CR1/CR2) (n = 5) or had smoldering disease (n = 7). All patients were at high risk of relapse and ineligible for post-remission intensification therapies. A standard 3 + 3 dose escalation design with extension to six patients in the highest dose was performed. Patients received four biweekly intradermal DCP-001 injections at different dose levels (10, 25, and 50 million cells DCP-001) and were monitored for clinical and immunological responses. Primary objectives of the study (feasibility and safety) were achieved with 10/12 patients completing the vaccination program. Treatment was well tolerated. A clear-cut distinction between patients with and without detectable circulating leukemic blasts during the vaccination period was noted. Patients with no circulating blasts showed an unusually prolonged survival [median overall survival 36 months (range 7-63) from the start of vaccination] whereas patients with circulating blasts, died within 6 months. Long-term survival was correlated with maintained T cell levels and induction of multi-functional immune responses. It is concluded that DCP-001 in elderly AML patients is safe, feasible and generates both cellular and humoral immune responses. PMID 30039426

Recent developments in immunotherapy of acute myeloid leukemia.
Apr. 2018 | Lichtenegger, Felix S; Krupka, Christina; Haubner, Sascha; Köhnke, Thomas; Subklewe, Marion
The advent of new immunotherapeutic agents in clinical practice has revolutionized cancer treatment in the past decade, both in oncology and hematology. The transfer of the immunotherapeutic concepts to the treatment of acute myeloid leukemia (AML) is hampered by various characteristics of the disease, including non-leukemia-restricted target antigen expression profile, low endogenous immune responses, and intrinsic resistance mechanisms of the leukemic blasts against immune responses. However, considerable progress has been made in this field in the past few years.Within this manuscript, we review the recent developments and the current status of the five currently most prominent immunotherapeutic concepts: (1) antibody-drug conjugates, (2) T cell-recruiting antibody constructs, (3) chimeric antigen receptor (CAR) T cells, (4) checkpoint inhibitors, and (5) dendritic cell vaccination. We focus on the clinical data that has been published so far, both for newly diagnosed and refractory/relapsed AML, but omitting immunotherapeutic concepts in conjunction with hematopoietic stem cell transplantation. Besides, we have included important clinical trials that are currently running or have recently been completed but are still lacking full publication of their results.While each of the concepts has its particular merits and inherent problems, the field of immunotherapy of AML seems to have taken some significant steps forward. Results of currently running trials will reveal the direction of further development including approaches combining two or more of these concepts. PMID 28743264

Anti-cancer vaccine therapy for hematologic malignancies: An evolving era.
Feb. 2018 | Nahas, Myrna R; Rosenblatt, Jacalyn; Lazarus, Hillard M; Avigan, David
The potential promise of therapeutic vaccination as effective therapy for hematologic malignancies is supported by the observation that allogeneic hematopoietic cell transplantation is curative for a subset of patients due to the graft-versus-tumor effect mediated by alloreactive lymphocytes. Tumor vaccines are being explored as a therapeutic strategy to re-educate host immunity to recognize and target malignant cells through the activation and expansion of effector cell populations. Via several mechanisms, tumor cells induce T cell dysfunction and senescence, amplifying and maintaining tumor cell immunosuppressive effects, resulting in failure of clinical trials of tumor vaccines and adoptive T cell therapies. The fundamental premise of successful vaccine design involves the introduction of tumor-associated antigens in the context of effective antigen presentation so that tolerance can be reversed and a productive response can be generated. With the increasing understanding of the role of both the tumor and tumor microenvironment in fostering immune tolerance, vaccine therapy is being explored in the context of immunomodulatory therapies. The most effective strategy may be to use combination therapies such as anti-cancer vaccines with checkpoint blockade to target critical aspects of this environment in an effort to prevent the re-establishment of tumor tolerance while limiting toxicity associated with autoimmunity. PMID 29475779

Efficacy of intracellular immune checkpoint-silenced DC vaccine.
Feb. 2018 | Wang, Danhong; Huang, Xue F; Hong, Bangxing; Song, Xiao-Tong; Hu, Liangding; Jiang, Min; Zhang, Bin; Ning, Hongmei; Li, Yuhang; Xu, Chen; Lou, Xiao; Li, Botao; Yu, Zhiyong; Hu, Jiangwei; Chen, Jianlin; Yang, Fan; Gao, Haiyan; Ding, Guoliang; Liao, Lianming; Rollins, Lisa; Jones, Lindsey; Chen, Si-Yi; Chen, Hu
DC-based tumor vaccines have had limited clinical success thus far. SOCS1, a key inhibitor of inflammatory cytokine signaling, is an immune checkpoint regulator that limits DC immunopotency. PMID 29415891

Dendritic cell vaccination as postremission treatment to prevent or delay relapse in acute myeloid leukemia.
Okt. 2017 | Anguille, Sébastien; Van de Velde, Ann L; Smits, Evelien L; Van Tendeloo, Viggo F; Juliusson, Gunnar; Cools, Nathalie; Nijs, Griet; Stein, Barbara; Lion, Eva; Van Driessche, Ann; Vandenbosch, Irma; Verlinden, Anke; Gadisseur, Alain P; Schroyens, Wilfried A; Muylle, Ludo; Vermeulen, Katrien; Maes, Marie-Berthe; Deiteren, Kathleen; Malfait, Ronald; Gostick, Emma; Lammens, Martin; Couttenye, Marie M; Jorens, Philippe; Goossens, Herman; Price, David A; Ladell, Kristin; Oka, Yoshihiro; Fujiki, Fumihiro; Oji, Yusuke; Sugiyama, Haruo; Berneman, Zwi N
Relapse is a major problem in acute myeloid leukemia (AML) and adversely affects survival. In this phase 2 study, we investigated the effect of vaccination with dendritic cells (DCs) electroporated with Wilms' tumor 1 () messenger RNA (mRNA) as postremission treatment in 30 patients with AML at very high risk of relapse. There was a demonstrable antileukemic response in 13 patients. Nine patients achieved molecular remission as demonstrated by normalization of transcript levels, 5 of which were sustained after a median follow-up of 109.4 months. Disease stabilization was achieved in 4 other patients. Five-year overall survival (OS) was higher in responders than in nonresponders (53.8% vs 25.0%; = .01). In patients receiving DCs in first complete remission (CR1), there was a vaccine-induced relapse reduction rate of 25%, and 5-year relapse-free survival was higher in responders than in nonresponders (50% vs 7.7%; < .0001). In patients age ≤65 and >65 years who received DCs in CR1, 5-year OS was 69.2% and 30.8% respectively, as compared with 51.7% and 18% in the Swedish Acute Leukemia Registry. Long-term clinical response was correlated with increased circulating frequencies of polyepitope WT1-specific CD8 T cells. Long-term OS was correlated with interferon-γ and tumor necrosis factor-α WT1-specific responses in delayed-type hypersensitivity-infiltrating CD8 T lymphocytes. In conclusion, vaccination of patients with AML with mRNA-electroporated DCs can be an effective strategy to prevent or delay relapse after standard chemotherapy, translating into improved OS rates, which are correlated with the induction of WT1-specific CD8 T-cell response. This trial was registered at as #NCT00965224. PMID 28830889

Hyperthermia enhances bortezomib-induced apoptosis in human white blood cancer cells.
Mai 2017 | Saliev, Timur; Feril, Loreto B; Begimbetova, Dinara; Baiskhanova, Dinara; Klodzinskyi, Anton; Bobrova, Xeniya; Aipov, Rassulbek; Baltabayeva, Tolkyn; Tachibana, Katsuro
At present, the current therapeutic strategy for apoptosis induction mainly relies on the administration of pharmacological apoptotic modulators. Apart from that, apoptosis can be induced by various external stimuli such as hyperthermia, ionizing radiation, and electric fields. Despite advantages, both physical and pharmacological approaches bear some limitations as well. The rationale of this study was to overcome the limitations by combining hyperthermia and apoptotic modulator 'bortezomib' (Velcade). Two types of human blood cancer cell lines were utilized: human leukemic monocyte lymphoma cell U937 line and peripheral blood mononuclear cells (PMBCs) derived from the patient diagnosed with acute myeloid leukemia. Prior to apoptosis experiments, cytotoxicity tests were performed at three types of temperature regimes (40°, 42° and 44°C). We observed a gradual inhibition of cell viability correlating with an increase of temperature and drug concentration in both cell lines. However, there was no significant difference between sham group and groups of leukemic PMBCs treated by high temperature (44°C) and bortezomib. In U937 cells, combined treatment by heat shock and bortezomib led to an increase the number of cells underwent the late apoptosis stage. At the same time, similar treatment of PMBCs resulted in the stimulation of early apoptosis. Our data suggest that combination of bortezomib and hyperthermia enhances apoptosis induction in human cancer white blood cells, indicating a therapeutic potential for blood cancer therapy. PMID 28558940

Immune responses and long-term disease recurrence status after telomerase-based dendritic cell immunotherapy in patients with acute myeloid leukemia.
Apr. 2017 | Khoury, Hanna J; Collins, Robert H; Blum, William; Stiff, Patrick S; Elias, Laurence; Lebkowski, Jane S; Reddy, Anita; Nishimoto, Kevin P; Sen, Debasish; Wirth, Edward D; Case, Casey C; DiPersio, John F
Telomerase activity in leukemic blasts frequently is increased among patients with high-risk acute myeloid leukemia (AML). In the current study, the authors evaluated the feasibility, safety, immunogenicity, and therapeutic potential of human telomerase reverse transcriptase (hTERT)-expressing autologous dendritic cells (hTERT-DCs) in adult patients with AML. PMID 28411378

Individualized vaccination of AML patients in remission is associated with induction of antileukemia immunity and prolonged remissions.
Dez. 2016 | Rosenblatt, Jacalyn; Stone, Richard M; Uhl, Lynne; Neuberg, Donna; Joyce, Robin; Levine, James D; Arnason, Jon; McMasters, Malgorzata; Luptakova, Katarina; Jain, Salvia; Zwicker, Jeffrey I; Hamdan, Ayad; Boussiotis, Vassiliki; Steensma, David P; DeAngelo, Daniel J; Galinsky, Ilene; Dutt, Poorvi Somaiya; Logan, Emma; Bryant, Mary Paty; Stroopinsky, Dina; Werner, Lillian; Palmer, Kristen; Coll, Max; Washington, Abigail; Cole, Leandra; Kufe, Donald; Avigan, David
We developed a personalized cancer vaccine in which patient-derived acute myeloid leukemia (AML) cells are fused with autologous dendritic cells, generating a hybridoma that potently stimulates broad antitumor responses. We report results obtained from the first 17 AML patients, who achieved remission after chemotherapy and were then serially vaccinated to target minimal residual disease and prevent relapse. Vaccination was well tolerated and induced inflammatory responses at the site of administration, characterized by the dense infiltration of T cells. Vaccination was also associated with a marked rise in circulating T cells recognizing whole AML cells and leukemia-specific antigens that persisted for more than 6 months. Twelve of 17 vaccinated patients (71%; 90% confidence interval, 52 to 89%) remain alive without recurrence at a median follow-up of 57 months. The results demonstrate that personalized vaccination of AML patients in remission induces the expansion of leukemia-specific T cells and may be protective against disease relapse. PMID 27928025

Induction of Immune Response after Allogeneic Wilms' Tumor 1 Dendritic Cell Vaccination and Donor Lymphocyte Infusion in Patients with Hematologic Malignancies and Post-Transplantation Relapse.
Sep. 2016 | Shah, Nirali N; Loeb, David M; Khuu, Hahn; Stroncek, David; Ariyo, Tolu; Raffeld, Mark; Delbrook, Cindy; Mackall, Crystal L; Wayne, Alan S; Fry, Terry J
Relapse of hematologic malignancies is the primary cause of treatment failure after allogeneic hematopoietic stem cell transplantation (HCT). Treatment for post-HCT relapse using donor lymphocyte infusion (DLI) has limited utility, particularly in the setting of acute leukemia, and can result in the development of graft-versus-host disease (GVHD). The Wilms' tumor 1 (WT1) gene product is a tumor-associated antigen that is expressed in acute leukemia and other hematologic malignancies, with limited expression in normal tissues. In this pilot trial, we assessed safety and feasibility of a WT1 peptide-loaded donor-derived dendritic cell (DC) vaccine given with DLI designed to enhance and direct the graft-versus-leukemia effect. Secondary objectives were to evaluate immunologic and clinical responses. A total of 5 subjects, median age 17 years (range, 9 to 19 years), with post-HCT relapse were enrolled. Disease subtypes included acute lymphoblastic leukemia (n = 3), acute myelogenous leukemia (n = 1), and Hodgkin lymphoma (n = 1). Successful vaccine production was feasible from all donors. DC vaccination and DLI were well tolerated. One recipient developed grade 1 skin GVHD not requiring systemic therapy. The most common adverse events included grade 1 reversible pain and pruritus at the vaccine injection and delayed-type hypersensitivity (DTH) skin testing sites. There were no grade 3 or higher adverse events related to the research. Immune responses consisted of ELISpot response in 3 recipients and positive DTH tests to WT1 peptide cocktail in 2 subjects. Our study provides 1 of the first attempts to apply tumor-specific vaccine therapy to the allogeneic setting. Preliminary results show the DC-based vaccination is safe and feasible after allogeneic HCT, with a suggestion that this approach can be used to sensitize the repopulated allogeneic-donor immune system to WT1. Future directions may include testing of vaccination strategies in the early post-transplantation setting for relapse prevention. PMID 27634018

Progress of dendritic cell-based cancer vaccines for patients with hematological malignancies.
Juni 2016 | Ni, Ming; Hoffmann, Jean-Marc; Schmitt, Michael; Schmitt, Anita
Dendritic cells (DCs) are the most professional antigen-presenting cells eliciting cellular and humoral immune responses against cancer cells by expressing these antigens on MHC class I/II complexes to T cells. Therefore, they have been employed in many clinical trials as cancer vaccines for patients with cancer. This review focuses on the use of DCs in leukemia patients expressing leukemia-associated antigens (LAAs). PMID 27238400

Clinical outcomes of a novel therapeutic vaccine with Tax peptide-pulsed dendritic cells for adult T cell leukaemia/lymphoma in a pilot study.
Apr. 2015 | Suehiro, Youko; Hasegawa, Atsuhiko; Iino, Tadafumi; Sasada, Amane; Watanabe, Nobukazu; Matsuoka, Masao; Takamori, Ayako; Tanosaki, Ryuji; Utsunomiya, Atae; Choi, Ilseung; Fukuda, Tetsuya; Miura, Osamu; Takaishi, Shigeo; Teshima, Takanori; Akashi, Koichi; Kannagi, Mari; Uike, Naokuni; Okamura, Jun
Adult T cell leukaemia/lymphoma (ATL) is a human T cell leukaemia virus type-I (HTLV-I)-infected T cell malignancy with poor prognosis. We herein developed a novel therapeutic vaccine designed to augment an HTLV-I Tax-specific cytotoxic T lymphocyte (CTL) response that has been implicated in anti-ATL effects, and conducted a pilot study to investigate its safety and efficacy. Three previously treated ATL patients, classified as intermediate- to high-risk, were subcutaneously administered with the vaccine, consisting of autologous dendritic cells (DCs) pulsed with Tax peptides corresponding to the CTL epitopes. In all patients, the performance status improved after vaccination without severe adverse events, and Tax-specific CTL responses were observed with peaks at 16-20 weeks. Two patients achieved partial remission in the first 8 weeks, one of whom later achieved complete remission, maintaining their remission status without any additional chemotherapy 24 and 19 months after vaccination, respectively. The third patient, whose tumour cells lacked the ability to express Tax at biopsy, obtained stable disease in the first 8 weeks and later developed slowly progressive disease although additional therapy was not required for 14 months. The clinical outcomes of this pilot study indicate that the Tax peptide-pulsed DC vaccine is a safe and promising immunotherapy for ATL. PMID 25612920

Clinical trials of dendritic cell-based cancer vaccines in hematologic malignancies.
Jan. 2015 | Pyzer, Athalia R; Avigan, David E; Rosenblatt, Jacalyn
The potential for the immune system to target hematological malignancies is demonstrated in the allogeneic transplant setting, where durable responses can be achieved. However, allogeneic transplantation is associated with significant morbidity and mortality related to graft versus host disease. Cancer immunotherapy has the capacity to direct a specific cytotoxic immune response against cancer cells, particularly residual cancer cells, in order to reduce the likelihood of disease relapse in a more targeted and tolerated manner. Ex vivo dendritic cells can be primed in various ways to present tumor associated antigen to the immune system, in the context of co-stimulatory molecules, eliciting a tumor specific cytotoxic response in patients. Several approaches to prime dendritic cells and overcome the immunosuppressive microenvironment have been evaluated in pre-clinical and early clinical trials with promising results. In this review, we summarize the clinical data evaluating dendritic cell based vaccines for the treatment of hematological malignancies. PMID 25625926

[Dendritic cell-based therapeutic vaccination for acute myeloid leukemia].
Juni 2012 | Anguille, Sébastien; Van Tendeloo, Vigor; Berneman, Zwi
The long-term outlook for adult patients with acute myeloid leukemia (AML) remains dismal. The main reason for this state of affairs lies in the fact that the majority of AML patients will eventually relapse, even after obtaining complete remission following front-line chemotherapy. Relapses are generally attributed to the persistence of a small number of chemotherapy-resistant leukemic (stem) cells, a condition known as minimal residual disease (MRD). The eradication of MRD, with the eventual aim of reducing the risk of relapse, therefore represents a high-priority goal of modern AML therapy. It is now well established that the immune system plays a crucial role in the defense against AML. This knowledge has fuelled the development of immune-based approaches to control MRD and, ultimately, to prevent relapse. One of the promising strategies that have emerged in this regard involves the use of dendritic cells for therapeutic vaccination. This review article aims to introduce the reader into the conceptual and practical aspects of DC-based vaccination for AML. Next, we will review the first clinical results obtained with this immunotherapeutic approach in AML patients. Finally, we will briefly reflect on the potential place of DC vaccination in the future therapy of AML. PMID 22641288

Anti-leukemic activity of Newcastle disease virus strains AF2240 and V4-UPM in murine myelomonocytic leukemia in vivo.
März 2012 | Alabsi, Aied M; Ali, Rola; Ideris, Aini; Omar, Abdul Rahman; Bejo, Mohd Hair; Yusoff, Khatijah; Ali, Abdul Manaf
Newcastle disease virus (NDV) is a member of the Paramyxoviridae that has caused severe economic losses in poultry industry worldwide. Several strains of NDV were reported to induce cytolysis to cancerous cell lines. It has prompted much interest as anticancer agent because it can replicate up to 10,000 times better in human cancer cells than in most normal cells. In this study, two NDV strains, viserotropic-velogenic strain AF2240 and lentogenic strain V4-UPM, showed cytolytic activity and apoptosis induction against Mouse myelomoncytic leukemia (WEHI 3B). The cytolytic effects of NDV strains were determined using microtetrazolium (MTT) assay. The cytolytic dose - fifty percent (CD(50)) were 2 and 8HAU for AF2240 and V4-UPM strains, respectively. Cells treated with NDV strains showed apoptotic features compared to the untreated cells under fluorescence microscope. NDV induced activation of caspase-3 and DNA laddering in agarose gel electrophoresis which confirmed the apoptosis. The anti-leukemic activity of both strains was evaluated on myelomoncytic leukemia BALB/c mice. The results indicated that both NDV strains significantly decreased liver and spleen weights. It also decreased blasts cell percentage in blood, bone marrow and spleen smears of treated mice (p<0.05). Histopathological studies for spleen and liver confirmed the hematological results of blood and bone marrow. From the results obtained, the exposure to both NDV stains AF2240 and V4-UPM showed similar results for Ara-c. In conclusion NDV strains AF2240 and V4-UPM can affect WEHI 3B leukemia cells in vitro and in vivo. PMID 22133641

Pulsing with blast cell lysate or blast-derived total RNA reverses the dendritic cell-mediated cytotoxic activity of cytokine-induced killer cells against allogeneic acute myelogenous leukemia cells.
Aug. 2011 | Schöttker, Björn; Schmidt-Wolf, Ingo G H
Immunotherapeutic strategies may be a treatment option in patients with refractory acute myelogenous leukemia (AML) or, in cases of complete remission after conventional therapy regimens, may help to reduce disease recurrence or delay time to progression. Evidence suggests a key role of dendritic cells (DCs) in cancer immunotherapy due to their capacity to present tumour antigens to effector cells. We generated cytokine-induced killer (CIK) cells from healthy donors and examined their responses in vitro in an LDH release assay against three cell lines and allogeneic HLA non-matched blasts from three patients with de novo AML after coincubation with autologous peripheral blood monocyte-derived DCs. Although DCs were unable to enhance CIK cell effects against all three cell lines tested, the cytotoxic activity against the patients' AML cells increased after coculture with mature DCs, which was significant in two of three patients. However, neither prior pulsing of the DCs with blast cell lysates nor with leukemic cell-derived total RNA further enhanced the lytic capacity of the CIK cells. On the contrary, pulsing reduced or even reversed the cytotoxic activity of the effector cells. This decrease of allogeneic cytotoxicity led us to conclude that monocyte-derived DCs may be useful in autologous or allogeneic vaccine strategies for the treatment of AML or in priming donor lymphocytes in vitro, but unfractionated antigens as pulsing agents may have inhibitory effects on T cell efficiency and their employment in immunotherapeutic strategies for AML seems questionable. PMID 21863132

[Roles of Newcastle disease virus in human acute monocytic leukemia in vitro and in vivo].
Feb. 2011 | Wang, Ya-Jun; Song, Chun; Li, Xiao-Hui; Zhang, Jian-Bai
Some research has shown that Newcastle disease virus (NDV) is effective in the treatment of various tumors, including transferred melanoma and well differentiated renal cell carcinoma. This study aimed to evaluate the effect of NDV against human acute monocytic leukemia SHI-1 cells in vitro and in vivo. PMID 21342628

Induction of complete and molecular remissions in acute myeloid leukemia by Wilms' tumor 1 antigen-targeted dendritic cell vaccination.
Aug. 2010 | Van Tendeloo, Viggo F; Van de Velde, Ann; Van Driessche, Ann; Cools, Nathalie; Anguille, Sébastien; Ladell, Kristin; Gostick, Emma; Vermeulen, Katrien; Pieters, Katrien; Nijs, Griet; Stein, Barbara; Smits, Evelien L; Schroyens, Wilfried A; Gadisseur, Alain P; Vrelust, Inge; Jorens, Philippe G; Goossens, Herman; de Vries, I Jolanda; Price, David A; Oji, Yusuke; Oka, Yoshihiro; Sugiyama, Haruo; Berneman, Zwi N
Active immunization using tumor antigen-loaded dendritic cells holds promise for the adjuvant treatment of cancer to eradicate or control residual disease, but so far, most dendritic cell trials have been performed in end-stage cancer patients with high tumor loads. Here, in a phase I/II trial, we investigated the effect of autologous dendritic cell vaccination in 10 patients with acute myeloid leukemia (AML). The Wilms' tumor 1 protein (WT1), a nearly universal tumor antigen, was chosen as an immunotherapeutic target because of its established role in leukemogenesis and superior immunogenic characteristics. Two patients in partial remission after chemotherapy were brought into complete remission after intradermal administration of full-length WT1 mRNA-electroporated dendritic cells. In these two patients and three other patients who were in complete remission, the AML-associated tumor marker returned to normal after dendritic cell vaccination, compatible with the induction of molecular remission. Clinical responses were correlated with vaccine-associated increases in WT1-specific CD8+ T cell frequencies, as detected by peptide/HLA-A*0201 tetramer staining, and elevated levels of activated natural killer cells postvaccination. Furthermore, vaccinated patients showed increased levels of WT1-specific IFN-gamma-producing CD8+ T cells and features of general immune activation. These data support the further development of vaccination with WT1 mRNA-loaded dendritic cells as a postremission treatment to prevent full relapse in AML patients. PMID 20631300

Dramatic efficacy improvement of a DC-based vaccine against AML by CD25 T cell depletion allowing the induction of a long-lasting T cell response.
Juli 2009 | Delluc, Stéphanie; Hachem, Patricia; Rusakiewicz, Sylvie; Gaston, Auguste; Marchiol-Fournigault, Carmen; Tourneur, Lea; Babchia, Narjes; Fradelizi, Didier; Regnault, Armelle; Sang, Kim Hanh Le Quan; Chiocchia, Gilles; Buzyn, Agnès
Dendritic cell (DC)-based vaccination is a promising approach to enhance anti-tumor immunity that could be considered for acute myeloid leukemia (AML) patients with high-risk of relapse. Our purpose was to study the efficiency and to optimize the immunogenicity of a DC-based vaccine in a preclinical AML murine model. In this report, C57BL6 mice were vaccinated with DC pulsed with peptides eluted (EP) from the syngeneic C1498 myelomonocytic leukemic cell line in a prophylactic setting. In this model, a natural antileukemic immunity mediated by NK cells was observed in the control unloaded DC-vaccinated group. On the other hand, we showed that the cytotoxic antileukemic immune response induced by vaccination with eluted peptides pulsed-DC (DC/EP), in vitro and in vivo, was mainly mediated by CD4(+) T cells. Treatment with anti-CD25 antibody to deplete CD4(+) CD25(+) regulatory T cells before DC-vaccination dramatically improved the antileukemic immune response induced by immunization, and allowed the development of long-lasting immune responses that were tumor protective after a re-challenge with leukemic cells. Our results suggest that this approach could be successful against weakly immunogenic tumors such as AML, and could be translated in human. PMID 19225777

The efficient generation of immunocompetent dendritic cells from leukemic blasts in acute myeloid leukemia: a local experience.
Mai 2009 | Bagheri, Kambiz; Alimoghadam, Kamran; Pourfathollah, Ali Akbar; Hassan, Zuhair Muhammad; Hajati, Jamshid; Moazzeni, Seyyed Mohammad
Dendritic cells (DCs) are the most important antigen presenting cells with potentially useful applications in cancer immunotherapy. Leukemic cells of patients with acute myeloid leukemia (AML) could be differentiated to DC-like cells possessing the ability of stimulating anti-leukemic immune response. Despite obvious progress in DC-based immunotherapy, some discrepancies were reported in differentiation potential of AML blasts from all patients toward DC like cells. The present study, as a local experience, was set up to generate DCs from AML blasts of various subtypes. Leukemic Blasts from 16 Iranian AML patients were differentiated into functional DCs by culturing in the presence of rhGM-CSF, rhIL-4 and TNF-alpha for 8 days. The morphology, expression of key surface molecules and allostimulatory activity of resultant DCs were compared with primary blasts and cultured but cytokine untreated control groups. The pattern of angiotensin-converting enzyme (ACE) expression was used to approve the leukemic origin of generated DCs. Neo-expression or upregulation of DC-associated markers were occurred during culturing period in cytokine treated cells compared with primary blasts and cultured but cytokine untreated control groups: CD1a (63.22% vs. 3.22% and 11.79%), CD83 (41.27% vs. 0.11% and 0.70%), CD40 (15.17% vs. 0.00% and 0.04%), CD80 (49.96 vs. 0.02% and 0.32%), CD86 (56.49% vs. 0.50% and 5.71%) and HLA-DR (52.52% vs. 14.32% and 2.49%) respectively. The potency of generated DCs to induce allogeneic T cell proliferation increased significantly compared to pre and post culture control groups (27,533.4 +/- 2,548.3, 8,820.4 +/- 1,639.4 and 3,200.35 +/- 976 respectively). The expression pattern of ACE in AML-DCs, blast cells and DCs derived from normal monocytes (7.93%, 1.28% and 74.97% respectively) confirmed the leukemic origin of DCs. Our data confirmed the generation of sufficient AML-derived cells with the properties of DCs in all cases. This potency of AML blasts, offers a useful route for active immunotherapy of AML patients. PMID 18807213

Immunotherapy of acute myeloid leukemia: current approaches.
März 2009 | Smits, Evelien L J M; Berneman, Zwi N; Van Tendeloo, Viggo F I
Following standard therapy that consists of chemotherapy with or without stem cell transplantation, both relapsed and refractory disease shorten the survival of acute myeloid leukemia (AML) patients. Therefore, additional treatment options are urgently needed, especially to fight residual AML cells. The identification of leukemia-associated antigens and the observation that administration of allogeneic T cells can mediate a graft-versus-leukemia effect paved the way to the development of active and passive immunotherapy strategies, respectively. The aim of these strategies is the eradication of AML cells by the immune system. In this review, an overview is provided of both active and passive immunotherapy strategies that are under investigation or in use for the treatment of AML. For each strategy, a critical view on the state of the art is given and future perspectives are discussed. PMID 19289488

Immunotherapy in acute leukemia.
Dez. 2008 | Leung, Wing
Recent advances in immunotherapy of cancer may represent a successful example in translational research, in which progress in knowledge and technology in immunology has led to new strategies of immunotherapy, and even past failures in many clinical trials have led to a better understanding of basic cancer immunobiology. This article reviews the latest concepts in antitumor immunology and its application in the treatment of cancer, with particular focus on acute leukemia. PMID 19100371

New therapeutic strategies in acute lymphoblastic leukemia.
Dez. 2008 | Jeha, Sima
While cure rates of over 80% are achieved in contemporary pediatric acute lymphoblastic leukemia (ALL) protocols, most adults with ALL succumb to their disease, and little progress has been made in the treatment of refractory and relapsed ALL. Moreover, the burden of therapy is high in a significant number of newly diagnosed patients, and in all those with relapse. Early response to therapy measured by minimal residual disease evaluation has proven the single most important prognostic factor and is increasingly used in risk stratification. However, as the benefit from intensification of frontline therapy becomes limiting, it becomes increasingly challenging to rescue patients who fail on contemporary risk-adapted protocols. New therapeutic strategies are needed, not only in salvage regimens but also in frontline protocols for patients who are at high risk of relapse. Current novel approaches include new formulations of existing chemotherapeutic agents, new antimetabolites and nucleoside analogs, monoclonal antibodies against leukemic-associated antigens, cellular immunotherapy, and molecular therapeutics. Some have already been adopted into standard regimens, while others remain in early stages of development. This review summarizes the current status of these novel therapies as they get integrated into ALL regimens. PMID 19100370

Dendritic cell-based immunotherapy in myeloid leukaemia: translating fundamental mechanisms into clinical applications.
Nov. 2008 | van de Loosdrecht, A A; van den Ancker, W; Houtenbos, I; Ossenkoppele, G J; Westers, T M
Immunotherapy for leukaemia patients, aiming at the generation of anti-leukaemic T cell responses, could provide a new therapeutic approach to eliminate minimal residual disease (MRD) cells in acute myeloid leukaemia (AML). Leukaemic blasts harbour several ways to escape the immune system including deficient MHC class II expression, low levels of co-stimulatory molecules and suppressive cytokines. Therapeutic vaccination with dendritic cells (DC) is now recognized as an important investigational therapy. Due to their unique antigen presenting capacity, immunosuppressive features of the leukaemic blasts can be circumvented. DC can be successfully cultured from leukaemic blasts in 60-70% of patients and show functional potential in vivo. Alternatively, monocyte derived DC obtained at time of complete remission loaded with leukaemia-specific antigens can be used as vaccine. Several sources of leukaemia-associated antigen and different methods of loading antigen onto DC have been used in an attempt to optimize antitumour responses including apoptotic cells, necrotic cell lysates and tumour-associated pep-tides. Currently, the AML-derived cell line MUTZ-3, an immortalized equivalent of CD34(+) DC precursor cells, is under investigation for vaccination purposes. For effective DC vaccination the intrinsic tolerant state of the patient must be overcome. Therefore, the development of efficient and safe adjuvants in antigen specific immunotherapeutic programs should be encouraged. PMID 19031033

Dendritic cell vaccines in acute leukaemia.
Sep. 2008 | Duncan, Caroline; Roddie, Huw
There is a need for novel treatment for acute leukaemia as relapse rates remain unacceptably high. Immunotherapy aims to stimulate the patient's immune responses to recognize and destroy leukaemia cells whilst activating immune memory. The qualities of the most potent professional antigen-presenting cell, the dendritic cell (DC), can be used to stimulate leukaemia-specific cytotoxic T cells. DCs can be loaded with leukaemia antigens, or leukaemia blasts can be modified to express DC-like properties for use in vaccine therapy. This chapter will review the rationale for DC vaccine therapy, the preclinical and clinical trials to date, the barriers to successful DC vaccine therapies and the role of immune adjuncts to improve outcomes. PMID 18790453

Quantitative expression of Toll-like receptor-2, -4, and -9 in dendritic cells generated from blasts of patients with acute myeloid leukemia.
Mai 2008 | Schmitt, Anita; Li, Li; Giannopoulos, Krzysztof; Greiner, Jochen; Reinhardt, Peter; Wiesneth, Markus; Schmitt, Michael
Dendritic cells (DCs) generated from leukemic blasts constitute a promising tool in immunotherapy for acute myeloid leukemia patients (AML-DCs), because AML-DCs express human leukocyte antigens and costimulatory molecules such as CD40, CD80, and CD86 at a higher level than leukemic blasts. Potentiation of AML-DC vaccine might become feasible by the addition of adjuvants such as lipopolysaccharides (LPS) or CPG-rich oligodeoxyribonucleotides binding to Toll-like receptors (TLR) and inducing a stronger Type 1 T-cell response. PMID 18208411

Potential of dendritic-cell immunotherapy for relapse after allogeneic hematopoietic stem cell transplantation, shown by WT1 peptide- and keyhole-limpet-hemocyanin-pulsed, donor-derived dendritic-cell vaccine for acute myeloid leukemia.
März 2008 | Kitawaki, Toshio; Kadowaki, Norimitsu; Kondo, Tadakazu; Ishikawa, Takayuki; Ichinohe, Tatsuo; Teramukai, Satoshi; Fukushima, Masanori; Kasai, Yasunari; Maekawa, Taira; Uchiyama, Takashi
Induction of leukemia-specific immune responses is a promising treatment for acute myeloid leukemia. A 58-year-old woman received Wilms' tumor 1 (WT1) peptide- and keyhole limpet hemocyanin (KLH)-pulsed, donor-derived dendritic cell (DC) vaccination for AML relapse after allogeneic stem cell transplantation. The vaccination induced immune responses to the naive antigen KLH, whereas definitive immune responses to WT1 were not detected. Leukemia gradually progressed despite of vaccination. This study indicates that DC vaccination can induce an antigen-specific immune response in a patient after allogeneic stem cell transplantation, thus representing a viable strategy to induce antigen-specific immune responses in such patients. PMID 18081032

Efficient monocyte-derived dendritic cell generation in patients with acute myeloid leukemia after chemotherapy treatment: application to active immunotherapy.
Feb. 2008 | Royer, Pierre-Joseph; Bougras, Gwenola; Ebstein, Frederic; Leveque, Lucie; Tanguy-Royer, Severine; Simon, Thomas; Juge-Morineau, Nadine; Chevallier, Patrice; Harousseau, Jean-Luc; Gregoire, Marc
While complete remission in acute myeloid leukemia (AML) can be achieved after chemotherapy (CT), relapses occur for the majority of patients, underlying the need to eliminate residual disease. Based on dendritic cell (DC) vaccination, the triggering of an immune response against residual leukemia cells after CT could maintain patients in remission. The aim of our study was to assess, for vaccine preparation, generation of monocyte-derived DCs in AML patients after CT. PMID 18207305

Large-scale generation of autologous dendritic cells for immunotherapy in patients with acute myeloid leukemia.
Aug. 2007 | Schmitt, Anita; Reinhardt, Peter; Hus, Iwona; Tabarkiewicz, Jacek; Roliñski, Jacek; Barth, Thomas; Giannopoulos, Krzysztof; Dmoszyñska, Anna; Wiesneth, Markus; Schmitt, Michael
Mononuclear cells (MNCs) of severely impaired acute myeloid leukemia (AML) patients may be collected by leukapheresis for large-scale generation of dendritic cells (AML-DCs) under good manufacturing practice (GMP) conditions for adoptive immunotherapy. PMID 17725721

Dendritic cell-based immunotherapy in acute and chronic myeloid leukaemia.
Aug. 2007 | Westers, Theresia M; Ossenkoppele, Gert J; van de Loosdrecht, Arjan A
Persistence of residual leukaemia cells in acute and chronic myeloid leukaemia will eventually lead to a relapse of the disease. Dendritic cell-based vaccines might constitute a therapeutic option for leukaemia patients to control or eradicate minimal residual disease. Dendritic cells have the unique property to stimulate naïve T cells. In a majority of the myeloid leukaemia patients these cells can be generated directly from leukaemia cells, although several factors hamper the feasibility of this approach. Other options are being explored to make active specific DC-based immunotherapy in leukaemia more broadly applicable. This review summarises data on active specific DC-based immunotherapy in acute and chronic myeloid leukaemia and discusses current optimisation strategies. PMID 17368821

Dendritic cell vaccines for leukemia patients.
März 2007 | Schmitt, Anita; Hus, Iwona; Schmitt, Michael
Dendritic cells are the most professional antigen-presenting cells to elicit T-cellular responses toward microbial agents and cancer cells. The graft-versus-leukemia effect observed after allogeneic stem cell transplantation strongly suggests that T lymphocytes play a major role in the rejection of leukemic cells. This graft-versus-leukemia effect might be enhanced through dendritic cell vaccination. The characterization of leukemia-specific antigens eliciting immune responses in the autologous host has prompted researchers and clinicians to broaden the spectrum of dendritic cell vaccines to hematological malignancies. Recently, the focus is on acute myeloid leukemia and chronic lymphocytic leukemia. This review summarizes data on the administration of autologous and allogeneic dendritic cells to leukemia patients as an interesting approach in cellular therapy of leukemias. PMID 17338648

Generation of functional dendritic cells (DC) in adult acute lymphoblastic leukemia: rationale for a DC-based vaccination program for patients in complete hematological remission.
Feb. 2007 | Maggio, Roberta; Peragine, Nadia; Calabrese, Elisabetta; De Propris, Maria Stefania; Intoppa, Stefania; Della Starza, Irene; Ariola, Cristina; Vitale, Antonella; Foà, Robin; Guarini, Anna
The capacity to generate effective dendritic cells (DC) from adult acute lymphoblastic leukemia (ALL) patients in complete remission (CR) and off-therapy was investigated. Monocyte-derived DC cultured in the presence of granulocyte-macrophage colony-stimulating factor, interleukin (IL)-4 and tumor necrosis factor (TNF)-alpha expressed maturation markers, produced IL-12 and loaded apoptotic bodies to a similar extent to normal DC. Patients' circulating T and NK lymphocytes were normally represented and, after stimulation, were capable of producing TNF-alpha and interferon-gamma to a similar extent to control lymphocytes. DC loaded with leukemia-derived apoptotic bodies increased their ability to stimulate both allogeneic and autologous lymphocytes, and to generate specific anti-leukemic CD3 + cells. These findings offer a rationale for the design of DC-based vaccine programs for adult ALL patients in CR with the aim of controlling/eradicating the disease. PMID 17325890

Optimization of the concentration of autologous serum for generation of leukemic dendritic cells from acute myeloid leukemic cells for clinical immunotherapy.
Dez. 2006 | Choi, Bo-Hwa; Kang, Hyun-Kyu; Park, Jung-Sun; Kim, Sang-Ki; Pham, Than-Nhan Nguyen; Zhu, Xiao-Wei; Cho, Duck; Nam, Jong-Hee; Chung, Ik-Joo; Kim, Young-Jin; Rhee, Joon-Haeng; Kim, Hyeoung-Joon; Lee, Je-Jung
Clinical application of immunotherapy for acute myeloid leukemia (AML) requires the efficient induction of dendritic cells (DCs) from AML blast cells using in vitro culture. We examined the effect of autologous serum on the properties of leukemic DCs derived from leukemic cells of AML patients by culture in AIM-V medium with GM-CSF, IL-4, TNF-alpha, and 0, 2, 5, or 10% human autologous serum. The expressions of CD80, CD83, CD86, and HLA-DR were upregulated under all culture conditions; however, 10% autologous serum induced the highest expression levels of several molecules. The capacity of leukemic DCs to stimulate allogeneic T cells increased with increasing serum concentration. Stimulation of autologous CD3(+) T cells with leukemic DCs grown in the presence of various concentrations of autologous serum resulted in induction of more IFN-gamma-secreting cells than was the case for unprimed CD3(+) T cells. Leukemic DCs cultured with 10% autologous serum induced the highest numbers of IFN-gamma-secreting cells and CD8(+)CD56(+) T cells from autologous T cells. These results suggest that culture of AML blast cells in the presence of autologous serum could be used to generate leukemic DCs for immunotherapy against AML. The highest serum concentration appeared optimal for generating the most potent leukemic DCs. PMID 17120232

Dendritic cells pulsed or fused with AML cellular antigen provide comparable in vivo antitumor protective responses.
Sep. 2006 | Weigel, Brenda J; Panoskaltsis-Mortari, Angela; Diers, Miechaleen; Garcia, Melissa; Lees, Chris; Krieg, Arthur M; Chen, Wei; Blazar, Bruce R
To investigate whether syngeneic BM-derived DCs generated in vitro and fused with syngeneic C1498 tumor cells (murine AML line) could induce a better antitumor protective effect compared to similarly generated DCs pulsed with C1498 lysate with or without co-injection of a class B CpG oligodeoxynucleotide (CpG 7909) in vivo. PMID 16982333

Feasibility of clinical dendritic cell vaccination in acute myeloid leukemia.
Aug. 2006 | Houtenbos, Ilse; Westers, Theresia M; Ossenkoppele, Gert J; van de Loosdrecht, Arjan A
Dendritic cells (DC) are increasingly being utilized for anti-cancer therapy. Acute myeloid leukemia (AML) blasts are able to differentiate towards leukemia-derived DC enabling efficient presentation of known and unknown leukemic antigens. Advances in culture techniques and AML-DC characterization justify clinical application. However, clinical trials using AML-DC are hampered by patient inclusion criteria which allow selective entering of patients in second complete remission. Clinical relevant responses to DC-based immunotherapy are likely to only occur in non-end-stage patients. Application in early stage disease is mandatory to permit ultimate proof of clinical benefit of AML-DC vaccination strategy. PMID 16920506

Current progress in the development of a cell-based vaccine for the immunotherapy of acute myeloid leukemia.
Apr. 2006 | Klammer, Matthias; Roddie, Patrick H
Evidence that immunological control contributes to the elimination of residual leukemia has emerged from allogeneic hematopoietic stem cell transplantation. This review assesses the current understanding of immunobiology of acute myeloid leukemia and how dendritic cells and T cells may be harnessed using in vitro and in vivo priming techniques. Preclinical and clinical dendritic cell vaccine trials reported to date are considered and the prospects for immunotherapy with dendritic cell-based vaccine constructs evaluated. PMID 16608421

Immunotherapy for patients with acute myeloid leukemia using autologous dendritic cells generated from leukemic blasts.
März 2006 | Li, Li; Giannopoulos, Krzysztof; Reinhardt, Peter; Tabarkiewicz, Jacek; Schmitt, Anita; Greiner, Jochen; Rolinski, Jacek; Hus, Iwona; Dmoszynska, Anna; Wiesneth, Markus; Schmitt, Michael
Vaccination with dendritic cells (DCs) as professional antigen presenting cells generated from autologous leukemic blasts might elicit anti-leukemic T cell responses in patients with acute myeloid leukemia (AML). To test this hypothesis, autologous AML-DC were generated under good manufacturing practice (GMP) conditions and injected s.c. into five AML patients up to four times at a biweekly interval. No severe adverse side effects were observed. Three patients remained in a stable condition for 5.5-13 months and two patients died from rapidly progressive AML. Compared to the initial T cell frequency, enzyme linked immunosorbent spot (ELISPOT) assays revealed a significant increase of granzyme B releasing CD8+ T cells specifically recognizing the PRAME derived peptide (ALYVDSLFFL), a leukemia associated antigen expressed by AML blasts. The cytokine levels in the serum of vaccination AML patients as assessed by cytokine bead assay changed over the period of vaccination to an elevated type 1 T helper cell pattern. Interferon gamma production by CD4+ T helper cells increased during vaccination. In summary, we demonstrated that autologous AML-DC vaccination is well tolerated and can result in an enhanced and specific response of cytotoxic T cells in AML patients. PMID 16525634

Dendritic cell-based immunotherapy for the treatment of hematological malignancies.
Mai 2003 | Büchler, Tomas; Michalek, Jaroslav; Kovarova, Lucie; Musilova, Romana; Hajek, Roman
Dendritic cells (DCs) are professional antigen-presenting cells and are frequently used in current immunotherapy protocols. The administration of DCs loaded with tumor-associated proteins or peptides results in the induction of immune responses against different types of malignant cells. Methods for large-scale generation of DCs in a sufficient quality and quantity have permitted their use in clinical experiments. DC-based vaccines have already shown promise in follicular non-Hodgkin's lymphoma, and to some extent, in other hematological malignancies. Several strategies have been developed to boost their potency as a new and relatively non-toxic treatment modality. Our review focuses on clinical trials using DCs in the treatment of hematologic malignancies and on recent studies of the immunophenotype, development, and maturation of DCs may have an important impact on designing DC-based antitumor vaccines. PMID 12745659

Hyperthermic enhancement of cis-diammine-1,1-cyclobutane dicarboxylate platinum(II) cytotoxicity in human leukemia cells in vitro.
Sep. 1987 | Cohen, J D; Robins, H I
Hyperthermic enhancement of cis-diammine-1,1-cyclobutane dicarboxylate platinum(II) (carboplatin) cytotoxicity was studied in vitro in JM, a human acute lymphoblastic leukemia cell line. Corrected for direct heat toxicity, hyperthermia enhanced carboplatin killing at the clinically relevant temperatures of 40.5 degrees and 41.8 degrees C. The thermal enhancement ratios at these temperatures were 1.89 and 3.32, respectively. Cell killing increased exponentially with increasing duration of combined treatment (41.8 degrees C, carboplatin 30 micrograms/ml) for at least 3.5 h. Hyperthermic enhancement was maximal when heat was given during or immediately before carboplatin; enhancement was diminished when heat preceded carboplatin by more than an hour and was not apparent when heat followed drug treatment. As carboplatin is associated with different clinical toxicity than is cis-diamminedichloroplatinum(II), carboplatin may represent an ideal drug in its class of anticancer agents to use in clinical whole body hyperthermia trials. PMID 3300964

A proposal for the addition of hyperthermia to treatment regimens for acute and chronic leukemia.
Okt. 1984 | Robins, H I; Dennis, W H; Steeves, R A; Sondel, P M
The application of hyperthermia to the treatment of neoplastic disease has focused on solid tumors. Human leukemias, both acute and chronic, may represent a unique category of diseases for which hyperthermia should be used in combination with other modalities with curative intent. Three clinical approaches to include hyperthermia are proposed. These are hyperthermia in combination with therapeutic low-dose whole-body irradiation, ablative high-dose total body irradiation, and bone marrow transplantation with the in vitro use of hyperthermia to purge remission bone marrow of abnormal cells. Current preclinical research further supporting these clinical applications of hyperthermia to leukemia therapy is presented. PMID 6381656