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Autologous Dendritic Cell Therapy in Mesothelioma Patients Enhances Frequencies of Peripheral CD4 T Cells Expressing HLA-DR, PD-1, or ICOS.
Sep. 2018 | de Goeje, Pauline L; Klaver, Yarne; Kaijen-Lambers, Margaretha E H; Langerak, Anton W; Vroman, Heleen; Kunert, André; Lamers, Cor H J; Aerts, Joachim G J V; Debets, Reno; Hendriks, Rudi W
Malignant pleural mesothelioma (MPM) is a malignancy with a very poor prognosis for which new treatment options are urgently needed. We have previously shown that dendritic cell (DC) immunotherapy provides a clinically feasible treatment option. In the current study, we set out to assess the immunological changes induced by DC immunotherapy in peripheral blood of MPM patients. Peripheral blood was collected from nine patients enrolled in a phase I dose escalation study, before and after treatment with DCs that were pulsed with an allogeneic tumor lysate preparation consisting of a mixture of five cultured mesothelioma cell lines. We used immune profiling by multiplex flow cytometry to characterize different populations of immune cells. In particular, we determined frequencies of T cell subsets that showed single and combinatorial expression of multiple markers that signify T cell activation, maturation and inhibition. Therapy-induced T cell reactivity was assessed in peptide/MHC multimer stainings using mesothelin as a prototypic target antigen with confirmed expression in the clinical tumor lysate preparation. T cell receptor (TCR) diversity was evaluated by gene PCR assays. We observed an increase in the numbers of B cells, CD4 and CD8 T cells, but not NK cells at 6 weeks post-treatment. The increases in B and T lymphocytes were not accompanied by major changes in T cell reactivity toward mesothelin nor in diversity. Notably, we did observe enhanced proportions of CD4 T cells expressing HLA-DR, PD-1 (at 2 weeks after onset of treatment) and ICOS (6 weeks) and a CD8 T cell population expressing LAG3 (2 weeks). DC immunotherapy using allogeneic tumor lysate resulted in enhanced frequencies of B cells and T cells in blood. We did not detect a skewed antigen-reactivity of peripheral CD8 T cells. Interestingly, frequencies of CD4 T cells expressing activation markers and PD-1 were increased. These findings indicate a systemic activation of the adaptive immune response and may guide future immune monitoring studies of DC therapies. PMID 30245692

Autologous Dendritic Cells Pulsed with Allogeneic Tumor Cell Lysate in Mesothelioma: From Mouse to Human.
Dez. 2017 | Aerts, Joachim G J V; de Goeje, Pauline L; Cornelissen, Robin; Kaijen-Lambers, Margaretha E H; Bezemer, Koen; van der Leest, Cor H; Mahaweni, Niken M; Kunert, André; Eskens, Ferry A L M; Waasdorp, Cynthia; Braakman, Eric; van der Holt, Bronno; Vulto, Arnold G; Hendriks, Rudi W; Hegmans, Joost P J J; Hoogsteden, Henk C
Mesothelioma has been regarded as a nonimmunogenic tumor, which is also shown by the low response rates to treatments targeting the PD-1/PD-L1 axis. Previously, we demonstrated that autologous tumor lysate-pulsed dendritic cell (DC) immunotherapy increased T-cell response toward malignant mesothelioma. However, the use of autologous tumor material hampers implementation in large clinical trials, which might be overcome by using allogeneic tumor cell lines as tumor antigen source. The purpose of this study was to investigate whether allogeneic lysate-pulsed DC immunotherapy is effective in mice and safe in humans. First, in two murine mesothelioma models, mice were treated with autologous DCs pulsed with either autologous or allogeneic tumor lysate or injected with PBS (negative control). Survival and tumor-directed T-cell responses of these mice were monitored. Results were taken forward in a first-in-human clinical trial, in which 9 patients were treated with 10, 25, or 50 million DCs per vaccination. DC vaccination consisted of autologous monocyte-derived DCs pulsed with tumor lysate from five mesothelioma cell lines. In mice, allogeneic lysate-pulsed DC immunotherapy induced tumor-specific T cells and led to an increased survival, to a similar extent as DC immunotherapy with autologous tumor lysate. In the first-in-human clinical trial, no dose-limiting toxicities were established and radiographic responses were observed. Median PFS was 8.8 months [95% confidence interval (CI), 4.1-20.3] and median OS not reached (median follow-up = 22.8 months). DC immunotherapy with allogeneic tumor lysate is effective in mice and safe and feasible in humans. . PMID 29233904

Extended Tumor Control After Dendritic Cell Vaccination With Low Dose Cyclophosphamide as Adjuvant Treatment in Patients With Malignant Pleural Mesothelioma.
Dez. 2015 | Cornelissen, Robin; Hegmans, Joost P J J; Maat, Alexander P W M; Kaijen-Lambers, Margaretha E H; Bezemer, Koen; Hendriks, Rudi W; Hoogsteden, Henk C; Aerts, Joachim G J V
We demonstrated before that autologous tumor lysate-pulsed dendritic cell-based immunotherapy in patients with malignant pleural mesothelioma is feasible, well-tolerated, and capable of inducing immunological responses against tumors. In our murine model we found that reduction of regulatory T cells with metronomic cyclophosphamide increased the efficacy of immunotherapy. PMID 26652184

Immunotherapy prospects in the treatment of lung cancer and mesothelioma.
März 2015 | Aerts, Joachim G; Lievense, Lysanne A; Hoogsteden, Henk C; Hegmans, Joost P
A very recent finding is the role of immune activation in cancer. The assumption that stimulating the patient's immune system to attack tumors is a valuable treatment option in malignant diseases has gained more acceptance. However the high immunosuppressive effects caused by the tumor limits this beneficial effect. There is a delicate balance between immunoactivation and immunosuppression in a patient. Especially in non small cell lung cancer (NSCLC), the role of immunosuppressive cells hampering immune activation is high. But also in small cell lung cancer (SCLC) and mesothelioma immunosuppressive activity is high. This is suggested to be related to the type of tumor, advanced stage of the disease, and the tumor load. In this review, we provide an overview of the progress and challenges in the immunotherapeutic approaches in lung cancer. We conclude with the concept that immunotherapy in thoracic malignancies must be tailored made to the balance of the immune system. PMID 25806279

Tumour-derived exosomes as antigen delivery carriers in dendritic cell-based immunotherapy for malignant mesothelioma.
Nov. 2013 | Mahaweni, Niken M; Kaijen-Lambers, Margaretha E H; Dekkers, Jacqueline; Aerts, Joachim G J V; Hegmans, Joost P J J
In 2001, it was postulated that tumour-derived exosomes could be a potent source of tumour-associated antigens (TAA). Since then, much knowledge is gained on their role in tumorigenesis but only very recently tumour-derived exosomes were used in dendritic cell (DC)-based immunotherapy. For this, DCs were cultured ex-vivo and loaded with exosomes derived from immunogenic tumours such as melanoma or glioma and re-administrated to induce anti-tumour responses in primary and metastatic tumour mouse models. In contrast, malignant mesothelioma (MM) is a non-immunogenic tumour and because only a few mesothelioma-specific TAA are known to date, we investigated whether mesothelioma-derived exosomes could be used as antigen source in DC-based immunotherapy. PMID 24223258

Dendritic cell-based immunotherapy in mesothelioma.
Nov. 2012 | Cornelissen, Robin; Lievense, Lysanne A; Heuvers, Marlies E; Maat, Alexander P; Hendriks, Rudi W; Hoogsteden, Henk C; Hegmans, Joost P; Aerts, Joachim G
Mesothelioma is a rare thoracic malignancy with a dismal prognosis. Current treatment options are scarce and clinical outcomes are rather disappointing. Due to the immunogenic nature of mesothelioma, several studies have investigated immunotherapeutic strategies to improve the prognosis of patients with mesothelioma. In the last decade, progress in knowledge of the modulation of the immune system to attack the tumor has been remarkable, but the optimal strategy for immunotherapy has yet to be unraveled. Because of their potent antigen-presenting capacity, dendritic cells are acknowledged as a promising agent in immunotherapeutic approaches in a number of malignancies. This review gives an update and provides a future perspective in which immunotherapy may improve the outcome of mesothelioma therapy. PMID 23148753

Genetically engineered oncolytic Newcastle disease virus effectively induces sustained remission of malignant pleural mesothelioma.
Okt. 2010 | Silberhumer, Gerd R; Brader, Peter; Wong, Joyce; Serganova, Inna S; Gönen, Mithat; Gonzalez, Segundo Jaime; Blasberg, Ronald; Zamarin, Dmitriy; Fong, Yuman
Malignant pleural mesothelioma is a highly aggressive tumor. Alternative treatment strategies such as oncolytic viral therapy may offer promising treatment options in the future. In this study, the oncolytic efficacy and induction of tumor remission by a genetically engineered Newcastle disease virus [NDV; NDV(F3aa)-GFP; GFP, green fluorescent protein] in malignant pleural mesothelioma is tested and monitored by bioluminescent tumor imaging. The efficacy of NDV(F3aa)-GFP was tested against several mesothelioma cell lines in vitro. Firefly luciferase-transduced MSTO-211H* orthotopic pleural mesothelioma tumor-bearing animals were treated with either single or multiple doses of NDV(F3aa)-GFP at different time points (days 1 and 10) after tumor implantation. Tumor burden was assessed by bioluminescence imaging. Mesothelioma cell lines exhibited dose-dependent susceptibility to NDV lysis in the following order of sensitivity: MSTO-211H > MSTO-211H* > H-2452 > VAMT > JMN. In vivo studies with MSTO-211H* cells showed complete response to viral therapy in 65% of the animals within 14 days after treatment initiation. Long-term survival in all of these animals was >50 days after tumor installation (control animals, <23 d). Multiple treatment compared with single treatment showed a significantly better response (P = 0.005). NDV seems to be an efficient viral oncolytic agent in the therapy of malignant pleural mesothelioma in an orthotopic pleural mesothelioma tumor model. PMID 20858727

Consolidative dendritic cell-based immunotherapy elicits cytotoxicity against malignant mesothelioma.
Juni 2010 | Hegmans, Joost P; Veltman, Joris D; Lambers, Margaretha E; de Vries, I Jolanda M; Figdor, Carl G; Hendriks, Rudi W; Hoogsteden, Henk C; Lambrecht, Bart N; Aerts, Joachim G
We previously demonstrated that dendritic cell-based immunotherapy induced protective antitumor immunity with a prolonged survival rate in mice. However, the clinical relevance is still in question. To examine this, we designed a clinical trial using chemotherapy followed by antigen-pulsed dendritic cell vaccination in mesothelioma patients. PMID 20167848

What's the place of immunotherapy in malignant mesothelioma treatments?
Apr. 2010 | Grégoire, Marc
Malignant pleural mesothelioma (MPM) is a rare malignancy of the pleura with a very poor prognosis. Treatments evaluated for malignant mesothelioma, including chemotherapy, radiotherapy and surgery are of limited efficacy. However, the fact that the tumors of some patients with MPM regress spontaneously or respond to immunotherapy suggests that the immune system may respond to MPM under some circumstances. In this respect, animal studies have demonstrated immunoreactivity of MPM to different immunotherapies. In the case of MPM, several clinical studies have demonstrated a correlation between the presence of a lymphocyte infiltrate and a better prognosis and humoral response directed against specific antigens related to tumor. Thus, MPM immunotherapy is undoubtedly a highly promising but also very challenging approach to the treatment of this disease that has slipped through the defense lines of the immune system. This article reviews past and recent developments of the clinical strategies that concern immunotherapy of mesothelioma. PMID 20179421

Laboratory and clinical basis for hyperthermia as a component of intracavitary chemotherapy.
Aug. 2007 | Sugarbaker, P H
Intraoperative chemotherapy with heat has been identified as a treatment option for patients with cancer spread to peritoneal surfaces. This treatment modality is viewed as a supplement to several other treatments for this group of patients including cytoreductive surgery, systemic chemotherapy, early postoperative intraperitoneal chemotherapy, and long-term bidirectional chemotherapy. The pharmacologic basis for using heat to supplement chemotherapy effects are related to the increased penetration of chemotherapy into tumor with hyperthermia, the delayed clearance of chemotherapy from the peritoneal cavity after direct instillation, and an increased cytotoxicity that has been documented with selected chemotherapy agents. Data to support the use of perioperative hyperthermic intraperitoneal chemotherapy with mucinous appendiceal carcinomatosis comes from a large number of single institution phase II studies. Also, peritoneal and pleural mesothelioma are benefited. In colon cancer carcinomatosis, large phase II multi-institutional trials and a single phase III trial documented an increased median survival of these patients from approximately 1 year to over 2 years. Prophylaxis against peritoneal carcinomatosis in gastric cancer has been demonstrated in phase III trials. In ovarian cancer the rationale for this treatment remains large but its current application is limited. Much work needs to be done to identify a proper clinical perspective on hyperthermia used with chemotherapy in patients with peritoneal surface malignancy. PMID 17701534

[Malignant peritoneal mesothelioma. Our experienced with triple combined therapy: cytoreduction, intraperitoneal perioperative chemotherapy and hyperthermia].
Feb. 2007 | Gómez Portilla, Alberto; Cendoya, Ignacio; Muriel, Jesús; Olabarria, Ignacio; Guede, Nera; Moraza, Nuria; Fernández, Elena; Martínez de Lecea, Concepción; Magrach, Luis; Martín, Ernesto; Romero, Erika; Aguado, Iker; Valdovinos, Mercedes; Larrabide, Iñaki
Malignant peritoneal mesothelioma is the most common primary neoplasm of the serous peritoneum. Most patients die of the complications of local disease confined to the peritoneal cavity, while nodal or distant dissemination is extremely rare. Prognosis with traditional therapeutic options is dismal, with a median survival of between 4 and 12 months from diagnosis. The application of a new combined therapy with cytoreductive surgery, intraperitoneal perioperative chemotherapy and heated intraperitoneal intraoperative chemotherapy, followed by early postoperative intraperitoneal chemotherapy is currently providing good results, in some instances even allowing curative intent. We present a series of patients treated with this triple combined therapy. PMID 17306123

[Immunotherapy and malignant mesothelioma: clinical perspectives].
Jan. 2007 | Grégoire, Marc; Ebstein, Frédéric
Malignant pleural mesothelioma (MPM) is a rare malignancy of the pleura with a very poor prognosis. Treatments evaluated for malignant mesothelioma, including chemotherapy, radiotherapy and surgery are of limited efficacy. Given that some patients with MPM bear tumours regressing spontaneously or responding to immunotherapy suggests that the immune system may respond to MPM under some circumstances. Animal studies have also demonstrated immunoreactivity to MPM to different immunotherapies. Clinical trials investigating new trends in the treatment of stage I and II malignant mesothelioma have shown both immunotherapy and systemic chemo-immunotherapy to be efficacious. In addition, recent progresses in early detection techniques also provide hope that patients can be treated efficiently, at an earlier stage and well monitored. Thus, immunotherapy of cancer is undoubtedly a highly promising but also very challenging approach in the treatment of a disease that has slipped through the defence lines of the immune system. This article will review past and recent developments of such a clinical strategy. PMID 17237002

Hyperthermia combined with intra-thoracic chemotherapy and radiotherapy for malignant pleural mesothelioma.
Nov. 2006 | Xia, Hongqiang; Karasawa, Katsuyuki; Hanyu, Nahoko; Chang, Ta-Chen; Okamoto, Masahiko; Kiguchi, Yurie; Kawakami, Mutsumi; Itazawa, Tomoko
Prognosis for patients with malignant pleural mesothelioma (MPM) remains poor and such patients require intensive treatment. Few studies have examined hyperthermia for MPM. The present study investigated the feasibility of hyperthermia combined with weekly chemo-radiotherapy for patients with MPM and estimated the efficacy of this regimen. PMID 17079218

Mesothelioma environment comprises cytokines and T-regulatory cells that suppress immune responses.
Juni 2006 | Hegmans, J P J J; Hemmes, A; Hammad, H; Boon, L; Hoogsteden, H C; Lambrecht, B N
Malignant mesothelioma is a cancer with dismal prognosis. The objective of the present study was to address the role of the immune system, tumour micro-environment and potential immunosuppression in mesothelioma. Expression profiles of 80 cytokines were determined in the supernatant of mesothelioma cell lines and the original patient's pleural effusion. Influx of immune effector cells was detected by immunohistochemistry. Angiogenin, vascular endothelial growth factor, transforming growth factor-beta, epithelial neutrophil-activating protein-78 and several other proteins involved in immune suppression, angiogenesis and plasma extravasation could be detected in both supernatant and pleural effusion. Surrounding stroma and/or infiltrating cells were the most likely source of hepatocyte growth factor, macrophage inflammatory protein (MIP)-1delta, MIP-3alpha, neutrophil-activating peptide-2, and pulmonary and activation-regulated chemokine that can cause leukocyte infiltration and activation. There was a massive influx of CD4+ and CD8+ T-lymphocytes and macrophages, but not of dendritic cells, in human mesothelioma biopsies. It was further demonstrated that human mesothelioma tissue contained significant amounts of Foxp3+CD4+CD25+ regulatory T-cells. When these CD25+ regulatory T-cells were depleted in an in vivo mouse model, survival increased. Mesothelioma is infiltrated by immune effector cells but also contains cytokines and regulatory T-cells that suppress an efficient immune response. Immunotherapy of mesothelioma might be more effective when combined with drugs that eliminate or control regulatory T-cells. PMID 16540497

Immunotherapy of murine malignant mesothelioma using tumor lysate-pulsed dendritic cells.
Mai 2005 | Hegmans, Joost P J J; Hemmes, Annabrita; Aerts, Joachim G; Hoogsteden, Henk C; Lambrecht, Bart N
Exploiting the immunostimulatory capacities of dendritic cells holds great promise for cancer immunotherapy. Currently, dendritic cell-based immunotherapy is evaluated clinically in a number of malignancies, including melanoma and urogenital and lung cancer, showing variable but promising results. PMID 15764728

Cytotoxic T cell responses against mesothelioma by apoptotic cell-pulsed dendritic cells.
Juni 2004 | Ebstein, Frédéric; Sapede, Carole; Royer, Pierre-Joseph; Marcq, Marie; Ligeza-Poisson, Catherine; Barbieux, Isabelle; Cellerin, Laurent; Dabouis, Gérard; Grégoire, Marc
Malignant pleural mesothelioma is an uncommon tumor largely confined to the thoracic cavity, which is resistant to conventional therapies, therefore prompting an intensive search for effective treatment alternatives. This study focuses on dendritic cell (DC) vaccination for malignant pleural mesothelioma and evaluates the in vitro efficacy of antigen-loaded DC-based vaccines for the induction of major histocompatibility complex Class I-restricted antimesothelioma cytotoxic T lymphocyte responses. The source of tumor-associated antigens for HLA-A2(+) DCs from healthy donors was apoptotic HLA-A2(-) mesothelioma cells either lacking or expressing heat shock protein 70 according to whether tumor cells were heat shocked or not before ultraviolet-mediated apoptosis. Our results show that both apoptotic preparations were equivalent regarding the responsiveness of DCs to combined treatment with tumor necrosis factor-alpha and poly(inosinic-cytidylic) acid, as determined by similar increased expression of costimulatory molecules and interleukin-12 production. However, only DCs loaded with apoptotic heat shock protein 70-expressing cells were found to be potent in vitro inducers of cytotoxic T lymphocyte activity against HLA-A2(+) mesothelioma cells. Such elicited cytotoxic T lymphocytes also exhibit cytotoxic activity against an HLA-A2(+) melanoma cell line, suggesting recognition of shared antigens. These findings therefore carry the potential of offering an alternative, promising approach for the therapy of patients with malignant pleural mesothelioma. PMID 15070823

[Evaluation of the therapeutic benefit of 41.8 degrees C whole body hyperthermia plus ifosfamide, carboplatin and etoposide (ICE) for patients with malignant pleural mesothelioma using the Modified Brunner-Score (MBS)].
Apr. 2004 | Bruns, I; Kohlmann, Th; Wiedemann, G J; Bakhshandeh, A
We performed a phase-II-study combining 41.8 degrees C whole body hyperthermia with ICE chemotherapy, i. e., ifosfamide (5 g/m (2) on day 1), carboplatin (300 mg/m (2) on day 1) and etoposide (150 mg/m (2) on days 2 and 3), administered every 4 weeks, to assess the treatment benefit for patients with malignant pleural mesothelioma. To date this is mainly done by measurement of response rates and overall survival, as it can be widely found in the literature. In fewer cases there is also a quality of life assessment. Here we describe an instrument well-capable for a more comprehensive statement on the therapeutic benefit by linking several study end points including quality of life assessment, the Modified Brunner-Score (MBS). PMID 15098157

Ifosfamide, carboplatin and etoposide combined with 41.8 degrees C whole body hyperthermia for malignant pleural mesothelioma.
Feb. 2003 | Bakhshandeh, A; Bruns, I; Traynor, A; Robins, H I; Eberhardt, K; Demedts, A; Kaukel, E; Koschel, G; Gatzemeier, U; Kohlmann, Th; Dalhoff, K; Ehlers, E M; Gruber, Y; Zumschlinge, R; Hegewisch-Becker, S; Peters, S O; Wiedemann, G J
We performed a phase II study combining 41.8 degrees C whole body hyperthermia with ICE chemotherapy, i.e. ifosfamide (5 g/m(2)), carboplatin (300 mg/m(2)) and etoposide (150 mg/m(2) on days 2 and 3), administered every 4 weeks, for patients with malignant pleural mesothelioma. Of 27 chemonäive, non-metastatic patients enrolled, 25 patients were evaluable for response. Overall response rate was 20% (five partial remissions; 95% CI 8.9-39.1%). Median survival time from the start of treatment for all patients was 76.6 weeks (95% CI 65.4-87.8 weeks). Progression free survival for all patients measured 29.6 weeks (95% CI 24.4-34.7 weeks). One year overall survival was 68% and 2 year overall survival was 20%. Major treatment toxicities included grade 3/4 neutropenia and thrombocytopenia in 74 and 33% of treatment cycles, respectively. One patient died due to sepsis. These promising results are consistent with continued clinical investigation; a phase III clinical trial with whole body hyperthermia as the independent variable has been initiated. PMID 12609573

Localised spontaneous regression in mesothelioma -- possible immunological mechanism.
Apr. 2001 | Robinson, B W; Robinson, C; Lake, R A
Malignant mesothelioma (MM) is an aggressive tumor usually associated with asbestos exposure. Although it can remain stable for prolonged periods, it has not been described to spontaneously regress. MM tumors are thought to be immunogenic based both on animal studies and on the good responses in some humans treated with immunotherapy. Here we present a case of pleural MM in which a transient spontaneous regression was associated with tumor tissue infiltration with mononuclear cells and serological evidence of anti-MM reactivity. The patient's tumor eventually progressed and with this progression there was evidence of loss of serological reactivity to some, but not all, of her MM antigens. The patient survived for 20 months and, in contrast to her initial biopsy, no significant lymphoid infiltrate was detected in her MM tissue at post mortem examination. PMID 11325491