Immunotherapy in atypical teratoid-rhabdoid tumors: Data from a survey of the HGG-Immuno Group.
Aug. 2016 | van Gool, Stefaan W; Holm, Stefan; Rachor, Johannes; Adamson, Lars; Technau, Antje; Maass, Eberhard; Frühwald, Michael C; Schlegel, Paul G; Eyrich, Matthias
Atypical rhabdoid/teratoid tumors (AT/RT) are the most common brain tumors in infants and associated with a dismal prognosis. Although intensification of first-line therapy has resulted in improvement of overall survival, novel treatment strategies are needed. Because immunotherapy has resulted in remarkable results in several adult tumor entities, incorporation of immunotherapy into AT/RT treatment offers a novel alternative. PMID 27421737
Immunotherapy in atypical teratoid-rhabdoid tumors: Data from a survey of the HGG-Immuno Group.
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
Exploiting the Immunogenic Potential of Cancer Cells for Improved Dendritic Cell Vaccines.
Feb. 2016 | Vandenberk, Lien; Belmans, Jochen; Van Woensel, Matthias; Riva, Matteo; Van Gool, Stefaan W
Cancer immunotherapy is currently the hottest topic in the oncology field, owing predominantly to the discovery of immune checkpoint blockers. These promising antibodies and their attractive combinatorial features have initiated the revival of other effective immunotherapies, such as dendritic cell (DC) vaccinations. Although DC-based immunotherapy can induce objective clinical and immunological responses in several tumor types, the immunogenic potential of this monotherapy is still considered suboptimal. Hence, focus should be directed on potentiating its immunogenicity by making step-by-step protocol innovations to obtain next-generation Th1-driving DC vaccines. We review some of the latest developments in the DC vaccination field, with a special emphasis on strategies that are applied to obtain a highly immunogenic tumor cell cargo to load and to activate the DCs. To this end, we discuss the effects of three immunogenic treatment modalities (ultraviolet light, oxidizing treatments, and heat shock) and five potent inducers of immunogenic cell death [radiotherapy, shikonin, high-hydrostatic pressure, oncolytic viruses, and (hypericin-based) photodynamic therapy] on DC biology and their application in DC-based immunotherapy in preclinical as well as clinical settings. PMID 26834740
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
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
Dendritic cell immunotherapy in uterine cancer.
Nov. 2014 | Coosemans, An; Tuyaerts, Sandra; Vanderstraeten, Anke; Vergote, Ignace; Amant, Frédéric; Van Gool, Stefaan W
Uterine cancer is the most common pelvic gynecological malignancy. Uterine sarcomas and relapsed uterine carcinomas have limited treatment options. The search for new therapies is urgent. Dendritic cell (DC) immunotherapy holds much promise, though has been poorly explored in uterine cancer. This commentary gives an insight in existing DC immunotherapy studies in uterine cancer and summarizes the possibilities and the importance of the loading of tumor antigens onto DC and their subsequent maturation. However, the sole application of DC immunotherapy to target uterine cancer will be insufficient because of tumor-induced immunosuppression, which will hamper the establishment of an effective anti-tumor immune response. The authors give an overview on the limited existing immunosuppressive data and propose a novel approach on DC immunotherapy in uterine cancer. PMID 25424788
Development and validation of a fully GMP-compliant production process of autologous, tumor-lysate-pulsed dendritic cells.
Juni 2014 | Eyrich, Matthias; Schreiber, Susanne C; Rachor, Johannes; Krauss, Jürgen; Pauwels, Femke; Hain, Johannes; Wölfl, Matthias; Lutz, Manfred B; de Vleeschouwer, Steven; Schlegel, Paul G; Van Gool, Stefaan W
One of the major challenges of dendritic cell (DC) vaccination is the establishment of harmonized DC production protocols. Here, we report the transfer and validation of a successfully used open DC manufacturing method into a closed system, good manufacturing practice (GMP)-compatible protocol. PMID 24831836
Wilms' tumor gene 1 immunotherapy in pelvic gynecological malignancies.
Mai 2014 | Coosemans, A; Vergote, I; Van Gool, S W
Pelvic gynecological malignancies account for 6% of all cancers. In the relapsed state, classical treatments are limited. There is an urgent need for new and personalized treatment. Wilms' tumor gene 1 (WT1) is the most important tumor-associated antigen. Although highly present in gynecological tumors, active immunotherapy against it is still underexplored. This review gives an insight into the importance of WT1 in pelvic gynecological malignancies and the first taken steps into the world of WT1 immunotherapy. PMID 24784346
Dendritic cell-based immunotherapy in ovarian cancer.
Feb. 2014 | Coosemans, An; Vergote, Ignace; Van Gool, Stefaan W
Worldwide, 80% of patients with ovarian cancer die of the disease. New treatments for this aggressive disease are therefore being intensively searched. Although dendritic cell-based vaccines against gynecological malignancies are in their infancy, this immunotherapeutic approach holds much promise. Here, we present our view on an optimal dendritic cell-based immunotherapeutic strategy against ovarian cancer. PMID 24501688
Wilms' Tumor Gene 1 (WT1)--loaded dendritic cell immunotherapy in patients with uterine tumors: a phase I/II clinical trial.
Dez. 2013 | Coosemans, An; Vanderstraeten, Anke; Tuyaerts, Sandra; Verschuere, Tina; Moerman, Philippe; Berneman, Zwi N; Vergote, Ignace; Amant, Frédéric; VAN Gool, Stefaan W
Treatment options are limited in uterine cancer, leading to a poor prognosis. Overexpression of Wilms' tumor gene 1 (WT1), the highest ranked tumor antigen, is attractive for immunotherapy. PMID 24324087
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
Immunological response after WT1 mRNA-loaded dendritic cell immunotherapy in ovarian carcinoma and carcinosarcoma.
Sep. 2013 | Coosemans, An; Vanderstraeten, Anke; Tuyaerts, Sandra; Verschuere, Tina; Moerman, Philippe; Berneman, Zwi; Vergote, Ignace; Amant, Frédéric; Van Gool, Stefaan W
Dendritic cell (DC)-based immunotherapy is an emerging new treatment option in ovarian cancer, an important cause of cancer-related mortality. PMID 24023319
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
Immunological response after therapeutic vaccination with WT1 mRNA-loaded dendritic cells in end-stage endometrial carcinoma.
Okt. 2010 | Coosemans, Ann; Wölfl, Matthias; Berneman, Zwi N; Van Tendeloo, Viggo; Vergote, Ignace; Amant, Frédéric; Van Gool, Stefaan W
Wilms' tumour gene 1 (WT1), a highly ranked immunotherapeutic target, is expressed in uterine cancer and therefore WT1 immunotherapy may present an attractive treatment option. PMID 20944158
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
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
Vaccine therapy in patients with renal cell carcinoma.
Juli 2009 | Van Poppel, Hein; Joniau, Steven; Van Gool, Stefaan W
Renal cell carcinoma (RCC) is one of the most immunoresponsive cancers in humans. Although immunotherapy is currently much less used than in the past, it remains an important option that warrants further exploration. PMID 19201522
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
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
Dendritic cell vaccination in patients with malignant gliomas: current status and future directions.
Dez. 2006 | de Vleeschouwer, Steven; Rapp, Marion; Sorg, Rüdiger V; Steiger, Hans-Jakob; Stummer, Walter; van Gool, Stefaan; Sabel, Michael
Despite recent advances in neurosurgical resection techniques, radiation therapy, and chemotherapy, malignant gliomas continue to have a dismal prognosis because relapses are unavoidable. PMID 17143233
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
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