Publications by authors named "Denis Migliorini"

29 Publications

  • Page 1 of 1

Challenging Hurdles of Current Targeting in Glioblastoma: A Focus on Immunotherapeutic Strategies.

Int J Mol Sci 2021 Mar 28;22(7). Epub 2021 Mar 28.

Department of Oncology, University Hospital of Geneva, 1205 Geneva, Switzerland.

Glioblastoma is the most frequent primary neoplasm of the central nervous system and still suffers from very poor therapeutic impact. No clear improvements over current standard of care have been made in the last decade. For other cancers, but also for brain metastasis, which harbors a very distinct biology from glioblastoma, immunotherapy has already proven its efficacy. Efforts have been pursued to allow glioblastoma patients to benefit from these new approaches, but the road is still long for broad application. Here, we aim to review key glioblastoma immune related characteristics, current immunotherapeutic strategies being explored, their potential caveats, and future directions.
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http://dx.doi.org/10.3390/ijms22073493DOI Listing
March 2021

Allogeneic CAR T Cells: An Alternative to Overcome Challenges of CAR T Cell Therapy in Glioblastoma.

Front Immunol 2021 3;12:640082. Epub 2021 Mar 3.

Center for Translational Research in Onco-Hematology, University of Geneva, Geneva, Switzerland.

Chimeric antigen receptor (CAR) T cell therapy has emerged as one of the major breakthroughs in cancer immunotherapy in the last decade. Outstanding results in hematological malignancies and encouraging pre-clinical anti-tumor activity against a wide range of solid tumors have made CAR T cells one of the most promising fields for cancer therapies. CAR T cell therapy is currently being investigated in solid tumors including glioblastoma (GBM), a tumor for which survival has only modestly improved over the past decades. CAR T cells targeting EGFRvIII, Her2, or IL-13Rα2 have been tested in GBM, but the first clinical trials have shown modest results, potentially due to GBM heterogeneity and to the presence of an immunosuppressive microenvironment. Until now, the use of autologous T cells to manufacture CAR products has been the norm, but this approach has several disadvantages regarding production time, cost, manufacturing delay and dependence on functional fitness of patient T cells, often reduced by the disease or previous therapies. Universal "off-the-shelf," or allogeneic, CAR T cells is an alternative that can potentially overcome these issues, and allow for multiple modifications and CAR combinations to target multiple tumor antigens and avoid tumor escape. Advances in genome editing tools, especially CRISPR/Cas9, might allow overcoming the two main limitations of allogeneic CAR T cells product, i.e., graft-vs.-host disease and host allorejection. Here, we will discuss how allogeneic CAR T cells could allow for multivalent approaches and alteration of the tumor microenvironment, potentially allowing the development of next generation therapies for the treatment of patients with GBM.
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http://dx.doi.org/10.3389/fimmu.2021.640082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7966522PMC
March 2021

Oncolytic Viruses as a Platform for the Treatment of Malignant Brain Tumors.

Int J Mol Sci 2020 Oct 9;21(20). Epub 2020 Oct 9.

Brain Tumor and Immune Cell Engineering Laboratory, Faculty of Medicine, University of Geneva, 1205 Geneva, Switzerland.

Malignant brain tumors remain incurable diseases. Although much effort has been devoted to improving patient outcome, multiple factors such as the high tumor heterogeneity, the strong tumor-induced immunosuppressive microenvironment, and the low mutational burden make the treatment of these tumors especially challenging. Thus, novel therapeutic strategies are urgent. Oncolytic viruses (OVs) are biotherapeutics that have been selected or engineered to infect and selectively kill cancer cells. Increasingly, preclinical and clinical studies demonstrate the ability of OVs to recruit T cells and induce durable immune responses against both virus and tumor, transforming a "cold" tumor microenvironment into a "hot" environment. Besides promising clinical results as a monotherapy, OVs can be powerfully combined with other cancer therapies, helping to overcome critical barriers through the creation of synergistic effects in the fight against brain cancer. Although many questions remain to be answered to fully exploit the therapeutic potential of OVs, oncolytic virotherapy will clearly be part of future treatments for patients with malignant brain tumors.
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http://dx.doi.org/10.3390/ijms21207449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589928PMC
October 2020

Single-Cell Analyses Identify Brain Mural Cells Expressing CD19 as Potential Off-Tumor Targets for CAR-T Immunotherapies.

Cell 2020 Oct 21;183(1):126-142.e17. Epub 2020 Sep 21.

Parker Institute for Cancer Immunotherapy, Stanford University School of Medicine, Stanford, CA, USA; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. Electronic address:

CD19-directed immunotherapies are clinically effective for treating B cell malignancies but also cause a high incidence of neurotoxicity. A subset of patients treated with chimeric antigen receptor (CAR) T cells or bispecific T cell engager (BiTE) antibodies display severe neurotoxicity, including fatal cerebral edema associated with T cell infiltration into the brain. Here, we report that mural cells, which surround the endothelium and are critical for blood-brain-barrier integrity, express CD19. We identify CD19 expression in brain mural cells using single-cell RNA sequencing data and confirm perivascular staining at the protein level. CD19 expression in the brain begins early in development alongside the emergence of mural cell lineages and persists throughout adulthood across brain regions. Mouse mural cells demonstrate lower levels of Cd19 expression, suggesting limitations in preclinical animal models of neurotoxicity. These data suggest an on-target mechanism for neurotoxicity in CD19-directed therapies and highlight the utility of human single-cell atlases for designing immunotherapies.
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http://dx.doi.org/10.1016/j.cell.2020.08.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7640763PMC
October 2020

An Experimentally Defined Hypoxia Gene Signature in Glioblastoma and Its Modulation by Metformin.

Biology (Basel) 2020 Sep 2;9(9). Epub 2020 Sep 2.

Center for Translational Research in Onco-Hematology, Division of Oncology, Geneva University Hospitals and University of Geneva, 1211 Geneva, Switzerland.

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor, characterized by a high degree of intertumoral heterogeneity. However, a common feature of the GBM microenvironment is hypoxia, which can promote radio- and chemotherapy resistance, immunosuppression, angiogenesis, and stemness. We experimentally defined common GBM adaptations to physiologically relevant oxygen gradients, and we assessed their modulation by the metabolic drug metformin. We directly exposed human GBM cell lines to hypoxia (1% O) and to physioxia (5% O). We then performed transcriptional profiling and compared our in vitro findings to predicted hypoxic areas in vivo using in silico analyses. We observed a heterogenous hypoxia response, but also a common gene signature that was induced by a physiologically relevant change in oxygenation from 5% O to 1% O. In silico analyses showed that this hypoxia signature was highly correlated with a perinecrotic localization in GBM tumors, expression of certain glycolytic and immune-related genes, and poor prognosis of GBM patients. Metformin treatment of GBM cell lines under hypoxia and physioxia reduced viable cell number, oxygen consumption rate, and partially reversed the hypoxia gene signature, supporting further exploration of targeting tumor metabolism as a treatment component for hypoxic GBM.
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http://dx.doi.org/10.3390/biology9090264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563149PMC
September 2020

Impact of Radiochemotherapy on Immune Cell Subtypes in High-Grade Glioma Patients.

Front Oncol 2020 14;10:89. Epub 2020 Feb 14.

Laboratory of Tumor Immunology and Center of Oncology, Geneva University Hospital, Geneva, Switzerland.

Glioblastoma is a dreadful disease with very poor prognosis, median overall survival being <2 years despite standard-of-care treatment. This has led to the development of alternative strategies, among which immunotherapy is being actively tested. In particular, many clinical trials of therapeutic vaccination using peptides or tumor cells are ongoing. A major issue in implementing therapeutic vaccines in patients with high-grade glioma is that immune responses have to be elicited in the context of immunosuppressive treatments. Indeed, radiotherapy, chemotherapy, and steroids, which are part of the standard of care for patients with glioblastoma, are known to deplete leukocytes. Whether lymphopenia is beneficial or detrimental to elicitation of efficient immune responses is still debated. Here, in order to determine the impact of standard radiochemotherapy on immune cell subsets, we analyzed the phenotype and function of immune populations in 25 patients with high-grade glioma along concomitant radiochemotherapy and adjuvant chemotherapy with temozolomide. Thirteen healthy individuals were studied along the same period. We show that absolute T and B cell counts are reduced upon concomitant radiochemotherapy. Importantly, T cell counts were not restored long-term after discontinuation of treatment. In addition, the percentage of T regulatory cells among CD4 T cells was increased during the same period and was not decreased upon treatment discontinuation. Finally, we show that the ability of T cells to proliferate is transiently reduced after concomitant radiochemotherapy but is restored at the time of adjuvant TMZ cycles. Although not experimentally validated, transient reduction in proliferation associated with strong lymphopenia during radiochemotherapy may suggest that vaccine-induced T cell stimulation would be suboptimal in that period and that therapeutic vaccination should be performed outside radiochemotherapy administration. In addition, strategies aiming at depleting Treg cells should be implemented in future trials.
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http://dx.doi.org/10.3389/fonc.2020.00089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7034105PMC
February 2020

Current strategies for vaccination in glioblastoma.

Curr Opin Oncol 2019 11;31(6):514-521

Laboratory of Tumor Immunology and Department of Oncology, Geneva University Hospital.

Purpose Of Review: Immunotherapy is viewed as a promising approach for glioblastoma and, in particular, therapeutic vaccines are being intensively studied. Here, we review results provided by recent clinical trials of glioblastoma vaccination and discuss the required strategies to optimize such approaches.

Recent Findings: Two studies showed the feasibility of generating mutation-derived personalized vaccines in the short time frame given by the fast course of disease in glioblastoma. However, one of these demonstrated lack of mutation-derived cell surface presented MHC class I or II peptides in tumors with low mutational burden.

Summary: Whereas glioblastoma vaccines are well tolerated, impact on patient survival has yet to be proven. Combinations with immune checkpoint inhibitors are being tested, but strategies aiming at targeting the tumor microenvironment should be implemented as well. Finally, accurate immunomonitoring should be promoted in order to identify the best vaccine strategies, alone or in combination.
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http://dx.doi.org/10.1097/CCO.0000000000000575DOI Listing
November 2019

Keeping the Engine Running: The Relevance and Predictive Value of Preclinical Models for CAR-T Cell Development.

ILAR J 2018 12;59(3):276-285

Department of Pathology and Laboratory Medicine, and Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania; and Parker Institute for Cancer Immunotherapy; and Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania.

The cellular immunotherapy field has achieved important milestones in the last 30 years towards the treatment of a variety of cancers due to improvements in ex-vivo T cell manufacturing processes, the invention of synthetic T cell receptors, and advances in cellular engineering. Here, we discuss major preclinical models that have been useful for the validation of chimeric antigen receptor (CAR)-T cell therapies and also promising new models that will fuel future investigations towards success. However, multiple unanswered questions in the CAR-T cell field remain to be addressed that will require innovative preclinical models. Key challenges facing the field include premature immune rejection of universal CAR-T cells and the immune suppressive tumor microenvironment. Immune competent models that accurately recapitulate tumor heterogeneity, the hostile tumor microenvironment, and barriers to CAR-T cell homing, toxicity, and persistence are needed for further advancement of the field.
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http://dx.doi.org/10.1093/ilar/ilz009DOI Listing
December 2018

Exploratory Study of the Effect of IMA950/Poly-ICLC Vaccination on Response to Bevacizumab in Relapsing High-Grade Glioma Patients.

Cancers (Basel) 2019 Apr 2;11(4). Epub 2019 Apr 2.

Laboratory of Tumour Immunology and Department of Oncology, Geneva University Hospital, 1211 Geneva, Switzerland.

Immunotherapy, including therapeutic vaccines, is increasingly being developed for patients with high-grade glioma, and combinations of immunotherapies and synergy with standard of care are being investigated. In this regard, bevacizumab (BEV) has been shown to synergize with immunotherapy in preclinical studies of glioma and in other tumour entities. Here, we conducted a post-hoc exploratory study to evaluate the effect of the IMA950/poly-ICLC peptide vaccine on subsequent BEV administration in high-grade glioma patients. 16 IMA950-vaccinated and 40 non-vaccinated patients were included. At initial diagnosis, patients benefited from surgery and chemoradiation. At first or subsequent recurrence, patients received 10mg/kg of BEV every 2-3 weeks. Primary endpoints were overall survival (OS) and progression-free survival (PFS) from BEV initiation. IMA950-vaccinated patients did not show improved response to BEV as compared to non-vaccinated patients: there was no difference in median PFS (2.6 vs. 4.2 months for vaccinated and control patients, respectively, = 0.50) nor in median OS (7.8 vs. 10.0 months for vaccinated and control patients, respectively, = 0.69). In conclusion, potential synergy of BEV and therapeutic vaccines, when administered sequentially, has yet to be established in the clinical setting of GBM recurrence. Potential synergy of concomitant administration should be tested in future trials.
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http://dx.doi.org/10.3390/cancers11040464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6520681PMC
April 2019

Phase I/II trial testing safety and immunogenicity of the multipeptide IMA950/poly-ICLC vaccine in newly diagnosed adult malignant astrocytoma patients.

Neuro Oncol 2019 07;21(7):923-933

Department of Oncology, Clinical Research Unit, Dr Dubois Ferrière Dinu Lipatti Research Foundation, Geneva University Hospital, Geneva, Switzerland.

Background: Peptide vaccines offer the opportunity to elicit glioma-specific T cells with tumor killing ability. Using antigens eluted from the surface of glioblastoma samples, we designed a phase I/II study to test safety and immunogenicity of the IMA950 multipeptide vaccine adjuvanted with poly-ICLC (polyinosinic-polycytidylic acid stabilized with polylysine and carboxymethylcellulose) in human leukocyte antigen A2+ glioma patients.

Methods: Adult patients with newly diagnosed glioblastoma (n = 16) and grade III astrocytoma (n = 3) were treated with radiochemotherapy followed by IMA950/poly-ICLC vaccination. The first 6 patients received IMA950 (9 major histocompatibility complex [MHC] class I and 2 MHC class II peptides) intradermally and poly-ICLC intramuscularly (i.m.). After protocol amendment, IMA950 and poly-ICLC were mixed and injected subcutaneously (n = 7) or i.m. (n = 6). Primary endpoints were safety and immunogenicity. Secondary endpoints were overall survival, progression-free survival at 6 and 9 months, and vaccine-specific peripheral cluster of differentiation (CD)4 and CD8 T-cell responses.

Results: The IMA950/poly-ICLC vaccine was safe and well tolerated. Four patients presented cerebral edema with rapid recovery. For the first 6 patients, vaccine-induced CD8 T-cell responses were restricted to a single peptide and CD4 responses were absent. After optimization of vaccine formulation, we observed multipeptide CD8 and sustained T helper 1 CD4 T-cell responses. For the entire cohort, CD8 T-cell responses to a single or multiple peptides were observed in 63.2% and 36.8% of patients, respectively. Median overall survival was 19 months for glioblastoma patients.

Conclusion: We provide, in a clinical trial, using cell surface-presented antigens, insights into optimization of vaccines generating effector T cells for glioma patients.

Trial Registration: Clinicaltrials.gov NCT01920191.
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http://dx.doi.org/10.1093/neuonc/noz040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6620642PMC
July 2019

Actively personalized vaccination trial for newly diagnosed glioblastoma.

Nature 2019 01 19;565(7738):240-245. Epub 2018 Dec 19.

University Hospital Heidelberg, Heidelberg, Germany.

Patients with glioblastoma currently do not sufficiently benefit from recent breakthroughs in cancer treatment that use checkpoint inhibitors. For treatments using checkpoint inhibitors to be successful, a high mutational load and responses to neoepitopes are thought to be essential. There is limited intratumoural infiltration of immune cells in glioblastoma and these tumours contain only 30-50 non-synonymous mutations. Exploitation of the full repertoire of tumour antigens-that is, both unmutated antigens and neoepitopes-may offer more effective immunotherapies, especially for tumours with a low mutational load. Here, in the phase I trial GAPVAC-101 of the Glioma Actively Personalized Vaccine Consortium (GAPVAC), we integrated highly individualized vaccinations with both types of tumour antigens into standard care to optimally exploit the limited target space for patients with newly diagnosed glioblastoma. Fifteen patients with glioblastomas positive for human leukocyte antigen (HLA)-A*02:01 or HLA-A*24:02 were treated with a vaccine (APVAC1) derived from a premanufactured library of unmutated antigens followed by treatment with APVAC2, which preferentially targeted neoepitopes. Personalization was based on mutations and analyses of the transcriptomes and immunopeptidomes of the individual tumours. The GAPVAC approach was feasible and vaccines that had poly-ICLC (polyriboinosinic-polyribocytidylic acid-poly-L-lysine carboxymethylcellulose) and granulocyte-macrophage colony-stimulating factor as adjuvants displayed favourable safety and strong immunogenicity. Unmutated APVAC1 antigens elicited sustained responses of central memory CD8 T cells. APVAC2 induced predominantly CD4 T cell responses of T helper 1 type against predicted neoepitopes.
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http://dx.doi.org/10.1038/s41586-018-0810-yDOI Listing
January 2019

Checkpoint Blockade Reverses Anergy in IL-13Rα2 Humanized scFv-Based CAR T Cells to Treat Murine and Canine Gliomas.

Mol Ther Oncolytics 2018 Dec 28;11:20-38. Epub 2018 Aug 28.

Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

We generated two humanized interleukin-13 receptor α2 (IL-13Rα2) chimeric antigen receptors (CARs), Hu07BBz and Hu08BBz, that recognized human IL-13Rα2, but not IL-13Rα1. Hu08BBz also recognized canine IL-13Rα2. Both of these CAR T cell constructs demonstrated superior tumor inhibitory effects in a subcutaneous xenograft model of human glioma compared with a humanized EGFRvIII CAR T construct used in a recent phase 1 clinical trial (ClinicalTrials.gov: NCT02209376). The Hu08BBz demonstrated a 75% reduction in orthotopic tumor growth using low-dose CAR T cell infusion. Using combination therapy with immune checkpoint blockade, humanized IL-13Rα2 CAR T cells performed significantly better when combined with CTLA-4 blockade, and humanized EGFRvIII CAR T cells' efficacy was improved by PD-1 and TIM-3 blockade in the same mouse model, which was correlated with the levels of checkpoint molecule expression in co-cultures with the same tumor . Humanized IL-13Rα2 CAR T cells also demonstrated benefit from a self-secreted anti-CTLA-4 minibody in the same mouse model. In addition to a canine glioma cell line (J3T), canine osteosarcoma lung cancer and leukemia cell lines also express IL-13Rα2 and were recognized by Hu08BBz. Canine IL-13Rα2 CAR T cell was also generated and tested by co-culture with canine tumor cells and in an orthotopic model of canine glioma. Based on these results, we are designing a pre-clinical trial to evaluate the safety of canine IL-13Rα2 CAR T cells in dog with spontaneous IL-13Rα2-positive glioma, which will help to inform a human clinical trial design for glioblastoma using humanized scFv-based IL-13Rα2 targeting CAR T cells.
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http://dx.doi.org/10.1016/j.omto.2018.08.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6174845PMC
December 2018

Glycan-directed CAR-T cells.

Glycobiology 2018 09;28(9):656-669

Center of Cellular Immunotherapies, Abramson Cancer Center and the Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Cancer immunotherapy is rapidly advancing in the treatment of a variety of hematopoietic cancers, including pediatric acute lymphoblastic leukemia and diffuse large B cell lymphoma, with chimeric antigen receptor (CAR)-T cells. CARs are genetically encoded artificial T cell receptors that combine the antigen specificity of an antibody with the machinery of T cell activation. However, implementation of CAR technology in the treatment of solid tumors has been progressing much slower. Solid tumors are characterized by a number of challenges that need to be overcome, including cellular heterogeneity, immunosuppressive tumor microenvironment (TME), and, in particular, few known cancer-specific targets. Post-translational modifications that differentially occur in malignant cells generate valid cell surface, cancer-specific targets for CAR-T cells. We previously demonstrated that CAR-T cells targeting an aberrant O-glycosylation of MUC1, a common cancer marker associated with changes in cell adhesion, tumor growth and poor prognosis, could control malignant growth in mouse models. Here, we discuss the field of glycan-directed CAR-T cells and review the different classes of antibodies specific for glycan-targeting, including the generation of high affinity O-glycopeptide antibodies. Finally, we discuss historic and recently investigated glycan targets for CAR-T cells and provide our perspective on how targeting the tumor glycoproteome and/or glycome will improve CAR-T immunotherapy.
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http://dx.doi.org/10.1093/glycob/cwy008DOI Listing
September 2018

Antigenic expression and spontaneous immune responses support the use of a selected peptide set from the IMA950 glioblastoma vaccine for immunotherapy of grade II and III glioma.

Oncoimmunology 2018;7(2):e1391972. Epub 2017 Nov 7.

Department of Oncology, Geneva University Hospital, Rue Gabrielle-Perret-Gentil 4, 1204 Geneva 11, Switzerland and Department of Internal Medicine Specialties, Faculty of Medicine, University of Geneva, Rue Michel-Servet 1, 1205 Geneva Switzerland.

Gliomas are lethal brain tumors that resist standard therapeutic approaches. Immunotherapy is a promising alternative strategy mostly developed in the context of glioblastoma. However, there is a need for implementing immunotherapy for grade II/III gliomas, as these are the most common CNS tumors in young adults with a high propensity for recurrence, making them lethal despite current treatments. We recently identified HLA-A2-restricted tumor-associated antigens by peptide elution from glioblastoma and formulated a multipeptide vaccine (IMA950) evaluated in phase I/II clinical trials with promising results. Here, we investigated expression of the IMA950 antigens in patients with grade II/III astrocytoma, oligodendroglioma or ependymoma, at the mRNA, protein and peptide levels. We report that the BCAN, CSPG4, IGF2BP3, PTPRZ1 and TNC proteins are significantly over-expressed at the mRNA (n = 159) and protein (n = 36) levels in grade II/III glioma patients as compared to non-tumor samples (IGF2BP3 being absent from oligodendroglioma). Most importantly, we detected spontaneous antigen-specific T cell responses to one or more of the IMA950 antigens in 100% and 71% of grade II and grade III patients, respectively (27 patients tested). These patients displayed T cell responses of better quality (higher frequency, broader epitope targeting) than patients with glioblastoma. Detection of spontaneous T cell responses to the IMA950 antigens shows that these antigens are relevant for tumor targeting, which will be best achieved by combination with CD4 epitopes such as the IDH1R132H peptide. Altogether, we provide the rationale for using a selective set of IMA950 peptides for vaccination of patients with grade II/III glioma.
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http://dx.doi.org/10.1080/2162402X.2017.1391972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5749651PMC
November 2017

Rapidly Growing Pulmonary Metastasis from Anaplastic Meningioma with Lethal Outcome: A Case Report.

J Neurol Surg Rep 2017 Oct 28;78(4):e129-e134. Epub 2017 Dec 28.

Service de Neurochirurgie, Département des Neurosciences Cliniques, Hôpitaux Universitaires de Genève, Genève, Switzerland.

Anaplastic meningioma is seldom encountered. Moreover, distant metastasis is extremely rare, with only a handful cases reported. Here, we report the case of a 74-year-old female patient who underwent a combined cranial and endonasal approach for an extensive spheno-orbital anaplastic meningioma (WHO grade III), followed by adjuvant radiotherapy. Although local tumor control was achieved, she presented with lung metastasis 2 years later. The patient then died from pulmonary complications related to chest metastasis. On the basis of this case, we discuss the available literature on metastatic meningiomas and radiologic follow-up strategies.
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http://dx.doi.org/10.1055/s-0037-1615808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5746346PMC
October 2017

CAR T-Cell Therapies in Glioblastoma: A First Look.

Clin Cancer Res 2018 02 20;24(3):535-540. Epub 2017 Nov 20.

Center for Cellular Immunotherapies and Parker Institute for Cancer Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

Glioblastoma is an aggressive malignancy with a poor prognosis. The current standard of care for newly diagnosed glioblastoma patients includes surgery to the extent, temozolomide combined with radiotherapy, and alternating electric fields therapy. After recurrence, there is no standard therapy and survival is less than 9 months. Recurrent glioblastoma offers a unique opportunity to investigate new treatment approaches in a malignancy known for remarkable genetic heterogeneity, an immunosuppressive microenvironment, and a partially permissive anatomic blood-brain barrier. Results from three first-in-man chimeric antigen receptor (CAR) T-cell trials targeting IL13Rα2, Her2/CMV, and EGFRvIII have recently been reported. Each one of these trials addresses important questions, such as T-cell trafficking to CNS, engraftment and persistence, tumor microenvironment remodeling, and monitoring of glioma response to CAR T cells. Objective radiologic responses have been reported. Here, we discuss and summarize the results of these trials and suggest opportunities for the field. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-2871DOI Listing
February 2018

First report of clinical responses to immunotherapy in 3 relapsing cases of chordoma after failure of standard therapies.

Oncoimmunology 2017;6(8):e1338235. Epub 2017 Jun 21.

Department of Oncology, Geneva University Hospital, Geneva, Switzerland.

Chordoma is a rare tumor of notochordal origin, currently principally treated by surgery and/or irradiation. Here, we describe the clinical outcome of 3 consecutive patients with metastatic and locally advanced chordoma, treated with different immunotherapeutic approaches. All patients presented fast growing tumors and failure of standard therapies. One was treated with a tumor-based vaccine, the 2 others with anti-PD1 antibodies, all with impressive clinical and radiological responses. We therefore propose that chordoma is an immunogenic tumor and thus that translational and clinical research is necessary to develop rationally designed immunotherapy approaches.
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http://dx.doi.org/10.1080/2162402X.2017.1338235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5593713PMC
June 2017

[Brain tumor immunotherapy: Illusion or hope?]

Bull Cancer 2017 May 17;104(5):476-484. Epub 2017 Mar 17.

Hôpitaux universitaires de Genève, centre d'oncologie, 4, rue Gabrielle-Perret-Gentil, 1211 Genève, Suisse. Electronic address:

Immunotherapy has proven efficient for many tumors and is now part of standard of care in many indications. What is the picture for brain tumors? The recent development of anti-CTLA-4 and PD1 immune checkpoint inhibitors, which have the ability to restore T lymphocytes activity, has gathered enthusiasm and is now paving the way towards more complex models of immune system manipulation. These models include, among others, vaccination and adoptive T cell transfer technologies. Complementary to those strategies, molecules capable of reshaping the immune tumor microenvironment are currently being investigated in early phase trials. Indeed, the tumor bed is hostile to anti-tumor immune responses due to many escape mechanisms, and this is particularly true in the context of brain tumors, a master in eliciting immunosuppressive cells and molecules. The goal of this review is to describe the hopes and challenges of brain tumors immunotherapy and to propose an inventory of the current clinical research with specific focus on the therapies targeting the tumor microenvironment.
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http://dx.doi.org/10.1016/j.bulcan.2017.01.014DOI Listing
May 2017

Immunotherapy of Malignant Tumors in the Brain: How Different from Other Sites?

Front Oncol 2016 7;6:256. Epub 2016 Dec 7.

Laboratory of Tumor Immunology, Center of Oncology, Geneva University Hospitals and University of Geneva , Geneva , Switzerland.

Immunotherapy is now advancing at remarkable pace for tumors located in various tissues, including the brain. Strategies launched decades ago, such as tumor antigen-specific therapeutic vaccines and adoptive transfer of tumor-infiltrating lymphocytes are being complemented by molecular engineering approaches allowing the development of tumor-specific TCR transgenic and chimeric antigen receptor T cells. In addition, the spectacular results obtained in the last years with immune checkpoint inhibitors are transfiguring immunotherapy, these agents being used both as single molecules, but also in combination with other immunotherapeutic modalities. Implementation of these various strategies is ongoing for more and more malignancies, including tumors located in the brain, raising the question of the immunological particularities of this site. This may necessitate cautious selection of tumor antigens, minimizing the immunosuppressive environment and promoting efficient T cell trafficking to the tumor. Once these aspects are taken into account, we might efficiently design immunotherapy for patients suffering from tumors located in the brain, with beneficial clinical outcome.
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http://dx.doi.org/10.3389/fonc.2016.00256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5141244PMC
December 2016

Upfront targeted therapy for symptomatic melanoma brain metastases: paradigm changing?

CNS Oncol 2016 Oct 12;5(4):199-201. Epub 2016 Sep 12.

Geneva University Hospitals, Center of Oncology, Geneva, Switzerland.

The standard management of a single brain metastasis is usually maximal resection when feasible followed by radiotherapy. In case of multiple lesions, several options have to be considered depending on the natural behavior of the primary tumor, the localization of brain lesions, their functional impact and related symptoms. In case of life-threatening brain metastasis, debulking surgery is often proposed first, with the risk of major bleeding and postponing the initiation of other treatments. This approach is now challenged by the rapid tumor shrinkage that could be observed with novel targeted therapies. Here we report the case of a patient suffering from a melanoma with multiple brain metastasis, treated with BRAF and MEK double blockade, with impressive and rapid response.
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http://dx.doi.org/10.2217/cns-2016-0019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6040041PMC
October 2016

[Immunotherapy for brain tumors: obstacles and perspectives].

Rev Med Suisse 2016 Apr;12(516):828-31

Glioblastomas are highly aggressive tumors. Their prognosis remain poor despite standard therapies combining surgery, radiation and temozolomide based chemotherapy. Among innovating strategies, there is a major interest for immunotherapy. During the past 3 decades, there has been a general scepticism concerning the efficacy of this approach. But the latest achievements, such as immune checkpoint inhibitors in solid tumors, and adoptive cell therapy in hematologic malignancies, have radically changed the face of the field and have already an impact on the daily practice. To which extent these advances have an impact for brain tumors also? This article aims to present the principal clinical applications of the various immune therapies currently under investigation in neurooncology and give an insight on the future perspectives in the field.
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April 2016

[Multidisciplinar approach to the management of gliomas].

Rev Med Suisse 2016 Apr;12(516):821-5

Gliomas represent two thirds of all primary brain tumors. Their prognosis depends directly upon their level of differentiation. On MRI, tumoral aggressivity is highlighted by contrast uptake and the infiltrative nature of the lesion. Clinical suspicion must however be confirmed by histology and molecular markers become essential to refine the diagnosis and tailor the treatment. Isocytrate dehydrogenase (IDH) mutations, codeletion of 1p and 19q and the presence of methylation of the MGMT promoter identify a subgroup of gliomas with better prognosis and may help predict response to treatment. Management of patients with primary brain tumors should always be defined in multidisciplinar tumor boards involving neurosurgeons, oncologists, radiation oncologists, neuropathologists and neuroradiologists.
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April 2016

Recurrent multiple CNS hemangioblastomas with VHL disease treated with pazopanib: a case report and literature review.

CNS Oncol 2015 26;4(6):387-92. Epub 2015 Oct 26.

Centre of Oncology, University Hospital of Geneva, Geneva, Switzerland.

Hemangioblastoma is a rare benign neoplasm, accounting for less than 2% of all primitive brain tumors. It may arise sporadically in a solitary form, or associated with Von Hippel-Lindau (VHL) disease with multiple tumors. Surgery is the mainstay treatment, but management is challenging in case of recurrent and/or multiple tumors. VHL protein is defective in both forms of hemangioblastoma, leading to the accumulation of hypoxia-inducible factor, stimulating angiogenesis via VEGF and PDGF mainly. Here, we report a 37-year-old woman's case with recurrent and rapidly progressive VHL-associated hemangioblastomas, causing severe disability. She was treated 24 months with pazopanib, a multityrosine kinase inhibitor (TKI) targeting VEGF and PDGF-β pathways. Despite moderate radiological changes, progressive improvement in her clinical condition persisting over 3 years was observed. Inhibiting angiogenesis is a therapeutic option that may improve the quality of life and the autonomy of VHL patients disabled with multiple hemangioblastomas.
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http://dx.doi.org/10.2217/cns.15.22DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6083944PMC
August 2016

Immunotherapy of Brain Tumors.

Prog Tumor Res 2015 4;42:11-21. Epub 2015 Sep 4.

Glioma is one of the most devastating cancers, affecting children and young adults, and associated with a very high morbidity and poor prognosis. The propensity of glioma cells to invade normal brain structures makes current treatments poorly efficient and new therapeutic strategies an urgent need. We now know that many of the rules governing immune responses in other tissues are also valid for the brain, providing solid scientific background for developing new strategies exploiting the immune system to fight brain tumors. Some vaccines use tumor-specific mutated peptides (EGFRvIII, IDH1 or personalized peptides), but most are tumor-associated or undefined tumor-derived peptides (tumor-eluted peptides, peptides predicted from tumor-associated proteins or bound to HSPPC-96 complexes), in some cases pulsed on dendritic cells. Cell therapy is less advanced but the first clinical trials exploring the safety of T cells with chimeric antigen receptors incorporating antibodies to EGFRvIII, IL-13Rα2 or Her2 are ongoing. Finally, various strategies designed at reshaping the glioma microenvironment are being tested, including TGFβ inhibition, Treg depletion and immune checkpoint blockade. Altogether, combining vaccines, cell therapy and reshaping of the tumor microenvironment will be the foundation for a new era of therapeutics for brain tumors.
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http://dx.doi.org/10.1159/000436986DOI Listing
March 2016

The CD40/CD40L axis in glioma progression and therapy.

Neuro Oncol 2015 Nov 22;17(11):1428-30. Epub 2015 Jul 22.

Centre of Oncology, Geneva University Hospitals and University of Geneva, Geneva, Switzerland (P.R.W., D.M.).

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http://dx.doi.org/10.1093/neuonc/nov138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4648308PMC
November 2015

[Cerebral lymphoma: a classic presentation?].

Rev Med Suisse 2015 Feb;11(460):371-3

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February 2015

Maximizing output from current glioma vaccine trials to construct robust next-generation immunotherapies.

Immunotherapy 2013 Nov;5(11):1147-50

Centre of Oncology, Geneva University Hospitals & University of Geneva, Geneva, Switzerland.

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http://dx.doi.org/10.2217/imt.13.115DOI Listing
November 2013