1. Combination lenalidomide-rituximab immunotherapy activates anti-tumour immunity and induces tumour cell death by complementary mechanisms of action in follicular lymphoma
- Author
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Marie-Hélène Delfau-Larue, Anita Gandhi, Preeti Trisal, Despoina Papazoglou, Asma Beldi-Ferchiou, Carla Guarinos, Karin Tarte, Patrick Hagner, Franck Morschhauser, Alan G. Ramsay, Soraya Carrancio, Chad C. Bjorklund, Hsiling Chiu, Estela G. Toraño, Celgene Corporation, School of Cancer and Pharmaceutical Sciences [London, UK] (Faculty of Life Sciences & Medicine), King‘s College London, Département d'immunobiologie et d'hématobiologie [CHU Henri Mondor], CHU Henri Mondor [Créteil], Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Hôpital Claude Huriez [Lille], CHU Lille, Celgene, CHU Henri Mondor, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Jonchère, Laurent, Université de Lille, Groupe de Recherche sur les formes Injectables et les Technologies Associées (GRITA) - EA 7365, Hôpital Henri Mondor, Centre Hospitalier Universitaire [Rennes], AP-HP, Hôpital Henri-Mondor Albert-Chenevier, Service d'Immunologie Clinique et Maladies Infectieuses 94000 Créteil, France, Groupe de Recherche sur les formes Injectables et les Technologies Associées - ULR 7365 [GRITA], Celgene Corporation [San Diego, CA, USA], Celgene Institute for Translational Research Europe [Seville, Spain], and Hôpital Claude Huriez
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[SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology ,Myeloid ,Immunological Synapses ,Neutrophils ,medicine.medical_treatment ,Follicular lymphoma ,CD8-Positive T-Lymphocytes ,Lymphocyte Activation ,immunomodulation ,antibody‐dependent cell‐mediated cytotoxicity ,0302 clinical medicine ,Immunophenotyping ,non-Hodgkin lymphoma ,antibody-dependent cell-mediated cytotoxicity ,lenalidomide ,follicular lymphoma ,Antineoplastic Combined Chemotherapy Protocols ,Tumor Cells, Cultured ,Cytotoxic T cell ,non‐Hodgkin lymphoma ,Lymphoma, Follicular ,Antibody-dependent cell-mediated cytotoxicity ,B-Lymphocytes ,Haematological Malignancy ,[SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology ,Hematology ,3. Good health ,Killer Cells, Natural ,medicine.anatomical_structure ,Vincristine ,030220 oncology & carcinogenesis ,Cytokines ,Rituximab ,Immunotherapy ,[SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy ,Research Paper ,medicine.drug ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,03 medical and health sciences ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,medicine ,Humans ,Lymphocyte Count ,Cyclophosphamide ,Cell Proliferation ,Lenalidomide ,business.industry ,Antibody-Dependent Cell Cytotoxicity ,[SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy ,medicine.disease ,Doxorubicin ,Drug Resistance, Neoplasm ,Cancer research ,Prednisone ,business ,030215 immunology - Abstract
International audience; Chemotherapy plus rituximab has been the mainstay of treatment for follicular lymphoma (FL) for two decades but is associated with immunosuppression and relapse. In phase 2 studies, lenalidomide combined with rituximab (R 2 ) has shown clinical synergy in front-line and relapsed/refractory FL. Here, we show that lenalidomide reactivated dysfunctional T and Natural Killer (NK) cells ex vivo from FL patients by enhancing proliferative capacity and T-helper cell type 1 (Th1) cytokine release. In combination with rituximab, lenalidomide improved antibody-dependent cellular cytotoxicity in sensitive and chemo-resistant FL cells, via a cereblon-dependent mechanism. While single-agent lenalidomide and rituximab increased formation of lytic NK cell immunological synapses with primary FL tumour cells, the combination was superior and correlated with enhanced cytotoxicity. Immunophenotyping of FL patient samples from a phase 3 trial revealed that R 2 treatment increased circulating T- and NK-cell counts, while R-chemotherapy was associated with reduced cell numbers. Finally, using an in vitro model of myeloid differentiation, we demonstrated that lenalidomide caused a reversible arrest in neutrophil maturation that was distinct from a cytotoxic chemotherapeutic agent, which may help explain the lower rates of neutropenia observed with R 2 versus R-chemotherapy. Taken together, we believe these data support a paradigm shift in the treatment of FL – moving from combination immunochemotherapy to chemotherapy-free immunotherapy. © 2019 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley and Sons Ltd.
- Published
- 2019
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