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Emerging Cell Therapies: Realizing the Vision of NextGen Cell Therapeutics | EK15


Donor-unrestricted targeting of CD1c-expressing leukemia by T cells engineered with a lipid-specific TCR


Jan 25, 2021 12:00am ‐ Jan 25, 2021 12:00am

Description

Donor-unrestricted targeting of CD1c-expressing leukemia by T cells engineered with a lipid-specific TCR Acute leukemia is currently treated by chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT). The major unmet clinical need of this approach remains the frequent post-transplant leukemia recurrence. Adoptive immunotherapy with allogeneic donor-derived T cells can control disease recurrence by inducing a beneficial graft-versus-leukemia (GVL) reaction. However, grafted alloreactive T cells can also attack patients’ non-hematopoietic tissues, resulting in detrimental graft-versus-host-disease (GVHD), prompting the search for more specific T-cell targets on malignant cells. We have shown that primary acute myelogenous (AML) and B-lymphoblastic (B-ALL) leukemia blasts express the CD1c molecule, and that a group of human CD1c-restricted, self-reactive T cell clones kills acute leukemia blasts by recognizing the leukemia-associated lipid antigen methyl-lysophosphatidic acid (mLPA). Because CD1c is identical in all individuals and expressed only by mature leukocytes, these results suggest a donor-unrestricted adoptive immunotherapy approach with reduced risk of GvHD induction. To assess the feasibility of ACT for acute leukemia with mLPA-specific T cells, we generated a library of lentiviral vectors encoding a panel of human mLPA-specific TCRs. Upon TCR transduction, either Jurkat T cells or human primary T cells are specifically retargeted against CD1c-expressing malignant cells in vitro, defining a lead mLPA-specific TCR suitable for adoptive immunotherapy. Indeed, we can engineer total T lymphocytes from any donor with the lead mLPA-specific TCR to kill any CD1c-expressing leukemia cell in vitro and in immunodeficient mouse xenografts. These results highlight a novel approach for ACT of acute leukemia with T cells engineered to recognize malignant cells by the transfer of a lipid-specific TCR that works across MHC-barriers like a CAR. Michela Consonni1, Claudio Garavaglia1, Andrea Grilli2, Claudia de Lalla1, Alessandra Mancino1, Lucia Mori3,Gennaro De Libero3, Daniela Montagna4, Angelo Lombardo5, Monica Casucci6, Marta Serafini7, Chiara Bonini8, Daniel Häussinger9, Fabio Ciceri10, Massimo Bernardi10, Sara Mastaglio10, Silvio Bicciato2, Paolo Dellabona1, Giulia Casorati1 1Experimental Immunology Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy; 2Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy; 3Experimental Immunology, Department of Biomedicine, University of Basel and University Hospital, Basel, Switzerland; 4Foundation IRCCS Policlinico San Matteo; Department of Sciences Clinic-Surgical, Diagnostic and Pediatric, University of Pavia, Pavia, Italy; 5San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy; 6Innovative Immunotherapies Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy; 7M. Tettamanti Research Center, University of Milano-Bicocca, Monza, Italy; 8Experimental Hematology Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy; 9NMR-Laboratory, Department of Chemistry, University of Basel; 10Hematology and Bone Marrow Transplant Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy

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