Author: Garnache, Francine ; Lecomte, Martin ; Souque, Philippe ; Certoux, Jean-Marie ; Anna, François ; Escande, Marie ; Loustau, Maria ; Bole-Richard, Elodie ; Caumartin, Julien ; Adotevi, Olivier ; LeMaoult, Joel ; Langlade-Demoyen, Pierre

BackgroundCAR-T cells immunotherapy is a breakthrough in the treatment of hematological malignancies such as acute lymphoblastic leukemia (ALL) and B-cell malignancies. However, CAR-T therapies face major hurdles such as the lack of tumor-specific antigen (TSA), and immunosuppressive tumor microenvironment sometimes caused by the tumorous expression of immune checkpoints (ICPs) such as HLA-G. Indeed, HLA-G is remarkable because it is both a potent ICP and a TSA. HLA-G tumor expression causes immune escape by impairing innate and adaptive immune responses and by inducing a suppressive microenvironment. Yet, to date, no immunotherapy targets it.MethodsWe have developed two anti-HLA-G third-generation CARs based on new anti-HLA-G monoclonal antibodies.ResultsAnti-HLA-G CAR-T cells were specific for immunosuppressive HLA-G isoforms. HLA-G-activated CAR-T cells polarized toward T helper 1, and became cytotoxic against HLA-G+tumor cells. In vivo, anti-HLA-G CAR-T cells were able to control and eliminate HLA-G+tumor cells. The interaction of tumor-HLA-G with interleukin (IL)T2-expressing T cells is known to result in effector T cell functional inhibition, but anti-HLA-G CAR-T cells were insensitive to this inhibition and still exerted their function even when expressing ILT2. Lastly, we show that anti-HLA-G CAR-T cells differentiated into long-term memory effector cells, and seemed not to lose function even after repeated stimulation by HLA-G-expressing tumor cells.ConclusionWe report for the first time that HLA-G, which is both a TSA and an ICP, constitutes a valid target for CAR-T cell therapy to specifically target and eliminate both tumor cells and HLA-G+suppressive cells.

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Indication	Highest Phase	Country/Location	Organization	Date
Hematologic Neoplasms	Preclinical	FR	Invectys SAS	26 Sep 2019

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