Immunotherapy targeting B cells and long-lived plasma cells effectively eliminates pre-existing donor-specific allo-antibodies.

Pre-existing anti-human leukocyte antigen (HLA) allo-antibodies constitute a major barrier to transplantation. Current desensitization approaches fail due to ineffective depletion of allo-specific memory B cells (Bmems) and long-lived plasma cells (LLPCs). We evaluate the efficacy of chimeric antigen receptor (CAR) T cells targeting CD19 and B cell maturation antigen (BCMA) to eliminate allo-antibodies in a skin pre-sensitized murine model of islet allo-transplantation. We find that treatment of allo-sensitized hosts with CAR T cells targeting Bmems and LLPCs eliminates donor-specific allo-antibodies (DSAs) and mitigates hyperacute rejection of subsequent islet allografts. We then assess the clinical efficacy of the CAR T therapy for desensitization in patients with multiple myeloma (MM) with pre-existing HLA allo-antibodies who were treated with the combination of CART-BCMA and CART-19 (ClinicalTrials.gov: NCT03549442) and observe clinically meaningful allo-antibody reduction. These findings provide logical rationale for clinical evaluation of CAR T-based immunotherapy in highly sensitized candidates to promote successful transplantation.
Competing Interests: Declaration of interests J.A.F. is an inventor on patents in the field of T cell therapy for cancer, from which he has received royalties. J.A.F. is also a member of the scientific advisory boards of Cartography Bio. and Shennon Biotechnologies, Inc. M.C.M. is an inventor on patents pending or granted related to CAR T cell technology that are assigned to the University of Pennsylvania and licensed to Novartis Ag, from which he receives royalties; these include patents on the CAR T cell therapies described in this study (PCT/US2011/064191, PCT/US2018/061239, PCT/US2018/063255). M.C.M. is also a founder, stockholder, and co-chair of the scientific advisory boards for Cabaletta Bio and Verismo Therapeutics. A.L.G. has received grants from Novartis, grants from National Institutes of Health, and grants from the Leukemia & Lymphoma Society while this study was conducted, grants and personal fees from Janssen, personal fees from GlaxoSmithKline, personal fees from Legend Biotech, grants from CRISPR Therapeutics, grants from Tmunity Therapeutics, personal fees from Amgen, grants from the Leukemia & Lymphoma Society, and grants from National Institutes of Health outside the submitted work; in addition, A.L.G. has a patent for US15/757,123 pending and licensed to Novartis, a patent for US16/764,459 pending, and a patent for US16/768,260 pending and stock ownership in Cabaletta Bio. V.G.B. is an inventor on patents pending or granted related to CAR T cell technology that are assigned to the University of Pennsylvania and licensed to Cabaletta Bio and Tmunity, from which he receives royalties.
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