Feasibility and preclinical efficacy of CD7-unedited CD7 CAR T cells for T cell malignancies.

Chimeric antigen receptor (CAR)-mediated targeting of T lineage antigens for the therapy of blood malignancies is frequently complicated by self-targeting of CAR T cells or their excessive differentiation driven by constant CAR signaling. Expression of CARs targeting CD7, a pan-T cell antigen highly expressed in T cell malignancies and some myeloid leukemias, produces robust fratricide and often requires additional mitigation strategies, such as CD7 gene editing. In this study, we show fratricide of CD7 CAR T cells can be fully prevented using ibrutinib and dasatinib, the pharmacologic inhibitors of key CAR/CD3ζ signaling kinases. Supplementation with ibrutinib and dasatinib rescued the ex vivo expansion of unedited CD7 CAR T cells and allowed regaining full CAR-mediated cytotoxicity in vitro and in vivo on withdrawal of the inhibitors. The unedited CD7 CAR T cells persisted long term and mediated sustained anti-leukemic activity in two mouse xenograft models of human T cell acute lymphoblastic leukemia (T-ALL) by self-selecting for CD7

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Copyright © 2022 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests H.E.H. is a cofounder with equity in Allovir and Marker Therapeutics; serves on advisory boards for Gilead Sciences, GSK, Tessa Therapeutics, Fresh Wind Biotherapeutics, Novartis, and Kiadis; and has received research funding from Tessa Therapeutics and Kuur Therapeutics. M.K.B. is a cofounder with equity in Allovir, Marker Therapeutics, and Tessa Therapeutics and serves on advisory boards for Tessa Therapeutics, Allogene Therapeutics, Memgen, Kuur Therapeutics, Walking Fish Therapeutics, Tscan, Abintus, and Turnstone Biologics.