Inhibitory CARs fail to protect from immediate T cell cytotoxicity.

Autor:	Funk MA; Center for Pathophysiology, Infectiology and Immunology, Institute of Immunology, Division for Immune Receptors and T Cell Activation, Medical University of Vienna, Vienna, Austria; University Hospital LMU Munich, Department of Medicine III, Munich, Germany; Gene Center, LMU Munich, Cancer and Immunometabolism Research Group, Munich, Germany; German Cancer Consortium (DKTK), Munich Site and German Cancer Research Center, Heidelberg, Germany., Heller G; Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria., Waidhofer-Söllner P; Center for Pathophysiology, Infectiology and Immunology, Institute of Immunology, Division for Immune Receptors and T Cell Activation, Medical University of Vienna, Vienna, Austria., Leitner J; Center for Pathophysiology, Infectiology and Immunology, Institute of Immunology, Division for Immune Receptors and T Cell Activation, Medical University of Vienna, Vienna, Austria., Steinberger P; Center for Pathophysiology, Infectiology and Immunology, Institute of Immunology, Division for Immune Receptors and T Cell Activation, Medical University of Vienna, Vienna, Austria. Electronic address: peter.steinberger@meduniwien.ac.at.
Jazyk:	angličtina
Zdroj:	Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2024 Apr 03; Vol. 32 (4), pp. 982-999. Date of Electronic Publication: 2024 Feb 22.
DOI:	10.1016/j.ymthe.2024.02.022
Abstrakt:	Chimeric antigen receptors (CARs) equipped with an inhibitory signaling domain (iCARs) have been proposed as strategy to increase on-tumor specificity of CAR-T cell therapies. iCARs inhibit T cell activation upon antigen recognition and thereby program a Boolean NOT gate within the CAR-T cell. If cancer cells do not express the iCAR target antigen while it is highly expressed on healthy tissue, CAR/iCAR coexpressing T cells are supposed to kill cancer cells but not healthy cells expressing the CAR antigen. In this study, we employed a well-established reporter cell system to demonstrate high potency of iCAR constructs harboring BTLA-derived signaling domains. We then created CAR/iCAR combinations for the clinically relevant antigen pairs B7-H3/CD45 and CD123/CD19 and show potent reporter cell suppression by iCARs targeting CD45 or CD19. In primary human T cells αCD19-iCARs were capable of suppressing T cell proliferation and cytokine production. Surprisingly, the iCAR failed to veto immediate CAR-mediated cytotoxicity. Likewise, T cells overexpressing PD-1 or BTLA did not show impaired cytotoxicity toward ligand-expressing target cells, indicating that inhibitory signaling by these receptors does not mediate protection against cytotoxicity by CAR-T cells. Future approaches employing iCAR-equipped CAR-T cells for cancer therapy should therefore monitor off-tumor reactivity and potential CAR/iCAR-T cell dysfunction. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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