Inhibitory CARs fail to protect from immediate T cell cytotoxicity.
Mol Ther
; 32(4): 982-999, 2024 Apr 03.
Article
en En
| MEDLINE
| ID: mdl-38384128
ABSTRACT
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Receptores Quiméricos de Antígenos
/
Neoplasias
Límite:
Humans
Idioma:
En
Revista:
Mol Ther
Asunto de la revista:
BIOLOGIA MOLECULAR
/
TERAPEUTICA
Año:
2024
Tipo del documento:
Article