Cbl-b inhibition improves manufacturing efficiency and antitumoral efficacy of anti-CD19 CAR-T cells.

Chimeric antigen receptor T (CAR-T) cells represent a promising approach for cancer immunotherapy, yet their efficacy is hindered by immunosuppressive signals in the tumor microenvironment. Casitas B-cell lymphoma protein b (Cbl-b) is a key negative regulator of T cell function. This study investigated whether inhibiting Cbl-b enhances the antitumor activity of human CAR-T cells. The Cbl-b inhibitor NX-1607 was shown to significantly improve CAR-T cell production and function. When applied during the manufacturing phase, NX-1607 increased the yield of anti-CD19 CAR-T cells. Treatment during the expansion phase enhanced cytokine secretion and cytotoxic activity. Notably, continuous NX-1607 treatment throughout manufacturing and expansion maximized CAR-T cell yield, cytokine production, and cytotoxicity. In vivo, NX-1607-treated CAR-T cells exhibited superior efficacy against hematological malignancies. These findings highlight Cbl-b as a therapeutic target for enhancing CAR-T cell manufacturing efficiency and antitumor efficacy, underscoring its potential for clinical applications.