CD24-targeted CAR-T cells mediated long-term anti-tumor efficacy through activation of endogenous tumor immune responses.

Abstract

Chimeric antigen receptor T cell (CAR-T) therapy has achieved remarkable progress in the treatment of B-cell malignancies, while suboptimal therapeutic outcomes have been observed in solid tumors. Immunosuppression from microenvironment of tumors causing decreased killing ability, poor expansion and persistence of CAR-T cells results in reduced efficacy. Endeavors aimed at eliciting endogenous immune responses have been found to enhance and sustain the anti-tumor effects of CAR-T therapy. Here we reported that CAR-T cells targeting CD24, a potential tumor biomarker and an innate immune checkpoint molecular, evoked robust anti-tumor efficacy and elicited long-term tumor regression. CD24-targeted CAR-T (CD24 CAR-T) cells showed strong cytotoxicity to CD24-positive cancer cells in vitro and mediated inhibition of tumor growth in immunodeficient mice. Moreover, in immunocompetent mice, CD24 CAR-T cells exhibited robust anti-tumor ability without side effects. Of note, mice received CD24 CAR-T cells withstand both CD24-positive and negative tumors rechallenge. It is detected that high level of IFN-γ release in splenic lymphocytes of the rechallenged mice, as well as tumor-reactive antibody in serum, indicating the endogenous tumor immune responses was activated. In summary, our findings showed that CD24 CAR-T cells targeting immune checkpoint have superior antitumor efficacy in preclinical models and may provide a strategy for the treatment of solid tumors.