CD24-Targeted CAR-T Cells Mediated Long-term Antitumor Efficacy through Activation of Endogenous Tumor Immune Responses

Chimeric antigen receptor-modified T (CAR-T) cell therapy has achieved remarkable progress in the treatment of B-cell malignancies, whereas 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 antitumor effects of CAR-T cell therapy. In this study, we reported that CAR-T cells targeting cluster of differentiation 24 (CD24), a potential tumor biomarker and an innate immune checkpoint molecule, evoked robust antitumor 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 antitumor ability without side effects. Of note, mice that received CD24 CAR-T cells withstood both CD24-positive and CD24-negative tumors rechallenge. We detected a 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.