B7H3 CAR T细胞疗法在多种免疫健全卵巢癌模型中的应用及可转移抗肿瘤免疫的证据

Immunocompetent models present additional challenges for CAR T therapy due to heterogeneous antigen expression and intact host immunity, making them a clinically relevant setting for evaluating therapeutic robustness. B7H3-targeted CAR T cell therapy has shown promise in some preclinical solid tumors, but its efficacy and ability to induce durable immunity in immunocompetent ovarian cancer models remain largely unexplored. Here, we evaluated the efficacy of a novel murine specific B7H3 CAR construct across multiple syngeneic immunocompetent ovarian cancer models with distinct genetic backgrounds and B7H3 antigen expression profiles. ID8 cell lines bearing Trp53 -/- (homologous recombination (HR) proficient) and Trp53 -/- Brca2 -/- (HR deficient) mutations with heterogeneous B7H3 expression, and BPPNM (Brca1 -/- Pten -/- Trp53 -/-R172H Nf1 -/- Myc OE ) cell lines and homogenous B7H3 expression were used to establish intraperitoneal tumors in immunocompetent C57BL/6 mice. Treatment with a single intraperitoneal dose of B7H3 CAR T cells resulted in significant tumor regression in all models tested, with varying degrees of response and increased survival in all 3 tumor models. Our findings lead us to speculate that heterogeneity in B7H3 antigen expression contributed to differential treatment outcomes. Notably, in a fallopian tube-derived BPPNM model, B7H3 CAR T cell therapy resulted in a complete responder that remained tumor-free following two tumor re-challenges, demonstrating durable anti-tumor immunity. To assess whether this protection was transferable, splenocytes from the complete responder were adoptively transferred into tumor-bearing recipient mice, resulting in pronounced tumor suppression and suggesting the presence of functional tumor-immunity. In summary, these results demonstrate that the murine specific B7H3 CAR T cells are active in immunocompetent ovarian cancer models and can induce systemic, long-lasting anti-tumor responses. Antigen heterogeneity remains a barrier to uniform efficacy, highlighting the need for future combination strategies to enhance consistency and durability of B7H3 CAR T cell responses.