B7-H3 CAR T-cells are effective against ependymomas, but limited by tumor size and immune response

Abstract

Purpose: Targeted treatments are desperately needed for ependymomas (EPNs). Chimeric antigen receptor (CAR) T-cells have immense potential to transform patient outcomes. However, CAR T-cell therapy for EPN has been largely understudied. Here, we explore the potential of targeting B7 homolog 3 (B7-H3/CD276) with CAR T-cells to treat pediatric EPN. Experimental Design: We profiled B7-H3 protein expression in 44 pediatric EPN samples by immunohistochemistry. We generated second generation human B7-H3.CAR T-cells and examined their anti-EPN activity in six in vitro and two in vivo xenograft models. We validated findings using HER2-targeted CAR T-cells. In addition, we used murine B7-H3.CAR T-cells to evaluate in vivo antitumor activity in a fully syngeneic supratentorial EPN model. Results: Majority of clinical EPN samples (29/44) stained positive for B7-H3, indicating high but heterogenous expression across patients. In vitro, human B7-H3.CAR T-cells had potent anti-EPN cytolytic activity, expansion, and persistence, which was inversely correlated with upregulation of B7-H3 on CAR T-cells. We found that CAR T-cells favor Th2 phenotypes after repeated exposure to EPN cell lines which may be driven by CCL2 secretion by EPN. In vivo, there was potent and significant antitumor activity in human xenograft EPN models. However, response durability was limited and significantly correlated with degree of tumor burden. In the syngeneic setting, murine B7-H3.CAR T-cell efficacy against EPN was limited and did not extend survival. Conclusions: Our results support ongoing clinical evaluation of B7-H3.CAR T-cells for EPNs and provide model systems for further studying determinants of anti-EPN CAR T-cell treatment efficacy and resistance.