Targeting brain lesions of non-small cell lung cancer by enhancing CCL2-mediated CAR-T cell migration
Hongxia Li, Emily B. Harrison, Huizhong Li, Koichi Hirabayashi, Jing Chen, Qi‐Xiang Li, Jared Gunn, Jared Weiss, Barbara Savoldo, Joel S. Parker, Chad V. Pecot, Gianpietro Dotti, Hongwei Du
Abstract
Metastatic non-small cell lung cancer (NSCLC) remains largely incurable and the prognosis is extremely poor once it spreads to the brain. In particular, in patients with brain metastases, the blood brain barrier (BBB) remains a significant obstacle for the biodistribution of antitumor drugs and immune cells. Here we report that chimeric antigen receptor (CAR) T cells targeting B7-H3 (B7-H3.CAR) exhibit antitumor activity in vitro against tumor cell lines and lung cancer organoids, and in vivo in xenotransplant models of orthotopic and metastatic NSCLC. The co-expression of the CCL2 receptor CCR2b in B7-H3.CAR-T cells, significantly improves their capability of passing the BBB, providing enhanced antitumor activity against brain tumor lesions. These findings indicate that leveraging T-cell chemotaxis through CCR2b co-expression represents a strategy to improve the efficacy of adoptive T-cell therapies in patients with solid tumors presenting with brain metastases.