Antitumor Responses in the Absence of Toxicity in Solid Tumors by Targeting B7-H3 via Chimeric Antigen Receptor T Cells

作者：R. Liu, Ciming Sun, N.P. Kren, XiaoYan Ma, Yining Chen, G. Dotti, S.G. Herrera, K. Hirabayashi, S.A. Montgomery, B. Savoldo, H. Du, J.J. Yeh, Y. Pylayeva-Gupta, K. Greene, D. Michaud, X. Wang, K. Tiruthani, S. Ahn, S. Ferrone, B. Mirlekar, C.R. Ferrone, Y. Xu · 发表于：Carolina Digital Repository (University of North Carolina at Chapel Hill) · 年份：2021 · DOI：10.17615/dcmm-aw54 · 被引用次数：18 · 研究领域：CAR-T cell therapy research、Immunotherapy and Immune Responses、Cancer Immunotherapy and Biomarkers

The high expression across multiple tumor types and restricted expression in normal tissues make B7-H3 an attractive target for immunotherapy. We generated chimeric antigen receptor (CAR) T cells targeting B7-H3 (B7-H3.CAR-Ts) and found that B7-H3.CAR-Ts controlled the growth of pancreatic ductal adenocarcinoma, ovarian cancer and neuroblastoma in vitro and in orthotopic and metastatic xenograft mouse models, which included patient-derived xenograft. We also found that 4-1BB co-stimulation promotes lower PD-1 expression in B7-H3.CAR-Ts, and superior antitumor activity when targeting tumor cells that constitutively expressed PD-L1. We took advantage of the cross-reactivity of the B7-H3.CAR with murine B7-H3, and found that B7-H3.CAR-Ts significantly controlled tumor growth in a syngeneic tumor model without evident toxicity. These findings support the clinical development of B7-H3.CAR-Ts.