B7-H3 specific T cells with chimeric antigen receptor and decoy PD-1 receptors eradicate established solid human tumors in mouse models

Oncoimmunology. 2019 Nov 4;9(1):1684127. doi: 10.1080/2162402X.2019.1684127. eCollection 2020.

Abstract

The application of chimeric antigen receptor (CAR)-T cell therapy in patients with advanced solid tumors remains a significant challenge. Simultaneously targeting antigen and the solid tumor microenvironment are two major factors that greatly impact CAR-T cell therapy outcomes. In this study, we engineered CAR-T cells to specifically target B7-H3, a protein commonly found in solid human tumors, using a single-chain variable fragment (scFv) derived from an anti-B7-H3 monoclonal antibody. We tested the antitumor activity of B7-H3 CAR-T cells in mouse models with solid human tumors and determined that B7-H3 CAR-T cells exhibited potent antitumor activity against B7-H3+ tumor cells in vitro and in vivo. In addition, PD-1 decoy receptors were engineered to include extracellular PD-1 fused to the intracellular stimulatory domain of either CD28 or IL-7 receptor, respectively, which were then introduced into B7-H3 CAR-T cells. As a result, these newly modified, superior CAR-T cells exhibited more persistent antitumor activity in B7-H3+/B7-H1+ tumors in vivo. Our findings indicate that B7-H3 specific CAR-T cells have the potential to treat multiple types of advanced solid tumors.

Keywords: B7-H3; CAR-T cells; IL-7R; PD-1; cancer immunotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B7-H1 Antigen
  • Cell Line, Tumor
  • Humans
  • Immunotherapy, Adoptive*
  • Mice
  • Neoplasms, Experimental / therapy*
  • Programmed Cell Death 1 Receptor
  • Receptors, Chimeric Antigen* / genetics
  • T-Lymphocytes
  • Xenograft Model Antitumor Assays

Substances

  • B7-H1 Antigen
  • Programmed Cell Death 1 Receptor
  • Receptors, Chimeric Antigen

Grants and funding

This work was supported by the Guangdong Province Innovative Research Program Project [No. 2011Y035]; 863 Project grants to Sun Yat-sen University; Endowed professorship from United Technologies Corporation to Yale University; Fujian Province Department of Science and Technology Research Program [2016L3006]; Fujian Province Department of Science and Technology Research Program [2015Y2002].