Helsen et al. constructed an MHC-independent T cell antigen coupler (TAC), a chimeric receptor that consists of an antigen-binding domain, a TCR recruitment domain, and a CD4+ or CD8+ co-receptor, and signals through the endogenous TCR. TAC-engineered T cells were effective against solid and liquid tumor targets in murine xenograft models with no observed autoactivation. TAC-engineered T cells accumulated faster and more exclusively within tumor tissues than first and second generation CAR T cells, were proliferative only within the tumor, and induced more efficient antitumor responses with less toxicity.
Engineering T cells with chimeric antigen receptors (CARs) is an effective method for directing T cells to attack tumors, but may cause adverse side effects such as the potentially lethal cytokine release syndrome. Here the authors show that the T cell antigen coupler (TAC), a chimeric receptor that co-opts the endogenous TCR, induces more efficient anti-tumor responses and reduced toxicity when compared with past-generation CARs. TAC-engineered T cells induce robust and antigen-specific cytokine production and cytotoxicity in vitro, and strong anti-tumor activity in a variety of xenograft models including solid and liquid tumors. In a solid tumor model, TAC-T cells outperform CD28-based CAR-T cells with increased anti-tumor efficacy, reduced toxicity, and faster tumor infiltration. Intratumoral TAC-T cells are enriched for Ki-67(+) CD8(+) T cells, demonstrating local expansion. These results indicate that TAC-T cells may have a superior therapeutic index relative to CAR-T cells.
Author Info: (1) Department of Pathology and Molecular Medicine, McMaster University, 1280 Main St W, Hamilton, ON, L8S 4L8, Canada. (2) Department of Pathology and Molecular Medicine, McMaster
Author Info: (1) Department of Pathology and Molecular Medicine, McMaster University, 1280 Main St W, Hamilton, ON, L8S 4L8, Canada. (2) Department of Pathology and Molecular Medicine, McMaster University, 1280 Main St W, Hamilton, ON, L8S 4L8, Canada. (3) Department of Pathology and Molecular Medicine, McMaster University, 1280 Main St W, Hamilton, ON, L8S 4L8, Canada. (4) Department of Pathology and Molecular Medicine, McMaster University, 1280 Main St W, Hamilton, ON, L8S 4L8, Canada. (5) Department of Pathology and Molecular Medicine, McMaster University, 1280 Main St W, Hamilton, ON, L8S 4L8, Canada. (6) Department of Pathology and Molecular Medicine, McMaster University, 1280 Main St W, Hamilton, ON, L8S 4L8, Canada. (7) Department of Pathology and Molecular Medicine, McMaster University, 1280 Main St W, Hamilton, ON, L8S 4L8, Canada. (8) Department of Pathology and Molecular Medicine, McMaster University, 1280 Main St W, Hamilton, ON, L8S 4L8, Canada. (9) Department of Pathology and Molecular Medicine, McMaster University, 1280 Main St W, Hamilton, ON, L8S 4L8, Canada. (10) Department of Pathology and Molecular Medicine, McMaster University, 1280 Main St W, Hamilton, ON, L8S 4L8, Canada. (11) Department of Pathology and Molecular Medicine, McMaster University, 1280 Main St W, Hamilton, ON, L8S 4L8, Canada. (12) Department of Pathology and Molecular Medicine, McMaster University, 1280 Main St W, Hamilton, ON, L8S 4L8, Canada. Department of Clinical Pathomorphology, Medical University of Lublin, Raclawickie 1 Street, 20-059, Lublin, Poland. (13) Department of Pathology and Molecular Medicine, McMaster University, 1280 Main St W, Hamilton, ON, L8S 4L8, Canada. (14) Trev & Joyce Deeley Research Centre, British Columbia Cancer Agency, 2410 Lee Ave, Victoria, BC, V8R 6V5, Canada. (15) Trev & Joyce Deeley Research Centre, British Columbia Cancer Agency, 2410 Lee Ave, Victoria, BC, V8R 6V5, Canada. (16) Trev & Joyce Deeley Research Centre, British Columbia Cancer Agency, 2410 Lee Ave, Victoria, BC, V8R 6V5, Canada. (17) Department of Pathology and Molecular Medicine, McMaster University, 1280 Main St W, Hamilton, ON, L8S 4L8, Canada. bramsonj@mcmaster.ca.
