Development of human ex vivo expanded Vδ1 γδ T cells armed with CAR as a metabolically fit, off-the-shelf cell therapy for solid tumors 2995

Abstract Description γδ T cells are unconventional T cells which kill tumors independently of antigen presentation by MHC class I, making them a promising candidate for allogeneic cell therapy. While Vδ2 γδ T cells are the most prominent in blood, the less prevalent Vδ1 subset has shown superior tumor killing. However, difficulties in expanding Vδ1 T cells has limited their clinical use. Here, we evaluated the expansion and activation of Vδ1 T cells using K562 feeder cells expressing membrane-bound IL-21. We first expanded γδ T cells from PBMCs long-term, and assessed their anti-tumor functions against breast and ovarian cancer cell lines and a xenograft model of human ovarian cancer. We also tested their metabolic function within the suppressive ovarian cancer ascites tumor microenvironment (TME) to assess metabolic fitness. Lastly, we generated Vδ1 cells with stable anti-HER2 chimeric antigen receptor (CAR) expression and assessed their cytotoxicity against HER2+ tumor cells. We found that expanded γδ T cells were primarily Vδ1 and displayed higher cytotoxicity than unexpanded γδ T cells. Expanded Vδ1 cells significantly reduced tumor burden in vivo and retained their cytotoxicity and metabolism in the ascites TME. Anti-HER2 CAR-Vδ1 T cells displayed enhanced cytotoxicity and degranulation against HER2+ breast cancer cells. Overall, we demonstrate the anti-tumor potential of HER2 CAR-expressing expanded Vδ1 cells as a metabolically fit, off-the-shelf cell therapy for hard-to-treat solid tumors. Funding Sources Supported by the Canadian Institutes of Health (CIHR) Research Doctoral Scholarship Award; CIHR Project Grant. Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)