Unlocking the potential of allogeneic V2 T cells for ovarian cancer therapy through CD16 biomarker selection and CAR/IL-15 engineering

Allogeneic V gamma 9V delta 2 (V delta 2) T cells have emerged as attractive candidates for developing cancer therapy due to their established safety in allogeneic contexts and inherent tumor-fighting capabilities. Nonetheless, the limited clinical success of V delta 2 T cell-based treatments may be attributed to donor variability, short-lived persistence, and tumor immune evasion. To address these constraints, we engineer V delta 2 T cells with enhanced attributes. By employing CD16 as a donor selection biomarker, we harness V delta 2 T cells characterized by heightened cytotoxicity and potent antibody-dependent cell-mediated cytotoxicity (ADCC) functionality. RNA sequencing analysis supports the augmented effector potential of V delta 2 T cells derived from CD16 high (CD16Hi) donors. Substantial enhancements are further achieved through CAR and IL-15 engineering methodologies. Preclinical investigations in two ovarian cancer models substantiate the effectiveness and safety of engineered CD16Hi V delta 2 T cells. These cells target tumors through multiple mechanisms, exhibit sustained in vivo persistence, and do not elicit graft-versus-host disease. These findings underscore the promise of engineered CD16Hi V delta 2 T cells as a viable therapeutic option for cancer treatment. V gamma 9V delta 2 (V delta 2) T cells have been proposed as cell carriers for off-the-shelf CAR therapies. Here the authors describe CD16 as a biomarker for the selection of V delta 2 T cells with high levels of cytotoxicity and report the anti-tumor activity of engineered CD16high V delta 2 T cells in ovarian cancer preclinical models.