- Lee, Derek;
- Dunn, Zachary Spencer;
- Guo, Wenbin;
- Rosenthal, Carl J;
- Penn, Natalie E;
- Yu, Yanqi;
- Zhou, Kuangyi;
- Li, Zhe;
- Ma, Feiyang;
- Li, Miao;
- Song, Tsun-Ching;
- Cen, Xinjian;
- Li, Yan-Ruide;
- Zhou, Jin J;
- Pellegrini, Matteo;
- Wang, Pin;
- Yang, Lili
Allogeneic Vγ9Vδ2 (Vδ2) 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 Vδ2 T cell-based treatments may be attributed to donor variability, short-lived persistence, and tumor immune evasion. To address these constraints, we engineer Vδ2 T cells with enhanced attributes. By employing CD16 as a donor selection biomarker, we harness Vδ2 T cells characterized by heightened cytotoxicity and potent antibody-dependent cell-mediated cytotoxicity (ADCC) functionality. RNA sequencing analysis supports the augmented effector potential of Vδ2 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 Vδ2 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 Vδ2 T cells as a viable therapeutic option for cancer treatment.