Harnessing the immunotherapeutic potentials of gamma delta T cells against hematological malignancies

Gamma delta (γδ) T cells, which constitute about 5%-10% of peripheral blood lymphocytes, play key roles in tumor immunosurveillance and are often enriched within epithelial tissues. They are unique in their Major Histocompatibility Complex-independent antigen recognition via the γδ T-cell receptor (TCR) as well as via innate receptors, making them ideal1 candidates for allogeneic "off-the-shelf" cell therapy products. In humans, two main structural subsets of γδ T cells-Vδ1 and Vδ2-have been defined, which differ in TCRδ chains, effector function, and tissue localizations. Vδ2 T cells constitute the majority of γδ T cells in peripheral blood and can be expanded with aminobisphosphonates such as zoledronic acid. In recent years, the potent antitumor functions of Vδ1 T cells have also been recognized, and new expansion protocols are being developed. Given the ample preclinical evidence of γδ T-cell efficacy against hematological malignancies, several γδ T-cell-based cell therapy products are currently in clinical development, and there has been an exponential increase in the number of adoptive γδ T-cell therapy clinical trials. This comprehensive review provides an overview of the rationale for γδ T-cell therapy, ongoing clinical trials, as well as the challenges and future role of γδ T-cell-based immune therapies in hematology.