V gamma 9V delta 2 T Cells: Can We Re-Purpose a Potent Anti-Infection Mechanism for Cancer Therapy?

Cancer therapies based on in vivo stimulation, or on adoptive T cell transfer of V gamma 9V delta 2 T cells, have been tested in the past decades but have failed to provide consistent clinical efficacy. New, promising concepts such as gamma delta Chimeric Antigen Receptor (CAR) -T cells and gamma delta T-cell engagers are currently under preclinical evaluation. Since the impact of factors, such as the relatively low abundance of gamma delta T cells within tumor tissue is still under investigation, it remains to be shown whether these effector T cells can provide significant efficacy against solid tumors. Here, we highlight key learnings from the natural role of V gamma 9V delta 2 T cells in the elimination of host cells bearing intracellular bacterial agents and we translate these into the setting of tumor therapy. We discuss the availability and relevance of preclinical models as well as currently available tools and knowledge from a drug development perspective. Finally, we compare advantages and disadvantages of existing therapeutic concepts and propose a role for V gamma 9V delta 2 T cells in immune-oncology next to Cluster of Differentiation (CD) 3 activating therapies.