CAR γδ T cells for cancer immunotherapy. Is the field more yellow than green?

Engineered immune cell therapy to treat malignancies refractory to conventional therapies is modernizing oncology. Although alpha beta T cells are time-tested chassis for CAR, potential graft versus host disease (GvHD) apart from cytokine toxicity and antigen escape pose limitations to this approach. alpha beta T cell malignancy challenges isolation and expansion of therapeutic T cells. Moreover, alpha beta T cells may pose toxicity risk to inflammation sensitive vital tissues bearing the tumor. The HLA independent, multivalent, versatile and systemic anti-tumor immunity increases the desirability of gamma delta T cells as an alternate chassis for CAR. Indeed, CD19 gamma delta CAR T cell therapy to treat advanced lymphoma reached a milestone with the fast track status by FDA. However, reduced tumor-toxicity, homing, in vivo persistence and heterogeneity limits the translation of this therapy. The field is gaining momentum in recent years with optimization of gene delivery approaches and mechanistic insights into co-signaling requirements in gamma delta T cells. There is a renewed interest in customizing design of CAR guided by the biology of the host immune cells. Progress has been made in the current good manufacturing practice compatible expansion and engineering protocols for the delta 1 and delta 2 T cells. gamma delta CAR T cells may find its niche in the clinical situations wherein conventional CAR therapy is less suitable due to propensity for cytokine toxicity or off-tumor effect. As the therapy is moving towards clinical trials, this review chronicles the hitherto progress in the therapeutic engineering of gamma delta T cells for cancer immunotherapy.