Cancer T-cell therapy: building the foundation for a cure [version 2; peer review: 3 approved]

T-cell cancer therapy is a clinical field flush with opportunity. It is part of the revolution in immuno-oncology, most apparent in the dramatic clinical success of PD-1/CTLA-4 antibodies and chimeric antigen receptor T-cells (CAR-Ts) to cure certain melanomas and lymphomas, respectively. Therapeutics based on T cells ultimately hold more promise because of their capacity to carry out complex behaviors and their ease of modification via genetic engineering. But to overcome the substantial obstacles of effective solid-tumor treatment, T-cell therapy must access novel molecular targets or exploit existing ones in new ways. As always, tumor selectivity is the key. T-cell therapy has the potential to address target opportunities afforded by its own unique capacity for signal integration and high sensitivity. With a history of breathtaking innovation, the scientific foundation for the cellular modality has often been bypassed in favor of rapid advance in the clinic. This situation is changing, as the mechanistic basis for activity of CAR-Ts and TCR-Ts is backfilled by painstaking, systematic experiments—harking back to last century’s evolution and maturation of the small-molecule drug discovery field. We believe this trend must continue for T-cell therapy to reach its enormous potential. We support an approach that integrates sound reductionist scientific principles with well-informed, thorough preclinical and translational clinical experiments.