Recently, two chimeric antigen receptor (CAR) T cell therapies were approved based on their remarkable efficacy in patients with hematological malignancies. By contrast, CAR-T cell therapies results in solid tumors have been less promising. To develop the next generation of T cell therapies a better understanding of T cell receptor (TCR) biology and its implication for the design of synthetic receptors is critical. Here, we review current and newly developed forms of T cell therapies and how their utilization of different components of the TCR signaling machinery and their requirement for engagement (or not) of human leukocyte antigen impacts their design, efficacy and applicability as cancer drugs. Notably, we highlight the development of human leukocyte antigen-independent T cell platforms that utilize the full TCR complex as having promise to overcome some of the limitations of existing T cell therapies.
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