Calibration of CAR activation potential directs alternative T cell fates and therapeutic potency

Chimeric antigen receptors (CARs) are synthetic receptors that target and reprogram T cells to acquire augmented antitumor properties¹. CD19-specific CARs that comprise CD28 and CD3ζ signaling motifs² have induced remarkable responses in patients with refractory leukemia^3-5 and lymphoma⁶ and were recently approved by the US Food and Drug Administration⁷. These CARs program highly performing effector functions that mediate potent tumor elimination^4,8 despite the limited persistence they confer on T cells^3-6,8. Extending their functional persistence without compromising their potency should improve current CAR therapies. Strong T cell activation drives exhaustion^9,10, which may be accentuated by the redundancy of CD28 and CD3ζ signaling^11,12 as well as the spatiotemporal constraints imparted by the structure of second-generation CARs². Thus, we hypothesized that calibrating the activation potential of CD28-based CARs would differentially reprogram T cell function and differentiation. Here, we show that CARs encoding a single immunoreceptor tyrosine-based activation motif direct T cells to different fates by balancing effector and memory programs, thereby yielding CAR designs with enhanced therapeutic profiles.