Pooled screening of CAR T cells identifies non-native signaling domains for next- generation immunotherapies
Goodman, D. B.; Azimi, C. S.; Kearns, K.; Garakani, K.; Garcia, J.; Patel, N.; Hwang, B.; Lee, D.; Park, E.; Ye, C. J.; Marson, A.; Bluestone, J.; Roybal, K.
Show abstract
Chimeric antigen receptors (CARs) repurpose natural signaling components to retarget T cells to refractory cancers, but have shown limited efficacy against solid tumors. Here, we introduce CAR Pooling, a multiplexed approach to rapidly identify CAR designs with clinical potential. Forty CARs with diverse immune costimulatory domains were assessed in pooled assays for their ability to stimulate critical T cell effector functions during repetitive stimulation that mimics long-term tumor antigen exposure. Several non-native domains from the TNF receptor family exhibited enhanced proliferation (CD40) or cytotoxicity (BAFF-R and TACI) relative to clinical benchmarks, and fell into distinct states of memory, cytotoxicity, and metabolism. BAFF-R CAR T cells were enriched for a highly cytotoxic and NK-cell-like innate phenotype previously associated with positive clinical outcomes. CAR Pooling enables efficient exploration of how CAR design affects cell activity and can be applied to optimize receptors across a range of applications and cell types.
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