Highlighted research articles
Chimeric antigen receptors (CAR) enable MHC-independence but do not recreate the precise molecular regulation induced by T-cell receptor (TCR) complexes. In an effort to engage endogenous TCR circuits, Chang and colleagues designed MHC-independent TCRs. Using predictive modeling, they found many biochemical and structural conflicts at the synthetic hybrid domain interface. Through iterative modeling and sequence modification, they “evolved” these receptors towards native-like structures, yielding significantly enhanced function across several models of cancer. Combination with 4-1BB costimulation enabled robust tumor control that was more durable than classic second-generation CARs. These observations pave a path for structure-informed design of novel antigen receptors.See article, p. 2109.Targeting oncogenic KRAS, the primary driver of pancreas cancer, holds promise, but responses are limited by acquired resistance. Singhal and colleagues found that acute resistance to KRAS inhibition
