Turning a tumor suppressor into a target: Tumor-suppressor genes such as TP53 (tumor protein P53) play key roles in the pathogenesis of cancer but, unfortunately, they are difficult to target because they do not create an overactive protein that can be inhibited with a drug. Hsiue et al. discovered a way to target a cancer-associated mutant form of the p53 protein using the body's own immune system (see the Perspective by Weidanz). The authors identified a distinct fragment of this mutant protein, characterized the structural basis for its presentation to T cells, and designed a bispecific antibody to stimulate T cell killing of p53-mutant cancer cells. Science , this issue p. eabc8697 ; see also p. 996

Bispecific T cell–engaging antibodies capable of specifically killing cancer cells expressing mutant RAS neoantigens were generated.

Significance: The lack of viable tumor-specific targets continues to thwart efforts to implement selective anticancer drugs in the clinic. Clonal loss of heterozygosity (LOH) occurs in the great majority of human tumors and represents an irreversible genetic alteration present in cancer cells that unequivocally distinguishes them from normal cells. Here, we report the development of NASCAR (Neoplasm-targeting Allele-Sensing CAR), a platform comprising pairwise chimeric receptors for detecting and targeting LOH events in cancer. As proof-of-concept, we demonstrate specific NASCAR T cell responses in models of HLA LOH in vitro and in vivo. This work lays the foundation for future exploration and exploitation of LOH-mediated vulnerabilities for precision cellular immunotherapy.

Bispecific antibodies directed against T cell receptor β chains promote killing of human T cell cancers while preserving most healthy T cells.