Dual-antigen combinations: MSLN+EGFR, MSLN+HER2/ERBB2

Class

Dual-antigen-targeted CAR-NK cell therapy

Pathway

NK-cell-mediated cytotoxicity via chimeric antigen receptor engagement, guarding against single-antigen escape

Notes

original target text: Dual-antigen combinations: MSLN+EGFR, MSLN+HER2/ERBB2, or EGFR+HER2/ERBB2 | original target text: Dual-antigen combinations: MSLN+EGFR, MSLN+HER2/ERBB2, or

Mesothelin (MSLN), EGFR, and HER2/ERBB2 are proteins frequently overexpressed on the surface of solid tumor cells, including mesothelioma, ovarian, pancreatic, lung, breast, and gastric cancers. Chimeric antigen receptor (CAR) cell therapies engineer immune cells to recognize one of these surface markers and destroy the cell bearing it. A persistent limitation of single-antigen CAR approaches is antigen escape: tumors are genetically heterogeneous, and cells that lose or downregulate the targeted antigen can survive treatment and repopulate the tumor. Dual-antigen constructs, such as those recognizing both MSLN and EGFR, or MSLN and HER2, address this by allowing the engineered cell to engage either target, broadening the population of tumor cells it can recognize and reducing the likelihood that antigen-negative clones escape detection. This approach uses natural killer (NK) cells rather than T cells as the chassis. NK cells kill through innate cytotoxic mechanisms that do not require prior antigen presentation, and they carry a comparatively lower risk of the severe immune overactivation seen with some T-cell therapies. This mechanism is broadly relevant to solid tumors where antigen heterogeneity and relapse after initial antigen-directed therapy are recurring clinical challenges.