One major hurdle to the success of adoptive T-cell therapy is the identification of antigens that permit effective targeting of tumors in the absence of toxicities to essential organs. Previous work has demonstrated that T cells engineered to express chimeric antigen receptors (CAR-T cells) targeting the murine homolog of the colorectal cancer antigen GUCY2C treat established colorectal cancer metastases， without toxicity to the normal GUCY2C-expressing intestinal epithelium， reflecting structural compartmentalization of endogenous GUCY2C to apical membranes comprising the intestinal lumen. Here， we examined the utility of a human-specific， GUCY2C-directed single-chain variable fragment as the basis for... More
One major hurdle to the success of adoptive T-cell therapy is the identification of antigens that permit effective targeting of tumors in the absence of toxicities to essential organs. Previous work has demonstrated that T cells engineered to express chimeric antigen receptors (CAR-T cells) targeting the murine homolog of the colorectal cancer antigen GUCY2C treat established colorectal cancer metastases， without toxicity to the normal GUCY2C-expressing intestinal epithelium， reflecting structural compartmentalization of endogenous GUCY2C to apical membranes comprising the intestinal lumen. Here， we examined the utility of a human-specific， GUCY2C-directed single-chain variable fragment as the basis for a CAR construct targeting human GUCY2C-expressing metastases. Human GUCY2C-targeted murine CAR-T cells promoted antigen-dependent T-cell activation quantified by activation marker upregulation， cytokine production， and killing of GUCY2C-expressing， but not GUCY2C-deficient， cancer cells GUCY2C CAR-T cells provided long-term protection against lung metastases of murine colorectal cancer cells engineered to express human GUCY2C in a syngeneic mouse model. GUCY2C murine CAR-T cells recognized and killed human colorectal cancer cells endogenously expressing GUCY2C， providing durable survival in a human xenograft model in immunodeficient mice. Thus， we have identified a human GUCY2C-specific CAR-T cell therapy approach that may be developed for the treatment of GUCY2C-expressing metastatic colorectal cancer. .
