FDA-approved CAR-T cell therapies, in which a patient’s own T cells are engineered to attack cancer cells, are currently limited to two types of cancer: B-cell non-Hodgkin’s lymphoma and acute lymphoblastic leukemia. One major hurdle for extending the reach of this therapy to other cancer types is the identification of specific antigens with minimal toxicity to normal cells. New results from a preclinical study may be the needed breakthrough to push the envelope to other cancers. The published work in Cancer Immunology Research from a team at Thomas Jefferson University focuses on a crucial human colorectal cancer antigen.
"The antigen we target for colorectal cancer is one that is shared across several high mortality cancers including esophageal and pancreatic cancer. Taken together, 25 percent of people who die from cancer could potentially be treated with this therapy,” said senior co-author Adam Snook.
The human antigen of interest is guanylate cyclase 2C, or GUCY2C, a receptor expressed in the intestinal epithelium. Previous studies have implicated GUCY2C as a potential biomarker and therapeutic target in colorectal cancer. Using in vitro and in vivo experiments, the team proceeded to test CAR-T cells that target GUCY2C.
In mice xenografted with human colorectal cancer cells, the team found that CAR-T cells for human GUCY2C successfully fought off tumor cells. All treated mice survived without side effects for 75 days, the full duration of the observation. In comparison, control mice only survived for an average of 30 days.
To investigate an equivalent of late-stage cancer in humans, the team also tested a mouse model of colorectal cancer that developed lung metastases. The CAR-T treated mice survived for over 100 days without metastases, compared to an average of 20 days for the control. No auto-immunity-related side effects were observed, suggesting there were likely no off-target effects.
"Safety is a major concern for the CAR-T therapy approach. In other cancers, the field has observed lethal autoimmune responses. Other researchers are developing fast-acting antidotes to CAR-T therapy to quell these safety concerns, but our data suggests that GUCY2C CAR-T therapy may be very effective and safe in cancer patients," said Snook.