Colorectal cancer has a high mortality rate in advanced stages of the disease with few effective therapies. Researchers at the Sidney Kimmel Cancer Center (SKCC) at Jefferson Health show that a type of immunotherapy called CAR-T cell therapy, successfully kills tumors and prevents metastases in mouse models of the disease. The work published in the journal Cancer Immunology Research, is the last step of preclinical testing prior to human clinical trials.
“The antigen we target for colorectal cancer is one that is shared across several high mortality cancers including esophageal and pancreatic cancer,” said Adam Snook, PhD, Assistant Professor in the department of Pharmacology & Experimental Therapeutics at Jefferson (Philadelphia University + Thomas Jefferson University). “Taken together, 25 percent of people who die from cancer could potentially be treated with this therapy.”
CAR-T immunotherapy uses the patients' immune system to target and kill tumors. The therapy requires a marker to target the cancer. For colorectal cancer that target, or tumor antigen, is called GUCY2C. The antigen was identified as a potential biomarker and therapeutic target in colorectal cancer by Scott Waldman, MD, PhD, Chair of the Department of Pharmacology & Experimental Therapeutics at Jefferson, and a leader of the SKCC’s Gastrointestinal Cancer program.
Dr. Snook created a CAR-T therapy made specifically to treat GUCY2C-expressing cancers such as colorectal cancer. In this study, the researchers tested a human-ready version of the therapy in mice.
They showed that mice with human colorectal tumors treated with CAR-T therapy successfully fought the tumor cells. All of the mice studied survived without side effects for the duration of the observation period – or 75 days, compared to a 30-day average survival of mice with control treatment.
In order to more closely replicate late-stage disease in humans, Dr. Snook and colleagues also looked at a mouse model of colorectal cancer that developed lung metastases, a common site for metastasis in colorectal cancer patients. Mice that were treated with the CAR-T therapy survived over 100 days with no metastases, whereas the control group survived an average of 20 days. Although the current experiments were not designed to test for autoimmunity-related side effects, earlier work by Dr. Snook and colleagues demonstrated no off-target effects. In that study, the researchers used a mouse-version of the CAR-T therapy that had the potential to react to off-target mouse organs, but saw no adverse effects.
“Safety is a major concern for the CAR-T therapy approach. In other cancers, the field has observed lethal autoimmune responses,” said Dr. Snook. “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.”
The next steps for the researchers would be a phase 1 clinical trial in humans.
