Colorectal cancer is the third most common cancer among men and women of all ages in the United States and is on track to be the leading cause of cancer death in adults younger than 50 by 2030. The alarming rise of colorectal cancer in people younger than age 50 prompted the U.S. Preventive Services Task Force to lower the colorectal cancer screening age from 50 to 45 in 2021.
Benjamin Schlechter, MD, a senior physician in the Gastrointestinal Cancer Treatment Center at Dana-Farber, is leading two studies to investigate novel treatment options for patients with colorectal cancer. “Translation of ideas from the laboratory to clinical medicine remains one of the huge hurdles. It’s fantastic to have multiple promising trials underway for patients with colorectal cancer,” said Dr. Schlechter.
Benjamin Schlechter, MD
Next-Generation Immunotherapy Shows Activity
One avenue of clinical research at Dana-Farber includes a study testing a combination of two next-generation immunotherapy drugs. The phase I trial included patients with metastatic colorectal cancer who had already been treated with several lines of drugs, including prior immunotherapies. These patients all had tumors classified as microsatellite stable, which account for most colorectal cancers. In previous studies, first-generation immunotherapies have had little effect on this type of tumor.
The two next-generation immunotherapy drugs in the trial are designed to “release the brakes” on the immune system in two different ways. One drug, botensilimab, aims to unleash T cells against the cancer by targeting one such brake, an immune checkpoint protein called CTLA-4. CTLA-4 is a receptor found on T cells and regulates T-cell activation. The other drug, balstilimab, frees the immune system to attack the cancer by blocking PD-1. The drug combination showed clinical activity in these patients, who otherwise had few treatment options. The main population of patients who benefited from the combination were those who did not have active metastatic cancer in the liver. Two randomized phase II trials in patients with microsatellite-stable colorectal cancer are opening in the coming weeks.
Novel CAR T-Cell Therapy Specifically Targets Colorectal Cancer
Another research avenue at Dana-Farber involves a phase I trial of a cell therapy called GCC19CART. Although effective at treating certain blood cancers, so far, chimeric antigen receptor (CAR) T-cell therapies have not been effective in solid tumors, such as colorectal cancer, in part because it has been extremely difficult to uniquely target tumor cells.
GCC19CART specifically targets colon cancer by binding to guanyl cyclase C (GCC), which is thought to be present in 70% to 80% of colon cancers. In addition, the GCC-specific CAR T cells are combined with CD19 CAR T cells to create a slingshot effect that causes the GCC T cells to activate and proliferate in the bloodstream. They then flow into the tumor, where they bind to and kill the cancer cells. The trial is currently enrolling patients.