Scientists Unlock Promising Key to Preventing Cancer Relapse After Immunotherapy
Findings lay roadmap for future clinical trials to improve efficacy and survival after targeted immunotherapies
Mount Sinai researchers have solved one of the enduring mysteries of cancer immunotherapy: Why does it completely eliminate tumors in many patients, even when not all the cells in those tumors have the molecular target that the therapy is aimed at?
The answer involves a protein called fas, and regulating fas may be a route to preventing cancer relapse, the researchers reported in a study published in Cancer Discovery in December.
Cancer immunotherapies target antigens, or proteins, on the surface of tumor cells. One common example is a protein called CD19. But even when most cells in a tumor express CD19 on their surface, some do not. And tumors are constantly evolving and often experience “antigen escape,” meaning that the target is no longer expressed, which can make the immunotherapy fail and the cancer relapse.
The researchers discovered that cancer immunotherapies that make use of immune system cells such as T cells and CAR-T cells kill not only tumor cells that express the drugs’ target, but also adjacent tumor cells that lack the targets, because of the presence of fas. This process, known as bystander killing, can be made more effective by adding therapeutics that turn off the regulation of fas proteins, the researchers said.
“This study should engender many clinical trials solving the common weakness of immunotherapies—antigen escape and relapse,” said Joshua Brody, MD, Director of the Lymphoma Immunotherapy Program at The Tisch Cancer Institute at Mount Sinai. “Specifically, by combining immunotherapies with small molecule inhibitors that increase fas-signaling, which are already being used in the clinic, bystander tumor cell killing may be potentiated and eliminate antigen-loss variants from heterogenous tumors.”
T cell-based immunotherapies—including CAR-T, bispecific antibodies, and anti-PD1 antibodies—have revolutionized cancer treatment. However, even with the remarkably high response rates of CAR-T-treated patients, most either progress or relapse within one year.
In this study, Mount Sinai researchers looked at tumors from patients in a large clinical trial studying CAR-T’s effectiveness in patients with non-Hodgkin’s lymphoma and found for the first time that the level of fas present in the tumors predicted the patients’ response to the drug and their long-term survival. Those with significantly elevated fas in their tumors had longer-lasting positive responses to the therapy.
Based on this, the researchers tested small-molecule therapies that increased the function of fas in the tumor cells, in turn increasing the targeted and bystander tumor cell killing induced by T cells, CAR-T cells, and bispecific antibodies.
About the Mount Sinai Health System
The Mount Sinai Health System is New York City's largest academic medical system, encompassing eight hospitals, a leading medical school, and a vast network of ambulatory practices throughout the greater New York region. Mount Sinai advances medicine and health through unrivaled education and translational research and discovery to deliver care that is the safest, highest-quality, most accessible and equitable, and the best value of any health system in the nation. The Health System includes approximately 7,300 primary and specialty care physicians; 13 joint-venture ambulatory surgery centers; more than 415 ambulatory practices throughout the five boroughs of New York City, Westchester, Long Island, and Florida; and more than 30 affiliated community health centers. The Mount Sinai Hospital is ranked on U.S. News & World Report's "Honor Roll" of the top 20 U.S. hospitals and is top in the nation by specialty: No. 1 in Geriatrics and top 20 in Cardiology/Heart Surgery, Diabetes/Endocrinology, Gastroenterology/GI Surgery, Neurology/Neurosurgery, Orthopedics, Pulmonology/Lung Surgery, Rehabilitation, and Urology. New York Eye and Ear Infirmary of Mount Sinai is ranked No. 12 in Ophthalmology. Mount Sinai Kravis Children's Hospital is ranked in U.S. News & World Report’s “Best Children’s Hospitals” among the country’s best in four out of 10 pediatric specialties. The Icahn School of Medicine is one of three medical schools that have earned distinction by multiple indicators: ranked in the top 20 by U.S. News & World Report's "Best Medical Schools," aligned with a U.S. News & World Report "Honor Roll" Hospital, and No. 14 in the nation for National Institutes of Health funding. Newsweek’s “The World’s Best Smart Hospitals” ranks The Mount Sinai Hospital as No. 1 in New York and in the top five globally, and Mount Sinai Morningside in the top 20 globally.