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
Mount Sinai Health System is one of the nation’s leading integrated academic health systems and one of the largest in the New York metropolitan area. Its comprehensive system includes seven hospitals, more than 400 outpatient practices, over 600 research and clinical laboratories, the Icahn School of Medicine at Mount Sinai, the Graduate School of Biomedical Sciences, and the Mount Sinai Phillips School of Nursing. Together, the Health System comprises approximately 48,000 employees, more than 9,000 physicians, and 8,600 nurses.
As a leading learning health system, Mount Sinai combines clinical expertise with scientific discovery to improve patient care while training the next generation of health care and biomedical leaders. The Health System provides care across every stage of life, from prenatal care through geriatrics, while advancing personalized medicine through artificial intelligence, data science, and biomedical research.
Mount Sinai is consistently recognized among the nation’s leading academic health systems for patient care, research, and education. The Mount Sinai Hospital is ranked No. 1 in New York by Newsweek and No. 5 on the magazine’s World’s Best Hospitals list. The Icahn School of Medicine at Mount Sinai ranks No. 11 among U.S. medical schools and No. 1 among freestanding medical schools for National Institutes of Health funding, reflecting the strength of its scientific enterprise and leadership in biomedical research.
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