Discovery Could Lead to Higher Response Rates for Bladder Cancer Patients Treated with Immunotherapy
Mount Sinai researchers have discovered that a particular type of cell present in bladder cancer may be the reason why so many patients do not respond to the groundbreaking class of drugs known as PD-1 and PD-L1 immune checkpoint inhibitors, which enable the immune system to attack tumors.
In a study published in Nature Communications, the Mount Sinai team reported that stromal cells, a subset of connective tissue cells often found in the tumor environment, may be preventing immune cells known as T-cells from seeking out and destroying the invading cancer. The researchers showed that expression of a set of genes that are typically linked to more aggressive cancers was actually more commonly linked to stromal cells rather than bladder cancer cells themselves. They also showed that tumors with increased expression of these genes, known as epithelial mesenchymal transition genes, did not respond well to immune checkpoint inhibitors. The researchers also found that in such tumors, T-cells were more likely to be separated from cancer cells by the stromal cells, suggesting that the stromal cells may be hindering the ability of the immune cells to reach and eradicate the cancer cells.
“Some bladder cancers may not respond to immunotherapy, even though the body has developed an immune response against them, because the T-cells are prevented from reaching the tumor by stromal cells that create an inhospitable ‘neighborhood,’” said Matthew Galsky, MD, Professor of Medicine and Director of Genitourinary Medical Oncology at The Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai, and senior author of the study.
Dr. Galsky and his colleagues are now trying to validate the gene expression identified in their study as a biomarker that could help refine clinical trials and treatment in the future by predicting the level of response or resistance to PD-1/PD-L1 inhibitors. In addition, according to Dr. Galsky, the group is identifying ways to “counteract the negative impact of the stromal cells and make that neighborhood more friendly to immune cells so they can finish their job.”
Since they were made available to patients about four years ago, immune checkpoint inhibitors have changed the treatment landscape for many types of cancer, particularly metastatic bladder cancer, which had gone several decades without significant therapeutic advances. While five different PD-1 and PD-L1 inhibitors have since been approved by the U.S. Food and Drug Administration, responses are achieved in only 15 percent to 25 percent of patients. Cancer researchers have turned their attention to attempting to learn why and, more specifically, to discovering ways to increase the proportion of patients with positive results.
The Mount Sinai team used several data sets for their study, including genomic data from The Cancer Genome Atlas’ bladder cancer dataset from the National Cancer Institute. In addition, in collaboration with researchers from Bristol-Myers Squibb, they demonstrated the potential clinical relevance of their findings in a large clinical trial dataset derived from patients with metastatic bladder cancer treated with the PD-1 inhibitor nivolumab.
“Our biologists and biostatisticians were able to harness ‘big data’ to generate valuable insights into responses and resistance to PD-1 therapies,” noted study co-author Jun Zhu, PhD, Professor in the Department of Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai and Head of Data Sciences at Sema4, a Mount Sinai venture. “We strongly believe those results will inform future studies at Mount Sinai and elsewhere.”
Dr. Galsky added, “What our group has done is add another important piece to a larger jigsaw puzzle about why PD-1/PD-L1 inhibitors don’t work in some patients. Through our work we have supported and extended important observations made by other researchers, and this makes us more confident than ever that we are on the right track to addressing a huge unmet need for patients with bladder cancer.”
About the Mount Sinai Health System
The Mount Sinai Health System is New York City's largest integrated delivery system, encompassing eight hospitals, a leading medical school, and a vast network of ambulatory practices throughout the greater New York region. Mount Sinai's vision is to produce the safest care, the highest quality, the highest satisfaction, the best access and the best value of any health system in the nation. The Health System includes approximately 7,480 primary and specialty care physicians; 11 joint-venture ambulatory surgery centers; more than 410 ambulatory practices throughout the five boroughs of New York City, Westchester, Long Island, and Florida; and 31 affiliated community health centers. 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's "Honor Roll" Hospital, No. 12 in the nation for National Institutes of Health funding, and among the top 10 most innovative research institutions as ranked by the journal Nature in its Nature Innovation Index. This reflects a special level of excellence in education, clinical practice, and research. The Mount Sinai Hospital is ranked No. 14 on U.S. News & World Report's "Honor Roll" of top U.S. hospitals; it is one of the nation's top 20 hospitals in Cardiology/Heart Surgery, Diabetes/Endocrinology, Gastroenterology/GI Surgery, Geriatrics, Gynecology, Nephrology, Neurology/Neurosurgery, and Orthopedics in the 2019-2020 "Best Hospitals" issue. Mount Sinai's Kravis Children's Hospital also is ranked nationally in five out of ten pediatric specialties by U.S. News & World Report. The New York Eye and Ear Infirmary of Mount Sinai is ranked 12th nationally for Ophthalmology, Mount Sinai St. Lukes and Mount Sinai West are ranked 23rd nationally for Nephrology and 25th for Diabetes/Endocrinology, and Mount Sinai South Nassau is ranked 35th nationally for Urology. Mount Sinai Beth Israel, Mount Sinai St. Luke's, Mount Sinai West, and Mount Sinai South Nassau are ranked regionally.