Researchers at Mount Sinai are using immunotherapy to deliver targeted treatment for endometrial cancer, potentially resulting in a significant advancement in care, says Stephanie V. Blank, MD, Director of Gynecologic Oncology, Mount Sinai Health System. The research is informed by Mount Sinai’s expertise in immunology research, its diverse patient population, and its commitment to health equity.

“At Mount Sinai, we have been researching the use of immunotherapy alongside other targeted therapies, allowing this approach to be effective for a broader group of patients,” Dr. Blank says. “These treatment approaches represent the most significant breakthrough in endometrial cancer care in many years.”

Most patients with endometrial cancer can be treated with a hysterectomy. Some of those patients also need local radiation. However, about 20 percent of patients need systemic therapy—which is the focus of research at Mount Sinai. In the past, chemotherapy has been the first-line treatment, but immunotherapy could take its place for well-selected patients, says Dr. Blank, Professor of Gynecologic Oncology in the Department of Obstetrics, Gynecology and Reproductive Science, Icahn School of Medicine at Mount Sinai.

Endometrial cancer is an attractive target for immunotherapy, largely because cancers arising in endometrial tissue are a type most likely to have the DNA abnormality microsatellite instability, also known as MSI-H. When a tumor is MSI-H, proteins that help repair broken DNA are missing or not working properly, causing mistakes in a patient’s genetic code and fueling the spread of cancer. MSI-H tumors are especially sensitive to immunotherapy, and this includes MSI-H endometrial cancer, which represents about 25 percent of endometrial cancers.

Because most endometrial cancers are not MSI-H, immunotherapy alone does not help as many patients with endometrial cancers as one would hope, Dr. Blank says. In September 2019, a regimen incorporating both immunotherapy and another targeted agent, a multi-tyrosine kinase inhibitor, was approved for the treatment of patients with endometrial cancer that is not MSI-H, broadening the indication for this approach to treatment.

Mount Sinai is conducting clinical trials to test the efficacy of various immunotherapy treatment combinations. One randomized controlled trial is investigating the impact of starting immunotherapy earlier in the treatment process. Currently, immunotherapy, alone or in combination, is FDA approved for disease that has not responded to front-line systemic treatment. But perhaps patients could benefit from immunotherapy sooner in the course of their disease, when they are strongest and least pretreated, Dr. Blank says. In other cases, immunotherapy might be used to treat recurrent cancer, rather than starting with chemotherapy. These adjustments would impact patient outcomes, because some endometrial cancers are not very responsive to chemotherapy, Dr. Blank says, and the side effects of immunotherapy can be more tolerable and short-lived than those of chemotherapy.

Mount Sinai is conducting investigator-initiated research into various immunotherapy agents and combinations. PARP (poly adenosine diphosphate ribose polymerase) inhibitors have changed the course of ovarian cancer treatment and may be applicable for endometrial cancer, in conjunction with other modalities. In addition, Mount Sinai is testing immunotherapy with an antiangiogenic drug that may help tumors elicit a stronger immune response.

Taking full advantage of Mount Sinai’s strength in translational research, the Department of Obstetrics, Gynecology and Reproductive Science is collaborating with leaders in immuno-oncology to conduct research on an endometrial cancer vaccine. Most cancer vaccines are customized for individual tumors, which is costly and time-intensive. This work focuses on developing an off-the-shelf vaccine and will start with building a background for an MSI-H tumor vaccine. In research in collaboration with immunologist Nina Bhardwaj, MD, PhD, the Ward Coleman Chair in Cancer Research, Icahn School of Medicine, a team is identifying shared neoantigens, or proteins that elicit immune responses found in endometrial cancer tumors. The research was highlighted in Cell in December 2020. Using blood from patients with cancer, the team is testing the immune responses these antigens elicit, which may lead to a vaccine that treats all types of MSI-H endometrial cancer. Vaccines offer advantages such as fewer side effects and long-lasting immune responses.

The research has confirmed thus far that immunotherapy—or any treatment for that matter—for endometrial cancer is not “one size fits all,” Dr. Blank says. Each of the four subtypes of endometrial cancer has a unique clinical course and genomic profile: MSI-H; copy number low (endometrioid); copy number high (serous-like); and POLE (pathogenic somatic missense mutations within the DNA polymerase epsilon). Some are more tenacious, Dr. Blank says, and researchers may find that only one subtype is receptive to vaccines, or that a different vaccine or completely different approach may be needed for each subtype. “This work is at an early stage,” she says. “But in the future, we may be able to vaccinate people with increased genetic risk for endometrial cancer, such as patients with Lynch syndrome, to prevent them from developing cancer.”

Although survival rates are improving for most cancers, they are not for endometrial cancer. Racial disparities are partly to blame, Dr. Blank says. Being nonwhite is a risk factor for many types of cancer, including endometrial cancer, and for myriad reasons, Black women tend to develop cancer types that lead to worse outcomes. Mount Sinai has a highly diverse patient population, which provides a unique opportunity to address disparities and study treatment options. For instance, one researcher is examining how levels of vitamin D exposure affect cancer outcomes specifically in Black patients.

“Gynecologic cancers are underfunded in terms of research, and as the most common of these cancers, endometrial cancer, has not received its share of attention,” Dr. Blank says. “With the incidence of endometrial cancer continuing to rise, finding more effective treatment options is essential. As we further define targeted and strategic therapeutic pathways, we will be able to offer endometrial cancer patients hope for longer, healthier, and better lives.”