Titles and Affiliations
Professor and Chair, Department of Radiation Oncology
Sandra and Edward Meyer Professor of Cancer Research
Radiation Oncologist in Chief
Associate Director of Translational Research, Meyer Cancer Center
Professor, Department of Medicine
Research area
Identifying ways to improve immunotherapy responses so that more patients can benefit from this promising treatment.
Impact
Immunotherapy stimulates a person’s immune system to recognize and destroy cancer cells and is a promising treatment for breast cancer. However, some tumors can evade immune attack. Checkpoint inhibitors (CPI), a type of immunotherapy, work by preventing tumor cells from evading a patient’s immune response. While CPI drugs are approved for treatment of various types of cancers, including some breast cancers, their effectiveness in breast cancer has been disappointing overall. Drs. Formenti and Demaria are investigating ways to improve response to immunotherapies by combining it with radiation treatment. Their research has shown that radiation therapy has the potential to convert a nonresponsive (immunogenically cold) tumor into a responsive (immunogenically hot) one. Their work will provide a critical step towards developing precision radiotherapy, facilitating its use in combination with immunotherapy as a successful and durable treatment approach for breast cancer patients.
Progress Thus Far
Drs. Formenti and Demaria have shown that radiotherapy not only kills tumor cells but also recruits the immune system to fight cancer. The team identified several genes that are significantly upregulated by radiation and serve important roles in the crosstalk between breast cancer cells and immune cells. They discovered that breast cancer cells can respond to radiation in very different ways. While some activate immune signals that mobilize the immune system and attack them, others block this process by disrupting key molecular pathways, a mechanism linked to resistance to immunotherapy. The team also developed a patient-derived metastatic breast cancer model that responds to radiation combined with immunotherapy and found that tumors can alter the immune makeup of distant organs where metastases form. Notably, they identified previously unreported changes in B cells in the lungs, raising new questions about how immune responses differ across organs. Together, these findings suggest that overcoming immune evasion and tailoring immunotherapy delivery to specific sites in the body may be critical for improving treatment outcomes.
What’s next
Drs. Formenti and Demaria will work to confirm the mechanisms of immune evasion that they identified in some breast cancer cells exposed to radiation therapy. Next, they will test multiple drugs that target different points in this process for their ability to stop the conversion of immune-activating signals into immunosuppressive signals in their patient-derived breast cancer models. If successful, this information could lead to the identification of a biomarker for to identify breast cancer patients that might benefit from the combination of radiation therapy and the drugs tested.
Biography
Dr. Silvia C. Formenti, an international expert in the use of radiation therapy for the treatment of cancer, is Chair of the newly established Department of Radiation Oncology at Weill Cornell Medical College and Radiation Oncologist-in-Chief at New York-Presbyterian/Weill Cornell Medical Center. A prolific researcher, she has published over 180 papers recognized by high impact journals like the Journal of the American Medical Association, Journal of Clinical Oncology, Lancet Oncology, Science and others.
During the past twelve years, Dr. Formenti has introduced a paradigm shift in radiation biology, by elucidating the role of ionizing radiation on the immune system, and demonstrating efficacy of combining radiotherapy with immunotherapy in solid tumors. She has translated her preclinical work to clinical trials in metastatic breast cancer, lung cancer and melanoma. She has introduced the concept of recovering an immunological equilibrium in metastatic disease, by converting a metastasis into an in situ, individualized vaccine. In the presence of immune checkpoint blockade (anti-CTLA-4 , anti-PDL-1) the irradiated tumor becomes an immunogenic hub, similar to a vaccine. Once immunized against one site, the host develops an anti-tumor immune response capable to reject the other metastases. In some patients with metastatic disease refractory to standard treatment the combination of local radiation and immune checkpoint blockade has resulted in durable complete remissions, sustained for years after treatment. Her work has opened a new field of application for radiotherapy, whereby localized radiation can be used as an adjuvant to immunotherapy of solid tumors and lymphomas.
