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Silvia Formenti, MD
Professor and Chairman
Department of Radiation Oncology
Weill Cornell Medical College
New York, New York
Goal: To improve response to immune-based therapies so that more patients can benefit from this promising treatment.
Impact: A new class of cancer immunotherapy drugs called checkpoint inhibitors have shown promise in several cancers including some breast cancers. Unfortunately, few breast cancer patients have benefitted thus far. Drs. Formenti and Demaria are investigating ways to improve response to immunotherapies such as checkpoint inhibitor (CPI) therapy with radiation treatment. This innovative approach can potentially make immunotherapy a successful and durable treatment approach for breast cancer patients.
What’s next: Having discovered that radiotherapy not only kills tumor cells but also recruits the immune system by triggering signals that mimic an infection, Drs. Formenti and Demaria will determine how to optimize the use of radiotherapy with immunotherapy to improve patient outcome.
Treatments that harness the power of the immune system to fight cancer can be very effective, but most breast cancer patients do not respond to the current immunotherapy with checkpoint inhibitors. Drs. Formenti and Demaria are studying the efficacy of combining immunotherapy with radiotherapy, which they have found has the potential to convert a tumor that is not responsive to immunotherapy into a responsive one.
Full Research Summary
Research area: Identifying ways to improve response to immunotherapy in breast cancer patients.
Impact: Immunotherapy—a type of treatment that stimulates a person’s immune system to recognize and destroy cancer cells—is a promising form of treatment. Checkpoint inhibitors (CPI) are a new calls of immunotherapy agents that work by preventing tumor cells from shutting down tumor immune response. Several CPI drugs are approved for treatment of various types of cancers, including some breast cancers, however, their effectiveness in breast cancer has been disappointing overall. Research by Drs. Formenti and Demaria has shown that radiation therapy has the potential to convert a nonresponsive (immunogenically cold) tumor into responsive (immunogenically hot) one.
Current investigation: The team has developed a platform to study the immunogenic effects of radiotherapy. They will use this platform to examine individual patients’ tumors to determine the tumor factors that mediate an optimal response to radiotherapy.
What they’ve learned so far: Drs. Formenti and Demaria have shown that radiotherapy may convert a tumor that is unresponsive to immunotherapy – sometimes referred to as a “cold” tumor – into a responsive “hot” one. It does this by generating T cells, the cancer-fighting cells of the immune system. Testing in laboratory models has revealed that it is possible to optimize the dose of radiotherapy to achieve this effect. In the last year, Drs. Formenti and Demaria have developed patient-derived tumor organoids from different types of breast cancers. This approach allows them to study the response of breast tumors to different doses of radiotherapy in the laboratory.
What’s next: The team will utilize patient-derived tumor organoids to optimize radiotherapy doses and to study radiation induced pro-immunogenic responses that occur in irradiated tumors. They will also study how circulating exosomes can be used as biomarkers of radiotherapy-induced pro-immunogenic responses. These studies provide a critical step towards developing precision radiotherapy and determining how it can be used to enhance response to immunotherapy.
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 JAMA, Journal of Clinical Oncology, Lancet Oncology, Science etc.
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.