Weill Cornell Medical College
New York, New York
Professor, Radiation Oncology
Professor, Pathology and Laboratory Medicine
Identifying ways to improve response to immunotherapy so that more patients can benefit from this promising treatment.
Immunotherapy stimulates a person’s immune system to recognize and destroy cancer cells and is a promising treatment for breast cancer patients. However, some tumors can evade immune attack. Checkpoint inhibitors (CPI), a type of immunotherapy agent, 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. Demaria and Formenti 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. It does this by generating T cells, the cancer-fighting cells of the immune system. Drs. Demaria and Formenti have taken cells from patients with different types of breast cancer and developed a series of laboratory models that recapitulate the 3D environment of the tumors. Using these innovative models, they are determining ways to enhance responses to immunotherapy with radiation—this 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.
Drs. Demaria and Formenti have shown that radiotherapy not only kills tumor cells but also recruits the immune system to fight cancer. They have found that hormone receptor-positive and triple-negative breast cancers (TNBCs) activate different inflammatory pathways in response to radiation. They identified several genes that are significantly upregulated by radiation in both subtypes. These genes serve important roles in the crosstalk between breast cancer cells and immune cells and studies are underway to further explore their functions. In addition, they characterized their 3D models and obtained additional established 3D models of TNBC. These models provide unique vehicles for further in-depth investigations to optimize the combination of radiation and CPI therapy, tailoring the treatment to specific characteristics of each tumor. Recently, they discovered that radiation therapy induces alterations in how breast cancer cells process specific biomolecules which results in activation of signaling pathways that are also activated by viruses. This suggests that radiation engages viral sensors that then mediate activation of the immune system against the tumor. Others have shown that some commonly mutated genes in breast cancer cells suppress the expression of such viral sensors. The team will pursue the implications of these observations and leverage their 3D models to do this.
Drs. Demaria and Formenti will continue to examine how the molecular subtype of breast cancer affects the ability of radiation therapy to induce the immune signals required for an anti-tumor response. Studies are underway to examine the previously identified genes and their role in tumor and immune cell crosstalk. In addition, they will continue to exploit the novel models they have developed in laboratory studies to define ways to monitor an immunogenic response to tumor irradiation, investigate what mutations modulate the ability of radiation therapy to increase breast cancer immunogenicity, and identify ways to improve the ability of radiation to make breast cancer more immunogenic. The new model system provides a powerful way to study the immunogenic effects of radiotherapy in an individual tumor. With this understanding, personalized treatment strategies can be developed to improve the success of immunotherapy for breast cancer.
Sandra Demaria, MD, a native of Turin, Italy, obtained her MD from the University of Turin. She then moved to New York City for her post-doctoral training in immunology as a Damon Runyon-Walter Winchell Cancer Research Fund awardee, followed by a residency in anatomic pathology at New York University School of Medicine. She remained on the faculty at NYU School of Medicine, where she was an attending pathologist in the breast cancer service, an independent investigator and co-leader of the Cancer Immunology program of NYU Cancer Institute until 2015, raising to the rank of Professor. She is currently Professor of Radiation Oncology and Pathology at Weill Cornell Medicine Medical College where she leads a NIH-funded laboratory.
Dr. Demaria is internationally known for her studies demonstrating the synergy of local radiation therapy with different immunotherapeutic agents in pre-clinical models of cancer. She was the first to show that radiotherapy can convert breast tumors unresponsive to immune checkpoint inhibitors into responsive ones. She has been working in partnership with Dr. Silvia Formenti for the past decade to develop a novel treatment paradigm exploiting the immune adjuvant effects of radiotherapy and translate the pre-clinical findings to the clinic.
Dr. Demaria’s current work is aimed at identifying the molecular mechanisms that regulate ionizing radiation’s ability to generate an in situ tumor vaccine in preclinical tumor models as well as cancer patients treated in clinical trials testing various combinations of radiation and immunotherapy. As a breast cancer pathologist, Dr. Demaria has also studied the immunological microenvironment of breast cancer in patients, and therapeutic strategies to modulate the immune infiltrate in preclinical breast cancer models.
She holds leadership positions in national professional societies, including the Society for Immunotherapy of Cancer (SITC) where she currently serves on the Board, and is a member of the Steering Committee of AACR Cancer Immunology Working Group. She is also an elected member of the European Academy for Tumor Immunology (EATI), and serves in the editorial board of several journals, including Radiation Research, The Journal of Immunology, Clinical Cancer Research, and Journal for ImmunoTherapy of Cancer.
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