Co-Leader, Cancer Immunology Program
Professor of Pathology and Radiation Oncology
NYU School of Medicine
New York, NY
Co-Investigator: Silvia Formenti, MD, NYU School of Medicine, New York, NY
Research developments in cancer immunology have elucidated important mechanisms of resistance to rejection of human tumors by our natural self-defense system, the immune system. When radiotherapy targets a cancer it elicits a series of specific danger signals that alert the patient’s immune system about the tumor. Dr. Formenti’s group has first hypothesized a role for local radiotherapy as an adjuvant to cancer immunotherapy. A milestone in 2005 came from experiments from this group, in a laboratory model of metastatic breast cancer: an immunotherapy found to be ineffective when used alone induced therapeutically effective anti-tumor immunity when combined with tumor radiotherapy. Importantly, the resulting immune response rejected the primary irradiated tumor, and induced an immune response capable to also reject lung metastases outside of the radiation field. In other words, it vaccinated the host against the irradiated tumor and its metastases. This finding is very relevant clinically, since it could be rapidly adopted to treat metastatic cancer patients. Nevertheless, the optimal combination of immunotherapy and radiotherapy remains to be defined.
In 2013-2014, Drs. Formenti and Demaria will direct their efforts to identify combinations of therapeutic antibodies that will neutralize key immunosuppressive mediators in the tumor thus removing the main obstacles to the conversion of a growing tumor into an in situ vaccine by radiotherapy. The time is mature for a fast-track progress of the proposed strategy to clinical translation due to improved understanding of the regulation of anti-tumor immune responses, together with availability of therapeutic antibodies suitable for clinical use. Therefore, Drs. Formenti and Demariaplan to devote the first year to preclinical experiments and, depending on the results obtained, rapidly move to a clinical protocol that will translate their preclinical findings. If successful, this approach can be easily implemented at any radiotherapy facility and can be incorporated in the management of metastatic breast cancer in the near future.
Research developments in cancer immunology have elucidated important mechanisms of resistance to rejection of human tumors by our natural self-defense system, the immune system. Radiotherapy has shown the ability to convert a growing tumor into an in situ vaccine by releasing tumor antigens and generating an acutely inflamed environment. The NYU team’s preclinical experiments show that two key immunosuppressive factors are also induced in response to radiation and hinder the development of effective anti-tumor responses. Inhibition of each of these immunosuppressive factors improves immune-mediated control of the irradiated tumor and non-irradiated metastases, but tumors persist or recur. They will determine if concomitant neutralization of both immunosuppressive factors in the context of radiotherapy can induce stronger anti-tumor immunity that cures laboratory models with metastatic breast cancer. If successful, they will rapidly move to a clinical protocol that will translate their preclinical findings.
As a breast cancer pathologist and a basic/translational investigator seeking more effective treatments for established and advanced cancers, the overall goal of Dr. Sandra Demaria's work is to employ pre-clinical models to better define the determinants of response to treatment, new treatment modalities, and to ultimately translate the findings into clinical practice. Her lab in collaboration with fellow grantee, Dr. Silvia Formenti, was the first to demonstrate that strategies combining local radiotherapy with anti-CTLA-4 antibodies can elicit anti-tumor CD8 T cell that are effective at inhibiting metastases in the 4T1 mouse model of metastatic breast cancer. They have since identified novel molecular mechanisms responsible for the synergy of radiation and immunotherapy, and they have published several reports describing strategies to optimize immunotherapy’s ability to inhibit metastatic disease. This data provide the rationale for further investigation of additional therapeutic interventions required for successful tumor rejection, a goal of their BCRF-funded project. It also provides additional rationale for the clinical translation of this strategy, and Dr. Demaria is a co-investigator in clinical protocols recently developed by Dr. Formenti to test the combination of radiation and immunotherapy in the clinic. She is also the co-leader of the NYU Cancer Immunology Program and a member of the Breast Cancer Program.