Jedd Wolchok, MD, PhD
Director, Immunotherapy Clinical Trials
Associate Director, Ludwig Center for Cancer Immunotherapy
Associate Attending Physician, Melanoma/Sarcoma Service
Memorial Sloan-Kettering Cancer Center
New York, New York
2013-2014 BCRF Project:
1) The Peter Jay Sharp Foundation Award
Co-Investigators: Alan Houghton, MD, PhD, Memorial Sloan-Kettering Cancer Center, New York, NY; Larry Norton, MD, Memorial Sloan-Kettering Cancer Center, New York, NY
Effective vaccination against breast cancer is difficult because breast cancer arises from cells that were once normal and our bodies have elaborate controls to stop the immune system from attacking our own tissues. However, research supported by the Peter Jay Sharp Foundation/BCRF has discovered a way to trick the immune system by vaccinating against cancer using a vaccine from a different species. The immune system recognizes the vaccine as “foreign” and generates an immune response to destroy breast cancer cells as if they were foreign invaders. This research has moved from the laboratory to patients— the Investigational New Drug (IND) application for a vaccine created under this support was approved by the Food and Drug Administration (FDA) and the clinical trial to test the first-generation vaccine against breast cancer is accruing patients. Specifically, with support from Peter Jay Sharp Foundation/BCRF, during this past year this team has been able to: (1) continue to accrue patients to the last cohort of a clinical study evaluating the HER2/neu DNA vaccine in patients with breast cancer and all patients in these cohorts have completed all vaccinations with no significant toxicity, (2) evaluate the efficacy of HER2/neu antibody (Equivalent to Herceptin) in combination with anti-CTLA-4 (equivalent of Ipilimumab), (3) Evaluate the combination of gemcitabine in combination with anti-CTLA-4, and (4) continue to accrue women with early-stage breast cancer to a clinical trial of ipilimumab and/or cryoablation. In the future, this group will continue their investigation of the optimal means to use the immune system to treat breast cancer. In addition to completing accrual to the HER2/new DNA vaccine study, in the coming year the researchers plan to further evaluate the efficacy of the combination therapy of the monoclonal antibody to HER2/neu (the equivalent of Herceptin in clinic) in combination with immunomodulatory antibodies (CTLA-4, CD137, PD-1, OX40, GITR) and determine the mechanism of action for the optimal combination; investigate radiation in combination with immune modulation in a laboratory model of breast cancer; and evaluate the effects of immunomodulatory antibodies in combination with chemotherapy. Further, they will continue accrual to the ipilimumab trial. Assuming that the primary end-point of safety and tolerability is met, which seems reasonable a larger randomized phase 2 study will be undertaken.
2) Co-Investigator: Heather McArthur, MD, MPH, Memorial Sloan-Kettering Cancer Center, New York, NY
Brain metastasis is a relatively common and devastating complication of breast cancer. Unfortunately, the treatment of breast cancer brain metastases with conventional drug therapies has been largely unsuccessful primarily due to the poor penetration across the blood-brain-barrier. Furthermore, brain metastasis can be more resistant to chemotherapy than systemic metastasis. Consequently, radiotherapy techniques such as whole brain radiation therapy (WBRT) and stereotactic radiosurgery remain the cornerstone of brain metastases management for most patients. There is a growing body of preclinical and clinical evidence indicating that the local effects of radiotherapy may be augmented when combined with immunotherapy. There is also some data indicating that radiotherapy administered in combination with immune therapy may confer benefits not only at the site of radiotherapy administration but also at distant sites of metastases.
Because of the growing body of compelling data in support of strategies that combine immune system modulation with radiotherapy, Drs. McArthur and Wolchok will conduct a randomized phase 2 study of WBRT with or without immune therapy with tremelimumab, a fully human anti-CTLA4 antibody, in women with hormone receptor-positive (HR+) or HER2-positive (HER2+) breast cancer metastases to the brain.