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.
During this past six months this research team has been able to: (1) Finish accrual to the last cohort of a clinical study evaluating the HER2/neu DNA vaccine in patients with breast cancer, (2) optimize a schedule for combining anti-Her2/neu (equivalent to Herceptin) with anti-CTLA-4 (equivalent of ipilimumab) and gemcitabine that will result in the greatest tumor protection (3) Evaluate the combination of gemcitabine with other immunomodulatory antibodies (4) continue to collect safety data from patients enrolled on the clinical trial of ipilimumab and/or cryoablation, (5) conduct the immune monitoring of these patients. It is anticipated that a related abstract will be submitted for presentation at ASCO in June 2014.
The researchers will continue their investigation of the optimal means to use the immune system to treat breast cancer.
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.
The central goal for this project is to make a major advance for women with breast cancer brain metastases (BCBM) by answering the research question, “Can local tumor-specific immune stimulation with brain radiotherapy (RT) be augmented by systemic immune modulation and, in turn, lead to specific and durable local and distant antitumor responses?” Since the BCRF grant was awarded the researchers have further developed and strengthened their study strategy. Specifically, because the proposed strategy of combined therapy with brain radiation and immune stimulation has not previously been evaluated in breast cancer, and because it is not known whether any breast cancer subtype is more likely than another to respond to this strategy, they have developed a two-step strategy to explore the research question. The first step will now be a small pilot study that will: 1) confirm the safety of combined therapy with immune modulation and brain RT 2) provide a signal about systemic disease control by evaluating responses at distant sites of disease (i.e. beyond the brain) at 12 weeks 3) allow patients a potentially clinically meaningful respite from chemotherapy 4) include all breast cancer subtypes 5) provide safety data for concurrent trastuzumab administration in HER2-positive disease 6) include both stereotactic radiosurgery (SRS) and whole brain RT (WBRT) modalities and 7) permit exploratory correlative studies. By adding the step of a brief pilot study that is broadly inclusive, the research team will better inform the final design of the second step, namely the randomized phase 2 study that formed the foundation of their original grant application. To that end, they have since developed a protocol entitled, “A Pilot Study of Brain Irradiation and Tremelimumab in Metastatic Breast Cancer” which is currently pending institutional approval and should be open to accrual in early 2014.