Directly Conjugated Single-Domain VHHs Targeting MHC Class II Prime T-Cell Responses Against Pancreatic Cancer Neoantigens
Abstract
Pancreatic cancer is one of the deadliest cancers, with a 5-year survival rate of 7%. The exceptionally poor prognosis of this disease can be traced to several factors. Located in a vital region of the body, the majority of primary pancreatic tumors are inoperable due to invasion of the surrounding vasculature. The disease is rapidly metastatic, with most patients presenting with metastases upon initial diagnosis. Finally, pancreatic cancers are dense, fibrotic masses that preclude adequate drug delivery. Immunotherapy has shown impressive clinical benefit, particularly for metastatic melanoma. The Food and Drug Administration has approved three immune-modulating drugs that target activation inhibitors on T cells, ipilimumab (anti-CTLA-4) and nivolumab/pembrolizumab (anti-PD-1). Since immunotherapy targets the immune system, and not a particular type of cancer, these new drugs were originally hoped to be applicable across all tumor types as a pan-cancer medication. Indeed, significant clinical results have been seen for ipilimumab in lung, renal cell, and prostate cancer. Likewise, PD-1 blockade is effective against Hodgkin s lymphoma, non-small cell lung cancer, and multiple cancer types deficient in mismatch repair. However, pancreatic cancer was among the cancer types in which ipilimumab and nivolumab have largely failed. Why has pancreatic cancer been so refractory to immunotherapy? In part, we do not fully understand how tumor-specific T cells infiltrate densely fibrotic pancreatic tumors or how to recruit more activated T cells to the tumor mass. We propose an entirely novel strategy of using an alpaca antibody to deliver vaccine components and effectively generate more T cells to better fight pancreatic cancer. Principal Investigator: Dr. Stephanie Dougan is a new Assistant Professor at Dana-Farber Cancer Institute. She performed her PhD work at Harvard University, which gave her a strong foundation in basic immunology and mouse models. As a postdoctoral fellow at Whitehead Institute/MIT, she generated several new mouse models for studying the immune response to cancer. This work launched her career in tumor immunology. As an independent investigator, she continues to use unique tools to address the role of different kinds of immune cells in the coordinated immune response to cancer. Her lab is focused on two major tumor types: melanoma and pancreatic cancer, both of which are Fiscal Year 2015 Peer Reviewed Cancer Research Program Topic Areas. Dr. Dougan is committed to a career in tumor immunology and is well-positioned to become a leader in this growing field. This grant would allow her to expand her research focus in pancreatic cancer and form the foundation for translating her basic research into clinical trials. Impact: We hope to extend the promise of immunotherapy to pancreatic cancer, a disease that has not yet benefited from current immunotherapy. The vaccination strategy proposed here combines a general approach (targeting MHC class II) with a patient-specific approach (delivering neoantigens). Important to note -- we already have an analogous drug that targets human MHC class II. Therefore, successes in the preclinical studies proposed here could be rapidly translated to a clinical trial for human pancreatic cancer. Such rapid translation of basic research findings is routinely done at Dana-Farber Cancer Institute, making this an ideal environment for the proposed work. Military Relevance: Vietnam Veterans have an increased risk of pancreatic cancer. Smoking and diabetes are both risk factors for pancreatic cancer, and exposure to pesticides such as DDT that were used in Vietnam has been correlated with increased risk of pancreatic cancer. Given that the prevalence of pancreatic cancer peaks at ages 65-79, and the majority of Vietnam Veterans are now reaching this age window, a treatment for pancreatic cancer would be of particular relevance to military beneficiaries.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610197
Entities
People
- Stephanie K Dougan
Organizations
- Dana–Farber Cancer Institute
- United States Army