Novel Approaches to Locoregional and Systemic Immunotherapy for Ovarian Cancer
Abstract
Rationale for Proposed Research: Cancer immunotherapies use strategies to activate the immune system to recognize and kill cancer cells. Scientific breakthroughs in cancer immunotherapy led to development of several drugs, such as drugs targeting the immune inhibitory molecules known as PD-1 and PD-L1. These drugs have resulted in significant tumor shrinkage and even cures in some patients. Unfortunately, in ovarian cancer, only a small fraction of patients responds to such treatments. It is thus necessary to identify the mechanisms that allow ovarian tumors to resist immunotherapy and to develop novel approaches that can target such mechanisms. Using tumor tissues from ovarian cancer patients treated with drugs targeting PD-1/PD-L1, the first major goal of the current study is to identify the mechanisms that allow ovarian cancer to resist immunotherapy. The second goal of the study is to use animal models of ovarian cancer to develop novel therapeutic approaches that could overcome the resistance to PD-1/PD-L1-targeted therapies. To achieve the latter, we are exploring a novel class of cancer drugs known as oncolytic viruses. We have demonstrated that one such virus called Newcastle Disease Virus (NDV) activates a potent immune response against cancer cells and results in complete elimination of mouse tumors when combined with drugs targeting PD-1/PD-L1. By using different NDVs that have been genetically modified to target different immune pathways in tumors, the current study will aim to identify the most effective treatment combinations using this novel strategy. Career Goals: At the completion of the training period, I aim to become an independent investigator specializing in immunotherapy for ovarian cancer. My research will consist of studies of immunotherapies in animal models and clinical trials with correlative laboratory studies. To achieve these goals, my career development plan draws on several components, including research and mentorship, coursework and conferences, advisory committee, clinical training, and teaching. The research and learning objectives of the research proposal are integrated to create a strong foundation for future studies that would sustain my career as an independent ovarian cancer researcher and allow me to make strong contributions to ovarian cancer: (1) The proposed learning objectives will allow me to acquire competencies in new technologies and analytical tools, which will be necessary for independent design, execution, and analysis of clinical and translational immunotherapy studies for ovarian cancer patients. (2) The results of the basic and translational research proposed in the current project will establish a rationale for new clinical/translational studies in ovarian cancer, which I would be well-positioned and qualified to lead. Applicability of Research: The results of this work will lead to development of novel immune treatments for ovarian cancer, which will hopefully be able to benefit a larger percentage of ovarian cancer patients and be applicable to patients with both early and advanced disease. As with other immune therapies, these treatments would carry advantages over conventional chemotherapies, with fewer side effects and more durable tumor reductions. Based on the rapid developments in the immunotherapy field with increasing availability of drugs targeting different immune pathways, some initial clinical trials evaluating these combinations in ovarian cancer would likely commence during the years 4-5 of this award period. Short- and Long-Term Contributions to Ovarian Cancer: In the short term, the results of these studies will help us understand some of the mechanisms by which ovarian cancer resists the immune system. In addition, they will lead to new clinical trials using combinations of drugs targeting PD-1/PD-L1 and other identified targets. In the long term, these treatment approaches will eventually also incorporate novel agents
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610298
Entities
People
- Dmitriy Zamarin
Organizations
- Memorial Sloan Kettering Cancer Center
- United States Army