Engineering T Cells Against the Tumor Extracellular Matrix for Enhanced Immunotherapy of Mesothelioma
Abstract
This project is directed towards the Fiscal Year 2016 Peer Reviewed Cancer Research Program Topic Areas of Immunotherapy and Mesothelioma. We propose here a novel therapy that has Military Relevance Focus by addressing current gaps in the efficient prognosis and treatment of malignant mesotheliomas, which are disproportionately common in military Veterans. The objective of this project is to determine the feasibility of a new approach to treat mesothelioma using immune cells engineered to recognize a protein, named fibulin-3, produced by the cancer cells. Due to the high concentration of fibulin-3 within the tumor, we expect that immune cells detecting this protein will be highly efficient to kill the tumor cells compared to prior approaches that are less specific or potent. First, we will determine if this approach is specific, safe, and effective to kill mesothelioma tumors in animal models. In addition, to further understand the molecular basis of our therapy, we will study the molecular mechanisms by which our engineered immune cells become activated in the tumor and prevent the escape or resistance of tumor cells. Successful completion of this project will allow us to develop targeted therapies to treat mesothelioma patients with cancer detected at any stage. Because fibulin-3 can be used not only as a target but also to diagnose mesothelioma more accurately, our proposed therapy could be rationally applied to mesothelioma patients with the highest chances of response to treatment, therefore increasing the treatment efficacy. Although this project is currently at a basic, preclinical stage, our interim goal is to establish feasibility of this approach towards further clinical application. We envision our strategy as a biological therapy that will be faster-acting and more efficacious than current chemotherapy approaches. The use of engineered immune cells has shown striking efficacy against some malignancies and has resulted in multiple clinical trials to develop these therapies and deal with known risks such as auto-immune or toxic adverse effects. The existence of standard methods to produce and test engineered immune cells and the initial clinical success of these immunotherapies has caused an explosive increase in research and commercial interest by major pharmaceutical companies, which actively support novel engineered immune cells once they are proven successful in the laboratory. Therefore, validation of our experimental therapy may result in pharmaceutical support and a preliminary application to the US Food and Drug Administration to test our engineered cells as Investigational New Drug for mesothelioma patients, within 3 years following the completion of this project. Overall, this study will advance the field of mesothelioma therapies at two levels. At a preclinical level, we will be able to demonstrate a novel approach for cancer immunotherapy focused on a protein that can serve both as a marker of the disease and a target for therapy. At the basic research level, we will further understand the molecular interactions between cancer cells and immune cells and will be able to optimize our engineered immune cells to overcome the resistance of mesothelioma cells to therapy. Combining our expected basic and preclinical advances, we will be able to formulate a rational approach for immunotherapy of mesothelioma that will improve the healthcare and long-term survival of patients with this devastating disease. Our research is particularly relevant to military Veterans, which present a disproportionately high incidence of mesothelioma because they have been chronically overexposed to asbestos and other mineral pollutants during their time in Service, either in asbestos-containing military installations or in combat zones. Due to the difficulty for accurate early diagnosis, mesothelioma is detected in Veterans usually as a high-grade malignant tumor with very low chances to be contained and e
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710444
Entities
People
- Mariano S Viapiano
Organizations
- State University of New York Upstate Medical University
- United States Army