Discovering Checkpoint Blockade Resistance Genes in Metastatic Lung Cancer
Abstract
Scientific Objective and Rationale: Our goal is to identify genes mediating resistance to immunotherapy using unbiased genetic screens. This will shed light on immunotherapy strategies for improved clinical outcome of lung cancer patients. Lung Cancer Research Program Area(s) of Emphasis: This study addresses two Areas of Emphasis: (1) Understand predictive and prognostic markers to identify responders and non-responders; and (2) understand susceptibility or resistance to treatment. Ultimate Applicability: This study will discover new factors modulating lung cancer immunotherapy, which can ultimately serve as biomarkers to classify patients for immunotherapy treatment, or as new drug targets for synergistic inhibition to enhance the efficacy of checkpoint blockade, or as targets of completely novel therapeutic route. What types of patients will it help, and how will it help them? The outcome from this study will help virtually all lung cancer patients by identifying more accurate biomarkers to group patients to receive immunotherapy and by discovering new therapeutic targets to improve checkpoint blockade treatments. What are the potential clinical applications, benefits, and risks? This study is basic research; yet, the genes discovered to modulate immunotherapy can readily be translated into biomarkers or new drug targets. Genes associated with better checkpoint blockade response are potential biomarkers to group patients for such treatments, and vice versa. Genes associated with immunotherapy resistance can be developed as new targets for synergistic inhibition to enhance the efficacy of such therapy. What is the projected time it may take to achieve a clinically relevant outcome? We anticipate this study will take 2 years, at the end of which a set of genes modulating checkpoint blockade immunotherapy treatment response will be discovered. Soon after identification of genes associated with better checkpoint blockade response, immediate clinical validation can be performed. What are the likely contributions of this study to advancing the field of lung cancer research? This study will provide new knowledge for the complex interactions cancer cell and immune cells. Furthermore, the approaches developed in this study can be broadly applied to study other aspects of lung cancer. How is the project relevant to military Service members, Veterans, and their families? Military Service members are constantly exposed to mutagens in their working environment, e.g., excess sunburn, toxic chemicals, polluted air or water, radiation, and other hazards. Such conditions cause additional risk of lung cancer. Mutation load is positively correlated to anti-PD1 response and is a prognosis factor of immunotherapy. This study utilizes mutagenesis-based genetic screens to study lung cancer response to immunotherapy, with direct relevance to military Service members, Veterans, their family members, who might suffer from extreme environmental exposure-related lung cancer. Immunotherapy improves survival for deadly metastatic lung cancer patients; however, only a subset responds and resistance can occur. Our study will globally reveal genetic factors governing susceptibility or resistance to PD-1 blockade therapy, which will provide insights for improved treatments and benefit military Service members, Veterans, their families, and civilian patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710235
Entities
People
- Sidi Chen
Organizations
- United States Army
- Yale University