Investigating the Role of a Novel Inhibitory Receptor Complex in Driving T Cell Dysfunction and Therapeutic Resistance Toward Immunotherapies in Lung Cancer
Abstract
Objective and Rationale: Lung cancer is the leading cause of cancer death in the United States, with the 5-year survival rate at only 15%. For active-duty military personnel and Veterans, the risk of developing lung cancer is 25% higher than among the general population, yet their survival rate is lower than among civilians. Thus, there is an urgent need for better treatments of lung cancer, particularly for military patients with late-stage and metastatic lung cancer. Inhibitors targeting PD-1 and PD-L1 immune checkpoint receptors have become the breakthrough therapies for lung cancer. However, durable responses are only seen in < 30% of patients, underscoring the urgent medical need to identify new targets and develop alternative immunotherapies that will overcome resistance. Our study will address the role of a new immune checkpoint receptor VISTA in promoting immune dysfunction and contributing to the therapeutic resistance to existing immunotherapies in lung cancer. Areas of Emphasis: This proposal addresses the FY21 LCRP Areas of Emphasis, including Identify innovative strategies for the treatment of lung cancer and Understand mechanisms of resistance to treatment post immunotherapy. The main objective of this proposal is to validate the role of a novel immune checkpoint receptor in promoting therapeutic resistance towards existing immunotherapies in lung cancer. A second objective is to develop novel inhibitors that will block the activity of this immuno- suppressive receptor. A third objective is to develop and test novel combinatorial therapies in preclinical models and determine the efficacy of such new therapies in preventing resistance to existing immunotherapies. These studies will have significant impact on the prognosis, treatment, and survivorship of lung cancer patients. Applicability of the Research and Military Relevance: Our proposed study has high impact on advancing cancer therapy in general, but also has direct impact on military cancer patients, including active-duty Service Members, Veterans, and other military beneficiaries in at least two areas. First, recent studies have demonstrated that cancer therapy is influenced not only by cell-autonomous oncogenic pathways, but also is controlled by tumor-extrinsic immune-mediated mechanisms such as tumor-specific killing by cytotoxic lymphocytes. Immunotherapy such as inhibitors blocking immune checkpoint proteins will invigorate a patient’s own immune cells to fight cancer; thus, it has wide applicability for treating cancers. Second, lung cancer is one of the common cancer types for military Service Members in U.S. By providing a novel therapeutic target and developing new therapeutics to overcome therapeutic resistance to existing immunotherapies, our study has near-future impact to improve the health of military Service Members and Veterans. Based on our study, we expect to develop novel inhibitors targeting a novel checkpoint protein. We will plan to secure the intellectual property of our inhibitors and license the technology to pharmaceutical entities that are interested in developing near-future clinical trials to test combinatorial therapies, with the goals of determining whether better clinical responses can be achieved by combining the existing immunotherapies with our inhibitors. These studies will directly benefit military lung cancer patients who carry late-stage and metastatic diseases and have limited options under traditional radio- and chemo-therapies or are resistant to the existing immunotherapies.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210460
Entities
People
- Li Wang
Organizations
- Cleveland Clinic
- United States Army