Augmenting Antitumor T-Cell Recruitment and Activation in Localized NSCLC Tumors to Improve Checkpoint Inhibitor Therapy
Abstract
Scientific Objective and Rationale: Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related death in the United States and worldwide. Traditional chemotherapy for NSCLC utilizes extremely toxic agents that can induce death in rapidly dividing lung tumor cells, but can also cause severe damage to healthy tissue and organs. More often, a patient will succumb to complications associated with chemotherapy rather than the cancer itself. Immunotherapy, which uses the patient’s own immune cells to recognize and eliminate the cancer, offers greater specificity and much lower toxicity. One type of immunotherapy, known as checkpoint inhibitor therapy, has shown incredible results in lung cancer patients that respond to the treatment, often extending progression-free survival indefinitely. However, only a small percentage of lung cancer patients will have a favorable response to checkpoint inhibition, with a much larger proportion of patients showing little to no clinical benefit. The reason for such low response rates is still not fully understood. However, based on the simple principle that checkpoint inhibitors and other types of immunotherapy require functional immune cells within the tumor, a lack thereof in the majority of patients could explain low response rates. Indeed, many solid malignancies, including NSCLC, develop ways to suppress the activity and prevent the recruitment of immune cells into the tumor mass. Our objective is to increase the immune cell density within NSCLC tumors in the hope that this will make checkpoint inhibition effective in tumors that were once insensitive to treatment. To do this, we have developed an agent that localizes to the tumor and secretes molecules known to guide or recruit immune cells, which we refer to as biological beacons or “bio-beacons.” We hypothesize that systemically administered bio-beacons will preferentially recruit and activate immune cells within lung tumors and will synergize with checkpoint inhibitor therapy to improve anti-tumor responses and overall survival. Through proof-of-principle preliminary experiments, we have shown that, indeed, bio-beacons are capable of recruiting desired immune cells into lung tumors. Furthermore, we have developed our bio-beacons using a delivery platform that has an excellent safety profile in cancer patients and can therefore be quickly translated into the clinic for further testing. Our proposed research directly addresses the FY18 Lung Cancer Research Program Area of Emphasis to “Identify Innovative Strategies for Prevention and Treatment of Lung Cancer.” Principal Career Goals in Lung Cancer Research: My goal is to become a leader in the field of lung cancer research and to develop therapeutic strategies that significantly extend lung cancer survivorship. This award will afford me protected time to achieve these goals. My mentoring team and I have identified key training opportunities, including departmental, disease team, interest group, and national and international conference meetings that will allow me to immerse myself and become integrated into the community of lung cancer research. My goal is to develop and validate a variety of bio-beacons for use alone or in combination with immunotherapy that can ultimately provide additional treatment options for NSCLC patients. My mentors, Drs. Ravi Salgia and Karen Reckamp, are clinical researchers who have tremendous expertise in translating discovery from the bench to the bedside. Thus, in addition to learning about the clinical aspects of lung cancer biology and treatment, my mentoring team can provide valuable training to bring bio-beacons into the clinic. Ultimate Applicability of the Research: The potential for immunotherapy to induce long-term remission of lung cancer has already been observed in the small percentage of patients that respond to checkpoint inhibition. Our goal is to expand this result to the majority of NSCLC patients throu
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910754
Entities
People
- Edwin Manuel
Organizations
- Beckman Research Institute of City of Hope
- United States Army