Characterizing Immunological and Genomic Resistance Mechanisms to Anti-PD-1 Immunotherapy in Smoking-Associated Head and Neck Cancer
Abstract
Career Development: Dr. Mandal is a recently appointed clinician-scientist Assistant Professor at Johns Hopkins University Department of Otolaryngology-Head and Neck Surgery. He is dedicated to a career at the forefront of head and neck cancer research (FY21 PRCRP Topic Area). The PRCRP Career Development Award will provide Dr. Mandal (i) a highly-structured multidisciplinary mentorship strategy, (ii) develop his research skillsets, and (iii) afford him continued protected time to allow him to fully immerse himself in laboratory-based translational research efforts for the study of head and neck cancer. FY21 PRCRP Topic Area: This proposal will specifically address FY21 PRCRP Topic Area: Head and Neck Cancer and will in the near-term benefit Veterans (Military Health Focus Areas) with smoking carcinogen-induced head and neck cancer by impacting their immediate treatment strategy. Background: Smoking-related head and neck cancer disproportionately affects the Veteran population and is unfortunately, in many cases, incurable. However, a newer treatment strategy known as immunotherapy, and specifically a class of drugs termed PD-1 immune-checkpoint inhibitors, has revolutionized cancer care for patients with advanced tumors in recent years. These drugs work by activating the patient s own immune system to fight their tumor. This strategy represents a major breakthrough for patients with advanced cancers including head and neck tumors. When these therapies work, the responses are often dramatic and sustained, effectively curing a small subset of patients with otherwise incurable disease. However, unfortunately, the vast majority of patients treated with these agents will enjoy no durable benefit, underscoring the pressing and unmet clinical need to better understand the mechanistic basis for why head and neck cancer patients fail immunotherapy. Objective and Rationale: We will implement a coordinated effort between laboratory scientists, clinicians, pathologists, and surgeons to dissect the mechanisms of variable resistance to checkpoint blockade using tumor samples from patients with head and neck cancer who have been treated with immunotherapy. Using cutting-edge technologies, we will uncover resistance mechanisms that develop after treatment with anti-PD-1 immunotherapy. The key targets of our hypothesized resistance mechanisms include other immune checkpoint receptors that also work to turn off the body s immune system in addition to the well understood PD-1 immune checkpoint receptors. Translational Impact: With this knowledge, we can provide rationale for new combinations of drug treatments that are added to traditional immunotherapy strategies while saving patients from the side effects of drugs that do not work. We anticipate the findings from our study to be rapidly translatable to the clinical setting. Many of the new drug combinations we are testing are already in clinical development, which would allow rapid development of clinical trials incorporating these agents in the appropriate manner based on our study findings. Therefore, we anticipate these findings could be applied to the clinical setting to benefit Veterans with smoking-related head and neck cancer in less than 5 years. Summary: The pattern knowledge generated in this study will facilitate both the timing and choice of combinatorial therapies to deliver with anti-PD-1 immunotherapy and will help inform future immunotherapy clinical trial designs and aid translational efforts to improve clinical response rates for Veterans with head and neck cancer (FY21 PRCRP Topic Area) treated with immunotherapy by impacting their immediate treatment strategies (Military Health Focus Area).
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210249
Entities
People
- Rajarsi Mandal
Organizations
- The Feinstein Institute for Medical Research
- United States Army