Elucidating Mechanisms of CAR ML NK cell biology to treat cancer and infection

PROJECT SUMMARY Candidate: During my training, I have been highly motivated to understand how cytotoxic lymphocytes can be used as an adoptive therapy and how immune cells are regulated during immunotherapy. I have served as first, co-, and corresponding author on numerous high-impact original research articles, representing advances in

basic, translational, and clinical immunology. I have successfully competed for career development awards that have allowed me to continue my research interests. My long-term research goals are to understand the mechanisms important for NK cell effector functions, how NK cells contribute to and are impacted by

immunomodulation and how host immune responses can promote or limit their NK cells as an effective cellular therapy in human and murine systems. Research Career Development Plan: As I begin my independent research program, I will utilize educational and research resources aimed specifically at junior faculty at Washington University to strengthen my career

development. While I have the scientific training and expertise to perform the proposed studies, I will utilize the opportunities at WUSM to prepare for my tenure-track position. Specifically, aspects of management, mentorship, and the learning the administrative responsibilities of running a research laboratory (animal

protocols, institutional approvals, budget management). Research Project: The long-term goal of this project is to improve our understanding of mechanisms operative in the successes and failures of innate immune therapy. Memory-like NK cells were first identified in mice over a decade ago and studies examining their persistence, anti-tumor responses, and metabolic adaptations to the

tumor microenvironment have laid the groundwork for both the human trials currently open to enrollment and the studies proposed herein. One current barrier in the field is translating these novel immune approaches which have had so much success in treating hematologic malignancies into successes treating solid tumors. We

hypothesize that ML NK cell differentiation combined with chimeric antigen receptor (CAR)-targeting will improve NK cell trafficking, effector responses, and fitness in both allogeneic and autologous immunotherapeutic paradigms. We will evaluate this concept against cancer and infection. These studies may reveal novel strategies

or therapeutic interventions for NK-cell based therapies that will likely be broadly relevant to other cellular therapies. Completion of these studies will lay the scientific groundwork for both future R01 applications and for a successful career studying the interactions of adoptive cell therapy and the host immune system.