Project Abstract: The funded research project will advance our understanding of immunologic risk factors for infections, morbidity, and mortality after chimeric antigen receptor (CAR) T-cell therapy. This research proposal utilizes a large retrospective cohort of patients to determine the immunologic impact and clinical significance of hypogammaglobulinemia following CAR T-cell therapy. Regression models and network analysis will be used to define risk factors for development of infections and poor outcomes and to develop a clinical risk prediction model. In accomplishing these aims, Dr. Barmettler will address critical gaps in our knowledge of immune dysregulation following the use of CAR T-cell therapy with the ultimate goal of improving patient outcomes. Dr. Barmettler will perform this work under the mentorship of Professor Carlos Camargo, an internationally recognized expert in clinical epidemiology with an outstanding track record of mentorship. Dr. Barmettler has assembled a team of mentors and collaborators with expertise in epidemiology, biostatistics, B-cell immunology, CAR T-cell therapy, and infectious disease, whose support will contribute to the success of this project. Dr. Barmettler is an Instructor in Medicine at Harvard Medical School (HMS) and Assistant in Medicine in Allergy- Immunology at Massachusetts General Hospital (MGH) who has demonstrated academic productivity and a strong commitment to clinical research. Her prior training and research in immune deficiency and investigating immunologic outcomes in other B-cell targeted therapies (including the largest cohort to date of rituximab-treated patients), have established the skills and experience critical for achieving her proposed research aims. The research aims outlined in this proposal, along with collaborative opportunities and research environment at MGH and HMS, will allow Dr. Barmettler to achieve the research and educational aims and to, thereby, establish herself as an independent physician-scientist with expertise in advanced biostatistical techniques and mechanisms of immune deficiency.

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of relapsed and refractory hematologic malignancies; however, the immunologic impact and risk for infections and mortality following treatment have not been well-characterized. This Career Development Award focuses on applying advanced clinical epidemiology and simulation modeling to understand the immunologic impact of CAR T-cell therapy. Our overall objective is to identify predictive risk factors and cost-effective screening methods to allow for risk stratification, protocols for immunologic monitoring, and initiation of earlier interventions to mitigate the risk for morbidity and mortality and improve quality of life.