PROJECT SUMMARY: This proposal details a five-year research training program that will allow Sara Barmettler, MD to achieve her goal of becoming an independent clinical researcher focused on improving outcomes among patients with primary and secondary immunodeficiency. 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 proposal will advance our understanding of immunologic risk factors for infections, morbidity, mortality, and decreased quality of life after chimeric antigen receptor (CAR) T-cell therapy. Aim 1 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 Bayesian network analysis will be used to define risk factors for development of infections and poor outcomes and to develop a clinical risk prediction model. Aim 2 will evaluate the impact of hypogammaglobulinemia and immunoglobulin replacement on morbidity, mortality, and quality of life and evaluate cost-effectiveness of early intervention. 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. In the exceptional training environment at MGH and HMS, Dr. Barmettler will complete coursework and training in advanced biostatistical techniques and epidemiology, leadership, and responsible conduct of research. The training and mentoring plans outlined in this Career Development proposal, along with the outstanding collaborative opportunities and intellectual 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.