Dr. Michael Khodadoust is an Instructor in Oncology at Stanford University. He and his mentors, Drs. Ash Alizadeh and Ronald Levy, have developed a comprehensive career development plan designed to prepare him for his long term goal of an independent career in translational studies of immunotherapy in non-Hodgkin lymphoma (NHL). The Applicant: Dr. Khodadoust has consistently pursued his goal of an academic career in translational oncology. He completed his MD/PhD training in Immunology at the University of Michigan Medical School discovering oncogenic functions of the DEK gene. More recently, Dr. Khodadoust applied a novel approach integrating genomic and proteomic data to profile mantle cell lymphoma (MCL) tumor antigens, revealing that the lymphoma immunoglobulin is a key antigen that is almost exclusively presented by class II MHC. Mentorship Environment and Career Development Plan: Both mentors are practicing physician-scientists with a history of providing seminal contributions to the understanding and treatment of NHL. Training will be focused in developing a foundation in computational aspects of immunology and enhancing prior immunology training. There will be specific practical training in T cell engineering with transgenic T cell receptors as a means to translate antigen profiling results into future clinical therapies. The plan incorporates didactic courses, seminar series, and participation in formal training programs, both internal and external to Stanford University. A distinguished advisory committee consisting of Drs. Mark Davis, Crystal Mackall, and Philip Greenberg will closely assist in training and mentorship. Research: The key antigens that determine immune recognition of NHL remain unknown. We have developed an innovative strategy to uncover novel tumor antigens, incorporating genomic and proteomic profiling to identify peptides presented by the major histocompatibility complex (MHC) of cancer cells. This approach was designed to specifically include patient-specific antigens including neoantigens. In preliminary work with MCL, we have discovered that the only presented neoantigens were derived from unique lymphoma immunoglobulin VDJ rearrangements and somatic hypermutation events. In the first aim, we now propose to extend this analysis to other more common subtypes of NHL including diffuse large B cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, marginal zone lymphoma, and Sezary syndrome. In the second aim, we will focus on identifying T cell receptors (TCRs) specific for common NHL shared immunoglobulin-derived antigens. These lymphoma-specific TCRs will be delivered into patient T cells and tested for cytolytic activity against primary lymphoma cells as a proof of principle for future T cell-based therapies targeting the lymphoma immunoglobulin.
PUBLIC HEALTH RELEVANCE STATEMENT Non-Hodgkin Lymphoma (NHL) will affect 2.1% of men and women in their lifetime, with over 70,000 new cases diagnosed annually. The proposed research will explore the relationship between the immune system and NHL, enhancing our understanding of the development and treatment of this malignancy. This project will build a foundation for future clinical trials by informing our use of immunotherapy in this illness, thus directly contributing to the NIH mission to seek basic knowledge about the nature of living systems that will help to improve health, reduce illness and disability, and lengthen life.