The candidate is an academic neurosurgeon at Washington University School of Medicine in the Department of Neurological Surgery and Pathology and Immunology and is the first faculty member recruited to the newly- created Center for Human Immunology and Immunotherapy Programs. He has a track record of high-level published research in tumor immunology and cancer genomics. To pursue the goal of successful transition to independent investigation, the candidate has assembled a career development plan with formal coursework, seminars, and meetings focused in genomics and tumor immunity in the central nervous system. The candidate's research training development program will take place at Washington University in St. Louis, which has deep expertise in genomics and immunology. This program will be co-mentored by Drs. Emil Unanue and Andrey Shaw, who together have significant expertise in T cell immunology, antigen presentation, murine immunobiology, and cell signaling that will provide a rich and excellent scientific environment for the proposed work in glioma immunobiology. Additional assistance from Drs. Schreiber, Mardis, Eberlein, and Kim will maximize opportunities to be successful during this transition to independent investigation. The proposed work centers on the immunobiology of malignant glioma. Although glioblastoma, the most aggressive primary brain tumor in patients, has been extensively characterized from a structural genomics standpoint, the mutation-to-drug paradigm observed in other cancer types has not been successful in this disease. The inefficacy of targeted therapies in glioblastoma is likely because the tumor cell dependencies are not well understood and because tumors themselves are incredibly heterogeneous. Therefore, alternative approaches to glioblastoma treatment are urgently being tested in clinical trials. Specifically, new checkpoint blockade cancer immunotherapy agents that target inhibitory T cell receptors CTLA-4 and PD-1/PD-L1 pathways-which have been successful in other cancers including metastatic melanoma-are entering clinical trials for patients with malignant glioma. The candidate is a site-PI for an anti-PD-L1 trial in human glioblastoma. However, the molecular mechanisms underlying the success of these agents in preclinical models are unclear. Moreover, broader issues in central nervous system immunobiology that has never been well understood-such as antigen presentation-likely will come to bear on the success of checkpoint blockade therapies in brain tumor treatment. Thus, this research proposal focuses on the immunobiology of checkpoint blockade therapy and biology in glioblastoma. Herein, in the first Aim of the research proposal, we will incorporate novel genomics-based approaches to identify tumor-specific antigens expressed by glioma cells and recognized by immune cells following checkpoint therapy. In the second Aim, we will deepen our initial observations that glioma cells express very high levels of the checkpoint therapy target PD-L1 and use a focused functional genomics strategy to dissect the molecular basis of this aberrant overexpression. Finally, in the third Aim we will characterize the role of dendritic cells in the glioma antigen presentation pathway and determine whether they are required in successful checkpoint blockade therapy. Together, these aims will reveal critical mechanistic underpinnings of promising anti-glioma immunotherapeutic approaches and target biological programs that may enhance their efficacy.
Contemporary cancer immunotherapies targeting T cell 'checkpoint' proteins represent an exciting new and effective approach in cancer treatment. These therapies are now in the early stages of being employed in patients with glioblastoma, but further work is necessary to understand in detail the mechanisms underlying their mode of action. Thus, this project will elucidate the role of these therapies in activating T cells specifi to tumors, the cell population that leads to T cell activation in these settings, and clarify how tumors overexpress immunosuppressive molecules targeted by checkpoint therapies.
