PROJECT SUMMARY/ABSTRACT Candidate. Dr. Vasquez is an Assistant Professor of Pediatrics at the Yale School of Medicine and a member of the Yale Cancer Center Cancer Immunology Program and trainee in the Yale Immuno-Oncology Training Program. This proposal is focused on the link between DNA damage and tumor immunogenicity and will provide Dr. Vasquez with essential research skills, such as methods for interrogating DNA repair and immune pathways and pre-clinical studies with syngeneic mouse models. Dr. Vasquez will take advanced coursework in cancer immunology, cellular and molecular biology of cancer, computational biology, and early phase clinical trial design. He will also participate in local and national cancer biology and immunology conferences. Dr. Vasquez’s primary mentor, Dr. Ranjit Bindra, is a physician-scientist with an R01-funded research laboratory and an expert in leveraging DNA repair pathways in the treatment of cancer. Dr. Vasquez’s advisory committee includes Dr. Hideho Okada, a physician-scientist and expert in preclinical glioma immunotherapy research, Dr. Gary Kupfer, a physician-scientist with expertise in the study of genomic instability in cancer and Dr. David Hafler, a physician-scientist and pioneer in neuro-immunology. This multidisciplinary mentorship team, along with the outstanding scientific resources available at Yale, will allow Dr. Vasquez to acquire additional mentored research experience so that he may become an independently funded investigator. Research Project. Immune checkpoint inhibitors (ICi) have, thus far, been ineffective in the treatment of glioma, largely due to the immunologically “cold” microenvironment and the low number of neoantigens. Our group recently discovered that IDH1/2 mutations, which are common in gliomas, induce homologous recombination (HR) defects and confer sensitivity to DNA damage response inhibitors (DDRi), such as poly (ADP-ribose) polymerase (PARP) inhibitors and Ataxia telangiectasia and Rad3-related (ATR) kinase inhibitors. Emerging evidence shows that inherited or acquired DDR defects increase tumor immunogenicity through DNA damage-induced activation of immune recognition pathways. Therefore, the central hypothesize of my proposal is that mutant IDH1/2-induced DNA repair defects can be exploited with PARP and ATR kinase inhibition to induce host and cancer cell-intrinsic immune activation and improve ICi response in otherwise poorly immunogenic gliomas. In Aim 1, we will perform a series of in vitro and in vivo studies to test the potential efficacy of combined PARP and ATR inhibition against IDH1/2-mutant glioma and explore DNA repair mechanisms contributing to this synthetic lethality. In Aim 2, we will probe the immune-mediated mechanisms of DDRi synthetic lethality and define the tumor-intrinsic and host-dependent immunomodulatory effects of combined PARP and ATR inhibition. In Aim 3, we will determine whether PARP and ATR inhibition, alone or in combination, improves t...