Project Summary/Abstract This SPORE renewal application represents the efforts of interdisciplinary teams of investigators from the Neuro- Oncology Program of the UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) to build on our accomplishments to continue to translate our findings to improve care for patients with brain cancer. We have three specific objectives: (1) to develop novel peripheral blood-based biomarkers for glioma patients, (2) to identify novel metabolic markers for noninvasive imaging to evaluate tumor burden and treatment response, and (3) to develop a novel immunotherapy strategy to overcome the current significant challenges. At the heart of the proposal are three translational research projects—each intended to evaluate paradigm-changing novel tools for prognostic, diagnostic, and therapeutic modalities with defined human endpoints. Project 1 will build on the team’s pioneering work during the current funding cycle that they established as immunomethylomics. The team identified GBM survival to be independently predicted by an interactive model of age and peripheral blood immune profiles, a methylation biomarker of myeloid-derived suppressor cells, or a methylation biomarker of dexamethasone response. Using prospectively collected >1,800 samples from the current cycle and additional samples from the new cycle, the team plans to create blood DNA methylation-based biomarkers for integrated GBM prognosis models, stratification of isocitrate dehydrogenase (IDH)-wild type vs. mutant gliomas, and assessments of treatment response. Project 2 team will also build on their achievements during the current funding cycle related to the development of hyperpolarized C-13 imaging as novel imaging markers of response. In the current proposal, the team will evaluate their central hypothesis that the use of hyperpolarized C-13 (HP) imaging probes (HP [2-13C]pyruvate or [1-13C]α-ketoglutarate [α-KG]) in magnetic resonance (MR) imaging will serve as metabolic markers of treatment response and tumor burden in patients with IDH-mutant glioma. The team will first evaluate their hypothesis in preclinical models and the roles of HP [2-13C ] pyruvate and HP [1- 13C]⍺-KG probes in the treatment response and tumor burden, respectively, in patients. Project 3 will develop the first-in-human phase I trial of adoptive transfer therapy using autologous T lymphocytes that are genetically engineered with a novel “prime and kill” gene circuit. Based on preclinical data, this approach will allow us to overcome significant challenges for developing effective immunotherapy for GBM, such as antigen- heterogeneity, on-target off-tumor toxicities, exhaustion, and the lack of effective GBM-homing of the therapeutic T lymphocytes. This SPORE proposal also requests continued support for the Career Enhancement and Developmental Research Programs and for three Cores (Administrative, Biospecimen/Pathology, and Biostatistics and Clinical) that will support the e...