ABSTRACT - NEURO-ONCOLOGY (NO) PROGRAM Overview and Goals: The long-term goal of the O’Neal Neuro-Oncology (NO) Program is to develop safe and innovative therapies for adult and pediatric patients with brain cancer through translation of laboratory research into safe and innovative clinical trials. To achieve this goal, NO emphasizes strategies to overcome treatment resistance, addresses the challenges of the central nervous system, tumor microenvironment, and designs creative therapies to overcome immunosuppression. Research Highlights: A significant effort has been the deployment and enhancement of oncolytic herpes simplex virus (oHSV) to create an immunologically active tumor microenvironment in both pediatric and adult patients. Preclinical studies supported by ANIM, FLOW, GEN, and TPRO have led to investigator initiated clinical trials. The use of the first-generation oHSV, G207, in pediatric recurrent malignant glioma patients demonstrates lasting responses and biological confirmation of immunological activation within the tumor (NEJM, 2021). Program Activities: NO has strong research and educational programs that strengthen translational neuro-oncology research. The monthly Brain Tumor Working Group reviews proposed clinical trials and discusses the progress of investigator-initiated trials as well as NO translational initiatives. NO Seminar enables monthly seminars from guest speakers to share their most recent research. Monthly Neuro-Oncology Faculty Grants club provides early-stage and senior scientists with the opportunity to discuss planned grant submissions. NO Retreat also permits strategic planning for the future of the Program. Trainees and faculty have additional opportunities to share their work and build collaborations through the Brain Tumor Research in Progress Meeting and Glial Biology Works in Progress Meeting. Members: NO is composed of 21 highly collaborative members across 8 departments in the School of Medicine. In the current cycle, NO members have published 243 manuscripts, with 67% being inter-institutional, 42% inter- programmatic, and 27% intra-programmatic. 20% were in high-impact journals. The program has a total of 54 funded projects totaling $6 million in direct costs, including 15 from the NCI with $2.9 million per year in direct costs. This external funding is built from strong O’Neal support via NO Program Activities and direct interactions with ET, CBI, and CCPS. Future Directions: We will build on our recent success with oncolytic HSV to determine predictors and enhancers of therapeutic response. Investigator Initiated Trials will be designed to test the efficacy of early deployment of oncolytic HSV in newly diagnosed pediatric and adult malignant glioma patients. We will apply institutional expertise in imaging to characterize novel PET tracers relevant to our therapeutic development in both metastatic and primary brain cancers. Innovative proton-based radiation therapy regimens will be developed for brai...