PROJECT SUMMARY / ABSTRACT There is an unmet clinical need of precise delivery of hyperthermia therapy (HT) to tumors. Novel immunotherapies, such as checkpoint inhibitors and therapeutic cancer vaccines, have dramatically improved responses to a wide variety of refractory malignancies, relative to standard of care chemotherapies. But benefits remain limited to a minority of patients, as low as 20%, who likely have a pre-existing immune response. HT has shown promise as an adjuvant to radiation, chemotherapy, and immunotherapy. A phase III clinical trial has demonstrated improved local progression- and disease-free survival for patients with soft tissue sarcomas when treated with HT in addition to radiation and chemotherapy. However, a non-invasive technique for precise delivery of HT to deep tumor targets remains lacking. MR-guided Focused Ultrasound (MRgFUS) is a novel technique for non-invasive ablation that is capable of targeted heating of deep focal spots with MRI temperature monitoring. It is currently being used for ablation of deep soft tissue tumors, such as uterine fibroids. Clinically available MRgFUS systems are technically capable of delivering prolonged moderate heating required for HT. If these devices could be modified to produce HT as an immunotherapy adjuvant, the combination of therapies may significantly improve response to these novel immunotherapies. The objective of this project is to develop a HT delivery system based on a commercially available FDA approved body focused ultrasound (FUS) transducer. The specific aims of the project are: 1. Establish MR thermometry techniques and parameters for monitoring and controlling hyperthermia therapy. 2. Identify ultrasound beam synthesis and control techniques, applicable to a sectored phased array in-table transducer, for conformal heating and maintenance of elevated temperature. 3. Validate the MR thermometry guidance, beam forming and control techniques for HT delivery in ex-vivo and in-vivo models. The project will utilize a novel combination of technologies, including real-time MR imaging, commercially available focused ultrasound system, and the sonication control system developed in our laboratory to implement an HT delivery platform that would perform precise prolonged heating of large user-defined regions with MR thermometry feedback. As an outcome of the proposed research, we expect that our ex-vivo and animal experiments will confirm the ability to do HT with commercial FUS transducers. This will enable future clinical trials of combination therapies and could dramatically improve survival for a wide variety of deep tissue tumors.