Novel approaches to enrich CAR-T cell Therapy in brain tumors using focused ultrasound - PROJECT SUMMARY Focused Ultrasound (FUS) is a powerful technology now FDA approved for several ablative brain therapies, and has demonstrated an impressive safety and efficacy profile for treating diseases such as essential tremor. Beyond ablation, early human studies demonstrate efficacy and safety of noninvasive microbubble-mediated blood-brain barrier (BBB) disruption with FUS for advanced therapeutic applications. In this high-risk, high- reward biomedical engineering project, we have assembled a uniquely qualified team to explore novel applications of FUS to improve Chimeric Antigen Receptor T cell (CAR-T) therapy for glioblastoma (GBM) treatment. CAR-Ts are a promising new treatment platform that allows directed targeting and killing of tumor cells. Locally administered CAR-Ts have demonstrated promising efficacy against GBM. However, like chemotherapeutic agents, systemically administered CAR-Ts suffer from limited access to the brain. We and others have demonstrated applications of focused ultrasound (FUS) with FDA approved microbubbles to amplify the deposition of ultrasound energy into tissue, inducing a variety of biological effects. Under certain ultrasound conditions, FUS can temporarily and reversibly alter the permeability of the BBB to deliver exogenous compounds into the brain, which has been demonstrated in preclinical models and early-stage clinical trials in humans. We have developed an ultrasound image-guided FUS therapeutic platform specific for rodents, capable of consistent and accurate targeting of BBB disruption and delivery of therapeutics to the brain, a necessary requirement for the proposed studies. Furthermore, we have identified the immunoregulatory protein B7-H3 as an attractive CAR-T target which is highly expressed in clinical GBM isolates but not in normal tissue. We have developed both murine B7-H3.CAR-Ts, which demonstrate efficacy in xenograft models, and human B7- H3.CAR-Ts, which are currently being evaluated in phase 1 clinical trials for safety and antitumor activity at our facility. Our team is therefore in a unique position to study the potential application of FUS to improve CAR-T therapy for GBM. Specifically, we hypothesize that FUS-mediated BBB disruption will result in increased trafficking of systemically administered B7-H3.CAR-Ts to GBM tumors; and FUS therapy will improve overall anti-tumor efficacy of B7-H3.CAR-Ts by modulating the immunosuppressive tumor microenvironment. These hypotheses will be addressed by 1) first establishing the effects of FUS with varying parameters to increase trafficking of B7-H3.CAR-Ts to GBM tumors, 2) determining B7-H3.CAR-T biodistribution, proliferation and persistence over time following systemic administration with FUS therapy, and finally 3) a pilot study to determine the impact of FUS therapy on the tumor immune microenvironment and how those changes augment B7- H3.CAR-T efficacy. Success of this biomedical engineering project would pave the way for further technology development as well as exploration and clinical translation of the synergy of these two relatively new and powerful technologies to make a substantial impact in the lives of GBM patients.
