Leveraging Focused Ultrasound to Potentiate Immunotherapy for Primary and Disseminated Solid Cancers
Sheybani, Natasha, Biomedical Engineering - School of Engineering and Applied Science, University of Virginia
Price, Richard, EN-Biomed Engr Dept, University of Virginia
Immunotherapy has demonstrated unparalleled clinical outcomes across an array of solid tumor types. However, a significant fraction of patients is unable to realize this benefit due to lack of spontaneous anti-tumor immunity. Poor T cell infiltration and persistence, alongside mechanisms of immune suppression within the tumor microenvironment (TME), severely limit the accessibility of most immunotherapies to a broad patient population. This limitation perpetuates the demand for therapeutic platforms that boost the immunogenicity of tumors while curbing the onset of adaptive resistance mechanisms, effectively converting immunologically “cold” (poorly infiltrated) tumors into immunologically “hot” (well-infiltrated) ones. In this dissertation, we explore focused ultrasound (FUS) as a method for stimulating anti-tumor immunity in cancers of the brain and periphery. FUS is a safe, non-invasive, non-ionizing technique for targeted acoustic energy deposition into tumors with sub-millimeter precision. The thermal and/or mechanical bioeffects of FUS application can elicit local damage/destruction to tumor tissue, transport of drugs and genes across the blood brain/blood tumor barriers (BBB/BTB), and have more recently been demonstrated as anti-tumor immune stimuli. The overarching goal of this dissertation is to systematically dissect the mechanisms of innate and adaptive immune responses to primary or disseminated tumors elicited by FUS and use this information to design and test immunotherapeutic approaches predicted to synergize with FUS.
The first aim of this dissertation examines the differential impact of parameters such as peak negative pressure and anesthesia on the induction of immunity in gliomas following MR image-guided FUS BBB/BTB disruption (BBB/BTB-D). We additionally leverage molecular imaging to spatiotemporally map the delivery of 89Zr-labeled monoclonal antibodies into murine gliomas following BBB/BTB-D and utilize these findings to design a combinatorial paradigm with CD47 blockade therapy. In the second aim of this dissertation, we engineer a strategy for elevating the immune modulatory capacity of FUS thermal ablation in combination with chemotherapy and/or immune checkpoint blockade for metastatic breast cancer therapy. We investigate the immunological mechanisms underpinning combination of FUS with gemcitabine, a myelo-reductive chemotherapy, and demonstrate that synergistic impact of these two therapies is dependent upon the adaptive immune system. Finally, we extend this paradigm to the setting of PD1 blockade. Taken together, the highly translational aims of this dissertation generate a robust foundation for future FUS immunotherapy investigations; more importantly, these aims expand our collective insights regarding how FUS can best be leveraged as a strategy for potentiating immunotherapy, generating timely and provocative considerations therein.
PHD (Doctor of Philosophy)
Focused Ultrasound, Immunotherapy, Glioblastoma, Breast Cancer, Molecular Imaging, Drug Delivery
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