Wielding Focused Ultrasound Induced Sterile Inflammation: A Double-Edged Sword in Cancer and the CNS
Mathew, Alexander, Biomedical Engineering - School of Engineering and Applied Science, University of Virginia
Price, Richard, EN-Biomed Engr Dept, University of Virginia
Focused ultrasound (FUS) is an exciting medical technology capable of inducing diverse therapeutic bioeffects applicable to a wide array of diseases. Often performed under image guidance, FUS generates acoustic waves outside the body and orients them to converge in diseased tissue without affecting surrounding healthy tissue. The ability of FUS to precisely ablate pathologic regions without the need for ionizing radiation has already garnered clinical utilization for treatment of uterine fibroids, bone metastases, and essential tremor. Research efforts have recently shifted to the investigation of more advanced applications of FUS, including immunomodulation and disruption of the blood brain barrier. We applied data-driven approaches to investigate each of these, generating actionable mechanistic insights toward accelerating clinical adoption of FUS as a precision medicine.
Immunotherapies have revolutionized cancer therapy in the last decade, empowering patients’ own immune systems to recognize and destroy tumor cells. However the success of these therapies is highly variable, dependent on the baseline immunologic cooperativity of the tumor microenvironment (TME). FUS thermal ablation (FUSTA) may provide an opportunity to sensitize immunologically “cold” tumors, increasing the proportion of patients who could benefit from immunotherapy. In addition to clinical utility as a tumor debulking therapy, a growing body of evidence has shown FUSTA generates pro-inflammatory signatures in the TME. Attempts to leverage these effects for enhancement of immunological tumor control have been mostly unsuccessful, in part due to an incomplete knowledge of how FUSTA interfaces with the TME. Here, used high throughput transcriptomic and immunophenotypic profiling to reveal pro- and anti-tumor mechanisms induced by FUSTA in a model of aggressive melanoma. These insights enabled design of novel FUSTA-drug combinations capable of significantly delaying tumor growth. We identified similarly nuanced immunomodulatory impacts in the first clinical trial to combine FUSTA with immunotherapy in breast cancer patients. These were then directly contrasted against a parallel study of the same immunotherapy when paired with high-dose conformal radiation therapy in solid human malignancies. Ultimately, we conclude that maximizing the immunogenicity of FUSTA will require pharmacological blockade of concomitant tissue repair mechanisms.
The blood brain barrier (BBB), a specialized vasculature unique to the central nervous system (CNS), remains one of the most significant neuropharmacological obstacles. Pulsed, low-intensity FUS in conjunction with systemically administered microbubbles (MBs) can transiently disrupt the BBB, facilitating localized delivery of therapeutics to the brain. FUS-mediated BBB disruption (BBBD) has been shown to enhance accumulation of chemotherapies, genes, neural stem cells, and antibodies in the brain, therapeutics normally too large to bypass the BBB. As this technology rapidly approaches clinical maturity, it is becoming increasingly important to understand the cellular consequences of perturbing the BBB, a protective physiological structure crucial to maintaining homeostasis in the CNS. Herein, we perform investigations of the nature of the parenchymal response to BBBD, as well as its experimental determinants. We first describe how anesthesia, used in all preclinical FUS BBBD studies, influences local reactivity and signaling networks following BBBD. Next, we investigate how FUS acoustic pressure affects gene delivery and transcription in distinct cell populations of the CNS. Finally, we identify the relative power of MB activation and contrast enhancement measured during FUS BBBD to predict transcript expression in the hours following treatment. Together these studies provide fundamental knowledge concerning the biological response to BBBD, with clear safety and therapeutically relevant implications.
PHD (Doctor of Philosophy)
Focused Ultrasound, Cancer Immunotherapy, Blood Brain Barrier, Bioinformatics