The roles of thermal and mechanical stress in focused ultrasound-mediated immunomodulation and immunotherapy for central nervous system tumors

• Authors: Chulyong Kim, Georgia Institute of Technology; Michael Lim, Stanford University; Graeme F Woodworth, University of Maryland; Costas D Arvanitis, Georgia Institute of Technology
• Journal Title: JOURNAL OF NEURO-ONCOLOGY
• Volume: Volume 157, Number 2
• Publisher: SPRINGER | 2022-03-02, Pages 221-236
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1007/s11060-022-03973-1
• Subjects: Engineering, Mechanical; Health Sciences, Medicine and Surgery; Health Sciences, Radiology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Oncology; Clinical Neurology; Neurosciences & Neurology; Focused ultrasound; Immunomodulation; Immunotherapy; Brain tumors; BLOOD-BRAIN-BARRIER; CHIMERIC ANTIGEN RECEPTOR; T-CELLS; NONTHERMAL ABLATION; ADVERSE EVENTS; DRUG-DELIVERY; HYPERTHERMIA; DISRUPTION; GLIOBLASTOMA; MICROBUBBLES

Abstract

Background: Focused ultrasound (FUS) is an emerging technology, offering the capability of tuning and prescribing thermal and mechanical treatments within the brain. While early works in utilizing this technology have mainly focused on maximizing the delivery of therapeutics across the blood–brain barrier (BBB), the potential therapeutic impact of FUS-induced controlled thermal and mechanical stress to modulate anti-tumor immunity is becoming increasingly recognized. Objective: To better understand the roles of FUS-mediated thermal and mechanical stress in promoting anti-tumor immunity in central nervous system tumors, we performed a comprehensive literature review on focused ultrasound-mediated immunomodulation and immunotherapy in brain tumors. Methods: First, we summarize the current clinical experience with immunotherapy. Then, we discuss the unique and distinct immunomodulatory effects of the FUS-mediated thermal and mechanical stress in the brain tumor-immune microenvironment. Finally, we highlight recent findings that indicate that its combination with immune adjuvants can promote robust responses in brain tumors. Results: Along with the rapid advancement of FUS technologies into recent clinical trials, this technology through mild-hyperthermia, thermal ablation, mechanical perturbation mediated by microbubbles, and histotripsy each inducing distinct vascular and immunological effects, is offering the unique opportunity to improve immunotherapeutic trafficking and convert immunologically “cold” tumors into immunologically “hot” ones that are prone to generate prolonged anti-tumor immune responses. Conclusions: While FUS technology is clearly accelerating concepts for new immunotherapeutic combinations, additional parallel efforts to detail rational therapeutic strategies supported by rigorous preclinical studies are still in need to leverage potential synergies of this technology with immune adjuvants. This work will accelerate the discovery and clinical implementation of new effective FUS immunotherapeutic combinations for brain tumor patients.