Image-Guided High Intensity Focused Ultrasound-based Boiling Histotripsy for Treatment of Neuroblastoma

Abstract

Recent advances in non-invasive therapies combined with the growing field of immunotherapy may enable safer and more efficacious treatments of solid tumors. Neuroblastoma is a solid tumor that is presented as an embryonal tumor of the autonomous nervous system, with over 650 cases diagnosed each year in the USA. More than 50% of these cases are classified as high-risk, and have abysmal prognosis owing to a small mutanome. High intensity focused ultrasound (HIFU) is a completely non-invasive therapy that uses focused acoustic waves to deposit ultrasound energy within the target tissue location. This increases target tissue temperature to greater than 60°C. We, and others, have developed and optimized a novel, alternative, HIFU technique that is capable of breaking-up the tumor in a precise manner, while keeping major blood vessels intact. We also characterized the spatial precision, temperature effects inside and around the treated region. Using this HIFU technique, we partially treated (<5%) refractory, and large tumors in mice using HIFU and in combination with checkpoint inhibitors. Our HIFU technique alone produced a significant upregulation of systemic immune cells within the tumors, lymph nodes, and spleen. This systemic immune response to HIFU further sensitized the tumor to checkpoint inhibitor therapy, leading to abscopal effects, long-term survival, and effector memory response. We have also demonstrated preclinical feasibility of performing tissue mechanical fractionation on a clinical HIFU system, and anticipate to start a clinical trial using this HIFU technique in combination with checkpoint inhibitors to treat children suffering from neuroblastoma.