Vascular normalization through histotripsy ablation therapy promotes anti-tumor immunity and enhances drug delivery in solid tumors 3610

Description Immunotherapies have revolutionized the treatment of many cancers. However, many solid tumors remain refractory to treatment owing to their “immune-excluded” phenotype. This characteristic is in part by virtue of the highly pro-angiogenic nature of the tumor microenvironment (TME) that gives rise to the abnormal vascular network, supporting tumor growth and metastasis while preventing cytotoxic T lymphocyte (CTL) infiltration and killing. We are investigating the therapeutic potential of histotripsy, which is a non-invasive tumor ablation technique that uses high-intensity focused ultrasound to liquefy solid tumors. Preliminary data from our laboratory show that histotripsy treatment downregulates hypoxia and vascular endothelial growth factor (VEGF), potentially remodeling the tumor vasculature and promoting an “immune-inflamed” tumor phenotype. Here we show that histotripsy can alter the physical properties of the TME, resulting in tumor vascular normalization that contributes to increased immune cell infiltration and enhanced intratumoral delivery of chemotherapy and monoclonal antibodies. Our findings suggest that, in addition to promoting a more conducive environment for immunotherapies, histotripsy can also be utilized as an alternative to systemic anti-angiogenic therapies. Combinatorial approach using histotripsy and immunotherapy thus provides a novel avenue to overcome the limitations of immunotherapy in solid tumors. Funding Sources This work is supported by NIH R01CA269394, NIH R01CA211217, VA I01BX005267, FUS 1285, UM PRR Grant U078622, and NIH NIAID T32 Training Grant AI007413.