Histotripsy dose selection influences immune response and tumor-free survival in an orthotopic liver tumor model

Histotripsy has recently gained FDA approval for the treatment of liver cancer. However, there is limited clinical understanding of how different histotripsy doses can generate varying levels of anti-tumor response, thereby impacting patient survival. This work evaluates the impact of histotripsy dosing on immune response and tumor-free survival outcomes in an orthotopic rodent liver model. Orthotopic McA-RH7777 liver tumors generated in immunocompetent Sprague Dawley rats were ablated using different histotripsy doses: dose 1 (50Hz PRF, 50 pulses per location[pp]), dose 2 (100Hz PRF, 100 ppl), and dose 3 (200Hz PRF, 200 ppl). Control animals received no treatment. In the survival cohort, animals were survived until 12 weeks or when tumors reached 2.5 cm. In the immune cohort, immunohistochemistry staining was performed on day 7 post-histotripsy. Complete homogenization of the targeted region was observed on acute histology. Doses 1 and 2 had more favorable survival outcomes and immune response compared to dose 3. There was significant difference in survival outcomes of histotripsy-treated animals at different doses vs. untreated controls (log-rank test, p<0.001). These trends suggest that higher doses may not translate to improved therapeutic outcomes after complete homogenization of the target region is achieved. These results demonstrate the importance of selecting optimal histotripsy doses for improving treatment outcomes and will have an immediate clinical impact.