Immunological Effects of Histotripsy for Cancer Therapy

Abstract

Cancer is the second leading cause of death worldwide despite major advancements in diagnosis and therapy over the past century. One of the most debilitating aspects of cancer is the burden brought on by metastatic disease. Therefore, an ideal treatment protocol would address not only debulking larger primary tumors but also circulating tumor cells and distant metastases. To address this need, the use of immune modulating therapies has become a pillar in the oncology armamentarium. A therapeutic option that has recently emerged is the use of focal ablation therapies that can destroy a tumor through various physical or mechanical mechanisms and release a cellular lysate with the potential to stimulate an immune response. Histotripsy is a non-invasive, non-ionizing, non-thermal, ultrasound guided ablation technology that has shown promise over the past decade as a debulking therapy. As histotripsy therapies have developed, the full picture of the accompanying immune response has revealed a wide range of immunogenic mechanisms that include DAMP and anti-tumor mediator release, changes in local cellular immune populations, development of a systemic immune response, and therapeutic synergism with the inclusion of checkpoint inhibitor therapies. These studies also suggest that there is an immune effect from histotripsy therapies across multiple murine tumor types that may be reproducible. Overall, the effects of histotripsy on tumors show a positive effect on immunomodulation.

Mechanical High-Intensity Focused Ultrasound (Histotripsy) in Dogs with Spontaneously Occurring Soft Tissue Sarcomas

“…These results are in line with previous investigations of histotripsy's immunostimulatory potential [9,12,15,16,[18][19][20][21] and suggest that a single histotripsy ablation can alter the local tumor immune microenvironment. Although there were no statistically significant differences between pre-and posttreatment cytokine concentrations for any of the analytes, it is possible that changes were missed due to the timing of cytokine data analysis in this study, which was conducted at various time points prior to histotripsy treatment and surgical removal.…”

“…In addition to its ablative potential, histotripsy may also promote immunostimulatory effects related to its ability to induce immunogenic cell death [16]. Studies of HIFU in rodent tumor models have demonstrated that HIFU is immunogenic and that histotripsy may result in more robust immune responses than thermal HIFU [17][18][19].…”

“…The resulting antitumor immune response may then stimulate local and systemic immune responses [19]. Early studies investigating these effects have reported that histotripsy treatment in a murine cancer model can alter the tumor microenvironment and activate the immune response [9,12,15,16,[18][19][20]. Similarly, a case of an abscopal effect was identified in the human clinical trial investigating histotripsy for liver tumor ablation [21].…”

Focused ultrasound for the treatment of glioblastoma

“…Early preclinical results suggest that histotripsy may elicit an immune response. For example, mouse studies in GBM models treated with focused ultrasound released tumor antigens and recruited and activated immune cells, changing the tumor microenvironment from cold to hot [36]. To date, there are no clinical trials with histotripsy for brain tumors.…”

Histotripsy Ablation of Spontaneously Occurring Canine Bone Tumors

“…The OS tumor microenvironment (TME), like other cancers, is immunosuppressive, allowing cancer cells to evade the immune response and proliferate and form malignant tumors [45,46]. We hypothesized that histotripsy treatment would modulate the immunosuppressive OS TME and stimulate a proinflammatory anti-tumor immune response, which has previously been reported to be associated with histotripsy treatment [47][48][49][50]. The stimulation of a pro-inflammatory immune response would lead to infiltration of proinflammatory macrophages, characterized by double positive staining of IBA1 and iNOS and potentially an infiltration of lymphocytes.…”