Presented By: Biomedical Engineering
Pre-Clinical Investigation of Histotripsy for Non-Invasive Ablation of Liver Cancer
BME PhD Defense: Tejaswi U. Worlikar
Liver cancer, including hepatocellular carcinoma (HCC) is one of the top ten causes of cancer related deaths worldwide and in the United States. The liver is also a frequent site for metastases originating from colorectal cancer, pancreatic cancer, melanoma, lung cancer and breast cancer. Depending on the location, severity and staging of liver cancer, multiple treatment options are currently available including surgical resection, liver transplantation, chemotherapy, radiation therapy, targeted drug therapy, immunotherapies, and ablation techniques including radiofrequency ablation (RFA), microwave ablation (MWA), cryoablation, high intensity focused ultrasound (HIFU), yet the prognosis of HCC remains poor with five-year survival rates reported at only 18% in the US. Even after treatment, the high prevalence of tumor recurrence and metastasis highlights the clinical need for improving outcomes of liver cancer.
Histotripsy is a novel non-invasive, non-ionizing, and non-thermal ablation technique that mechanically destroys target tissue by controlled acoustic cavitation. High pressure (p->30MPa), microsecond-length ultrasound pulses cause endogenous nanometer-scale gas nuclei in the target tissue to rapidly expand and collapse, generating high mechanical stress and strain to disrupt the cellular structure into an acellular homogenate. This dissertation investigates histotripsy as a therapeutic ultrasound treatment option of liver cancer and other solid tumors.
The first study evaluated the safety and feasibility and survival benefits of histotripsy in an in vivo murine liver tumor model. Results showed that non-invasive histotripsy ablation reduced local tumor progression of subcutaneous human-derived HCC tumor and improved survival outcomes in immunocompromised mice. This study also characterized the radiological features correlating to the histotripsy tumor response.
The second study investigated the anti-tumor immune response generated by histotripsy ablation of subcutaneous murine melanoma and HCC tumors. Histotripsy stimulated potent local intratumoral infiltration of innate and adaptive immune cell populations, promoted abscopal immune responses at untreated tumor sites and inhibited growth of pulmonary metastases. Histotripsy was capable of releasing tumor antigens with retained immunogenicity and was able to amplify the efficacy of checkpoint inhibition immunotherapy.
The third study evaluated the safety, feasibility, and tumor volume reduction effects of histotripsy for liver cancer ablation in an orthotopic, immune-competent in vivo rat HCC model. For the first time, it was demonstrated that complete as well as partial histotripsy ablation of tumors can result in complete tumor regression with no recurrence.
The fourth study evaluated the effects of partial histotripsy tumor ablation on tumor response, risk of metastases and immune infiltration in an orthotopic, immunocompetent, metastatic rodent hepatocellular carcinoma (HCC) model. Results showed that histotripsy significantly improved survival outcomes with no increased risk of metastasis compared to controls and demonstrated that augmented tumor immune infiltration may have contributed to the eventual regression even with partial treatment of tumors.
The fifth study compared the safety, tumor response and survival outcomes between single and repeat histotripsy treatments of human-derived HCC tumors in immunocompromised murine hosts and mouse-derived HCC tumors in immunocompetent murine hosts. One week after the initial histotripsy treatment, animals received a repeat histotripsy treatment. Results showed that while both histotripsy groups significantly improved survival outcomes over control, the repeat histotripsy group demonstrated slower tumor growth and increased survival compared to single histotripsy.
Overall, this dissertation demonstrated the potential and in vivo feasibility of histotripsy for successful non-invasive tumor ablation, reduction of local tumor burden and prevention of metastasis. Future studies will continue to investigate the safety, efficacy, and biological effects of histotripsy liver cancer treatment for potential translation to clinic.
Date: Friday, March 18, 2022
Time: 1:30 PM EST
Zoom: https://umich.zoom.us/j/95042725076 Passcode: EarthPass
Chair: Professor Zhen Xu
Histotripsy is a novel non-invasive, non-ionizing, and non-thermal ablation technique that mechanically destroys target tissue by controlled acoustic cavitation. High pressure (p->30MPa), microsecond-length ultrasound pulses cause endogenous nanometer-scale gas nuclei in the target tissue to rapidly expand and collapse, generating high mechanical stress and strain to disrupt the cellular structure into an acellular homogenate. This dissertation investigates histotripsy as a therapeutic ultrasound treatment option of liver cancer and other solid tumors.
The first study evaluated the safety and feasibility and survival benefits of histotripsy in an in vivo murine liver tumor model. Results showed that non-invasive histotripsy ablation reduced local tumor progression of subcutaneous human-derived HCC tumor and improved survival outcomes in immunocompromised mice. This study also characterized the radiological features correlating to the histotripsy tumor response.
The second study investigated the anti-tumor immune response generated by histotripsy ablation of subcutaneous murine melanoma and HCC tumors. Histotripsy stimulated potent local intratumoral infiltration of innate and adaptive immune cell populations, promoted abscopal immune responses at untreated tumor sites and inhibited growth of pulmonary metastases. Histotripsy was capable of releasing tumor antigens with retained immunogenicity and was able to amplify the efficacy of checkpoint inhibition immunotherapy.
The third study evaluated the safety, feasibility, and tumor volume reduction effects of histotripsy for liver cancer ablation in an orthotopic, immune-competent in vivo rat HCC model. For the first time, it was demonstrated that complete as well as partial histotripsy ablation of tumors can result in complete tumor regression with no recurrence.
The fourth study evaluated the effects of partial histotripsy tumor ablation on tumor response, risk of metastases and immune infiltration in an orthotopic, immunocompetent, metastatic rodent hepatocellular carcinoma (HCC) model. Results showed that histotripsy significantly improved survival outcomes with no increased risk of metastasis compared to controls and demonstrated that augmented tumor immune infiltration may have contributed to the eventual regression even with partial treatment of tumors.
The fifth study compared the safety, tumor response and survival outcomes between single and repeat histotripsy treatments of human-derived HCC tumors in immunocompromised murine hosts and mouse-derived HCC tumors in immunocompetent murine hosts. One week after the initial histotripsy treatment, animals received a repeat histotripsy treatment. Results showed that while both histotripsy groups significantly improved survival outcomes over control, the repeat histotripsy group demonstrated slower tumor growth and increased survival compared to single histotripsy.
Overall, this dissertation demonstrated the potential and in vivo feasibility of histotripsy for successful non-invasive tumor ablation, reduction of local tumor burden and prevention of metastasis. Future studies will continue to investigate the safety, efficacy, and biological effects of histotripsy liver cancer treatment for potential translation to clinic.
Date: Friday, March 18, 2022
Time: 1:30 PM EST
Zoom: https://umich.zoom.us/j/95042725076 Passcode: EarthPass
Chair: Professor Zhen Xu
Livestream Information
ZoomMarch 18, 2022 (Friday) 1:30pm
Meeting ID: 95042725076
Meeting Password: EarthPass
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