Histotripsy Ablation Alters the Tumor Microenvironment and Promotes Immune System Activation in a Subcutaneous Model of Pancreatic Cancer. Hendricks-Wenger, A., Sereno, J., Gannon, J., Zeher, A., Brock, R. M., Beitel-White, N., Simon, A., Davalos, R. V., Coutermarsh-Ott, S., Vlaisavljevich, E., & Allen, I. C. IEEE Trans Ultrason Ferroelectr Freq Control, 68(9):2987-3000, 2021. 1525-8955 Hendricks-Wenger, Alissa Sereno, Jacqueline Gannon, Jessica Zeher, Allison Brock, Rebecca M Beitel-White, Natalie Simon, Alexander Davalos, Rafael V Coutermarsh-Ott, Sheryl Vlaisavljevich, Eli Allen, Irving Coy R21 EB028429/EB/NIBIB NIH HHS/United States Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't United States 2021/05/07 IEEE Trans Ultrason Ferroelectr Freq Control. 2021 Sep;68(9):2987-3000. doi: 10.1109/TUFFC.2021.3078094. Epub 2021 Aug 27.
doi  abstract   bibtex   
Pancreatic cancer is a significant cause of cancer-related deaths in the United States with an abysmal five-year overall survival rate that is under 9%. Reasons for this mortality include the lack of late-stage treatment options and the immunosuppressive tumor microenvironment. Histotripsy is an ultrasound-guided, noninvasive, nonthermal tumor ablation therapy that mechanically lyses targeted cells. To study the effects of histotripsy on pancreatic cancer, we utilized an in vitro model of pancreatic adenocarcinoma and compared the release of potential antigens following histotripsy treatment to other ablation modalities. Histotripsy was found to release immune-stimulating molecules at magnitudes similar to other nonthermal ablation modalities and superior to thermal ablation modalities, which corresponded to increased innate immune system activation in vivo. In subsequent in vivo studies, murine Pan02 tumors were grown in mice and treated with histotripsy. Flow cytometry and rtPCR were used to determine changes in the tumor microenvironment over time compared to untreated animals. In mice with pancreatic tumors, we observed significantly increased tumor-progression-free and general survival, with increased activation of the innate immune system 24 h posttreatment and decreased tumor-associated immune cell populations within 14 days of treatment. This study demonstrates the feasibility of using histotripsy for pancreatic cancer ablation and provides mechanistic insight into the initial innate immune system activation following treatment. Further work is needed to establish the mechanisms behind the immunomodulation of the tumor microenvironment and immune effects.
@article{RN118,
   author = {Hendricks-Wenger, A. and Sereno, J. and Gannon, J. and Zeher, A. and Brock, R. M. and Beitel-White, N. and Simon, A. and Davalos, R. V. and Coutermarsh-Ott, S. and Vlaisavljevich, E. and Allen, I. C.},
   title = {Histotripsy Ablation Alters the Tumor Microenvironment and Promotes Immune System Activation in a Subcutaneous Model of Pancreatic Cancer},
   journal = {IEEE Trans Ultrason Ferroelectr Freq Control},
   volume = {68},
   number = {9},
   pages = {2987-3000},
   note = {1525-8955
Hendricks-Wenger, Alissa
Sereno, Jacqueline
Gannon, Jessica
Zeher, Allison
Brock, Rebecca M
Beitel-White, Natalie
Simon, Alexander
Davalos, Rafael V
Coutermarsh-Ott, Sheryl
Vlaisavljevich, Eli
Allen, Irving Coy
R21 EB028429/EB/NIBIB NIH HHS/United States
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
United States
2021/05/07
IEEE Trans Ultrason Ferroelectr Freq Control. 2021 Sep;68(9):2987-3000. doi: 10.1109/TUFFC.2021.3078094. Epub 2021 Aug 27.},
   abstract = {Pancreatic cancer is a significant cause of cancer-related deaths in the United States with an abysmal five-year overall survival rate that is under 9%. Reasons for this mortality include the lack of late-stage treatment options and the immunosuppressive tumor microenvironment. Histotripsy is an ultrasound-guided, noninvasive, nonthermal tumor ablation therapy that mechanically lyses targeted cells. To study the effects of histotripsy on pancreatic cancer, we utilized an in vitro model of pancreatic adenocarcinoma and compared the release of potential antigens following histotripsy treatment to other ablation modalities. Histotripsy was found to release immune-stimulating molecules at magnitudes similar to other nonthermal ablation modalities and superior to thermal ablation modalities, which corresponded to increased innate immune system activation in vivo. In subsequent in vivo studies, murine Pan02 tumors were grown in mice and treated with histotripsy. Flow cytometry and rtPCR were used to determine changes in the tumor microenvironment over time compared to untreated animals. In mice with pancreatic tumors, we observed significantly increased tumor-progression-free and general survival, with increased activation of the innate immune system 24 h posttreatment and decreased tumor-associated immune cell populations within 14 days of treatment. This study demonstrates the feasibility of using histotripsy for pancreatic cancer ablation and provides mechanistic insight into the initial innate immune system activation following treatment. Further work is needed to establish the mechanisms behind the immunomodulation of the tumor microenvironment and immune effects.},
   keywords = {*Adenocarcinoma
Animals
*High-Intensity Focused Ultrasound Ablation
Immune System
Mice
*Pancreatic Neoplasms/therapy
Tumor Microenvironment},
   ISSN = {0885-3010 (Print)
0885-3010},
   DOI = {10.1109/tuffc.2021.3078094},
   year = {2021},
   type = {Journal Article}
}

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