Single Treatment Boiling Histotripsy Focused Ultrasound Ablation - Neither Negates nor Enhances the Activity of α-CD40 in a Pancreatic Cancer Model

Sep 30, 2026

Objective: Pancreatic adenocarcinoma (PDAC) tumors are often unresectable and resistant to standard anti-cancer therapies. Boiling histotripsy (BH) is a mechanical focused ultrasound ablation intended to target non-operable tumors, and may synergize with emerging immunotherapies. This study tested whether BH-mediated antigen release and damage-associated molecular patterns would augment tumor immunity and cooperate with α-CD40 therapy. Methods: BH was evaluated as monotherapy or combined with systemically administered α-CD40 agonistic antibodies, with immune changes and antigen release assessed by flow cytometry.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages30

Reading Time1 h 16 min

AccessFree to download

Abstract

Objective

Methods

Results

Conclusion

Significance

Introduction

PDAC background and immunosuppressive microenvironment

CD40 biology and therapeutic rationale

Author Manuscript Author Manuscript Author Manuscript Author Manuscript | | HHS Public Access
Author manuscript
IEEE Trans Biomed Eng. Author manuscript; available in PMC 2026 January 07. | | --- | --- | Published in final edited form as: IEEE Trans Biomed Eng. 2025 November ; 72(11): 3404–3418. doi:10.1109/TBME.2025.3568594 . Single Treatment Boiling Histotripsy Focused Ultrasound Ablation Neither Negates nor Enhances the Activity of α-CD40 in a Pancreatic Cancer Model Mariia Stepanechko, Department of Pathology, School of Medicine, University of Virginia, USA, and also with the Beirne B. Carter Center for Immunology Research, University of Virginia, USA. Awndre Gamache, Department of Pathology, School of Medicine, University of Virginia, USA, and also with the Beirne B. Carter Center for Immunology Research, University of Virginia, USA. Frederic Padilla, Focused Ultrasound Foundation, USA Department of Radiology, University of Virginia Health System, USA. Madison Nemshick, Department of Pathology, School of Medicine, University of Virginia, USA, and also with the Beirne B. Carter Center for Immunology Research, University of Virginia, USA. Lydia Kitelinger, Department of Pathology, School of Medicine, University of Virginia, USA, and also with the Beirne B. Carter Center for Immunology Research, University of Virginia, USA. Claire Conarroe, Department of Pathology, School of Medicine, University of Virginia, USA, and also with the Beirne B. Carter Center for Immunology Research, University of Virginia, USA. Matthew DeWitt, Department of Biomedical Engineering, School of Engineering and Applied Sciences, University of Virginia, USA. John A Hossack [Fellow, IEEE], Department of Biomedical Engineering, School of Engineering and Applied Sciences, University of Virginia, USA. Timothy N. J. Bullock Department of Pathology, School of Medicine, University of Virginia, Charlottesville, VA 22903 USA, and also with the Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA 22908 USA This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License. For more information, see [https://creativecommons.org/licenses/by-nc-nd/4.0/](https://creativecommons.org/licenses/by-nc-nd/4.0/) [Corresponding author: Timothy N. J. Bullock.](Corresponding author: Timothy N. J. Bullock. tb5v@virginia.edu)[ tb5v@virginia.edu](Corresponding author: Timothy N. J. Bullock. tb5v@virginia.edu). Author Manuscript Author Manuscript Author Manuscript Author Manuscript Stepanechko et al. Page 2 Abstract Objective: Pancreatic adenocarcinoma (PDAC) tumors are often unresectable and do not respond to standard anti-cancer treatments. Boiling histotripsy (BH) is a mechanical focused ultrasound ablation regimen that can target non-operable tumors. BH is a non-invasive procedure that might synergize with immunotherapies being developed for PDAC. We reasoned that BH-mediated release of tumor antigen and damage-associated molecular patterns would augment tumor immunity and cooperate with α-CD40 therapy. Methods: We explored the efficacy of BH ablation either as monotherapy for PDAC or in combination with systemically administered α-CD40 agonistic antibodies in controlling tumor outgrowth. We further assessed the changes in the tumor immune compartment and the ability of BH to release tumor antigens by flow cytometry. Results: A single BH treatment could not control tumor growth and had limited independent immunostimulatory properties. BH effectively liberated tumor antigen into the tumor microenvironment for acquisition by local phagocytes but did not promote its presence in the tumor-draining lymph nodes. BH did not activate either tumor-or lymph node-resident conventional dendritic cells. BH did not impede the ability of α-CD40 immunotherapy to reduce the tumor burden and promote the infiltration of M1-like macrophages and IFN-γ+ C

FAQs

What is the main goal of this study on boiling histotripsy (BH) in PDAC?

To determine whether a single BH treatment can control pancreatic adenocarcinoma and whether BH can enhance or interfere with α-CD40 immunotherapy by shaping tumor immunity and antigen release.

How was BH evaluated in relation to α-CD40 therapy?

BH was tested either as monotherapy for PDAC or in combination with systemically administered α-CD40 agonistic antibodies, and outcomes included tumor growth and immune compartment changes.

Did a single BH treatment control tumor growth or activate key immune cells?

A single BH treatment could not control tumor growth and showed limited independent immunostimulatory effects. It liberated tumor antigen for acquisition by local phagocytes but did not promote antigen presence in tumor-draining lymph nodes or activate conventional dendritic cells resident in tumors or lymph nodes.

Did BH affect the effectiveness of α-CD40 immunotherapy?

BH did not impede α-CD40 immunotherapy from reducing tumor burden and promoting infiltration of M1-like macrophages and IFN-γ+ CD8+ T cells, suggesting antibody access to ablated tissue was not obstructed.

Sep 30, 2026

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