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Biomedical Imaging and Instrumentation

Biomedical Imaging and Instrumentation - Poster Session B

Poster G3 - Engineering Immunogenic Focused Ultrasound (FUS) Paradigms By Targeting Adenosinergic Signaling in Breast Cancer

Thursday, October 24, 2024

2:45 PM – 3:45 PM EST

Location: Exhibit Hall E, F & G

Presenting Author(s)

BA

Beyzanur Ak (she/her/hers)

Undergraduate Research Assistant
University of Virginia, United States

Co-Author(s)

Zehra Demir, B.S.

Graduate Research Assistant
University of Virginia, United States

Last Author(s)

Natasha D. Sheybani, PhD (she/her/hers)

Assistant Professor of Biomedical Engineering, Radiology & Medical Imaging (by courtesy), and Neurosurgery (by courtesy), Research Director of UVA Focused Ultrasound Cancer Immunotherapy Center
University of Virginia
Charlottesville, Virginia, United States

Co-Author(s)

TS

Thomas Sherlock

University of Virginia, United States
Stefanyda Maslova, BS

PhD Candidate
University of Virginia, United States
MD

Matthew DeWitt

Senior Scientist
University of Virginia, United States
AT

Andrew Thede

Graduate Research Assistant
University of Virginia, United States
OB

Owen Brown

University of Virginia, United States

Introduction:

Introduction: Every year approximately 2.3 million women are diagnosed with breast cancer (BC) worldwide, with approximately 240,000 of those cases occurring in the United States alone [1]. Triple negative BC (TNBC) is considered to be the most aggressive subtype with the highest risk of metastasis and recurrence [2]. Currently, there are no FDA-approved targeted therapies for TNBC patients. This emphasizes the pressing requirement for innovative combination treatments that can effectively target both primary and distant lesions. Focused ultrasound (FUS) offers promise toward fulfilling this need as a strategy for non-ionizing, non-invasive ablation of tumors using sound waves [3].The spatial precision of FUS enables highly targeted thermal and/or mechanical bioeffects that cause damage to and eliminate tumor tissue while protecting healthy surrounding tissues [3]. Previous studies have shown that FUS ablation alone is moderately immunogenic, often requiring combination with immunoadjuvants to elaborate productive T cell responses. Evidence has been established for FUS-ablated cancer cells releasing endogenous danger signals, such as ATP, due to mechanical and/or thermal disruption [4]. As elevated levels of extracellular adenosine can dampen anti-tumor activity and elicit mechanisms of immunosuppression in tumors, this study sets forth the goal of understanding and therapeutically targeting adenosinergic signaling in preclinical TNBC models undergoing thermal or mechanical FUS ablation [5].

Materials and

Methods: MATERIALS &

Methods: Wild-type female C57/Bl6 mice were inoculated with 1 million E0771 mammary carcinoma cells in the 4th mammary fat pad to establish orthotopic BCs. At ~80mm3, mice were randomized into volume-matched groups and treated with FUS. A custom-built B-mode ultrasound imaging-guided FUS system with four therapeutic 2.5 MHz transducers (Figure A,B) was used for ablations. Experimental groups received T-FUS (18W,15s) or BH (5 ms burst, 2 Hz pulse repetition frequency, 10s) sparsely rastered over the ultrasound-visible tumor volume. Tumor outgrowth was measured daily by digital calipers. Post-ablative ATP production was acutely assessed by performing i.v. co-administration of luciferase/luciferin and bioluminescence imaging acutely following FUS (up to 70 mins).

Results, Conclusions, and Discussions:

Results: E0771 tumors were successfully ablated with T-FUS and BH regimens, as evidenced by presence of hyperechoic signatures on B-mode imaging and histological assessment (data not shown). Outgrowth studies demonstrated statistically significant (p=0.0274) control of E0771 tumors with a single session of T-FUS and a trend toward control with BH (Figure C-F). In-vivo ATP assessment revealed a trend of higher ATP signaling in the primary tumor microenvironment of both FUS ablation groups relative to volume-matched shams (Figure G-K).

CONCLUSION &

Discussion: In this study, we confirm the acute release of ATP and acute temporal kinetis therein following thermal and mechanical FUS ablation regimens. Ongoing studies are leveraging these insights to explore rational dosing and timing of treatment paradigms combining FUS ablation with pharmacologic targeting of adenosinergic signaling (anti-CD73, small molecule adenosine receptor inhibitors). Due to the ongoing assessment of these individual treatment prongs in BC clinical trials, we expect that findings from this study will be rapidly translatable.

REFERENCES
Iacopetta, D., Ceramella, J., Baldino, N., Sinicropi, M. S., & Catalano, A. (2023, February 11). Targeting breast cancer: An overlook on current strategies. MDPI. https://www.mdpi.com/1422-0067/24/4/3643
E. C. Dietze, C. Sistrunk, G. Miranda-Carboni, R. O'Regan, V. L. Seewaldt, Triple-negative breast cancer in AfricanAmerican women: disparities versus biology. Nat Rev Cancer 15, 248-254 (2015).
Sheybani, N. D., Witter, A. R., Thim, E. A., Yagita, H., Bullock, T. N. J., & Price, R. J. (2020). Combination of thermally ablative focused ultrasound with gemcitabine controls breast cancer via adaptive immunity. Journal for immunotherapy of cancer, 8(2), e001008. https://doi.org/10.1136/jitc-2020-001008
Hu, Z., Yang, X. Y., Liu, Y., Morse, M. A., Lyerly, H. K., Clay, T. M., & Zhong, P. (2005). Release of endogenous danger signals from HIFU-treated tumor cells and their stimulatory effects on APCs. Biochemical and Biophysical Research Communications, 335(1), 124-131. https://doi.org/10.1016/j.bbrc.2005.07.071
Hammami, A., Allard, D., Allard, B., & Stagg, J. (2019). Targeting the adenosine pathway for cancer immunotherapy. Seminars in Immunology, 42, 101304. https://doi.org/10.1016/j.smim.2019.101304

Acknowledgements (Optional): Acknowledgements: This study is supported by NIH DP5OD031846-01, UVA SEAS Dean’s Undergraduate Summer Research Fellowship, Focused Ultrasound Foundation, Wallace H. Coulter Foundation and Purnovate Pharmaceuticals.