SIR 2024
Interventional Oncology
Alexander A. Pieper, MD, PhD
Radiology Resident
University of Pennsylvannia
Financial relationships: Full list of relationships is listed on the CME information page.
Nicholas Stowe, RA
Research Assistant
University of Wisconsin-Madison School of Medicine and Public Health
Disclosure information not submitted.
Sarvesh Periyasamy, PhD
Medical Student and Post-doctoral Researcher
University of Wisconsin School of Medicine and Public Health
Disclosure information not submitted.
Brian M. Burkel, PhD
Associate Scientist
University of Madison-Wisconsin
Disclosure information not submitted.
Noah Tzarovsky, RA
Research Assistant
University of Wisconsin-Madison School of Medicine and Public Health
Disclosure information not submitted.
Ajay P. Singh, MS
Medical Student
University of Wisconsin-Madison School of Medicine and Public Health
Disclosure information not submitted.
Alexander L. Rakhmilevich, MD, PhD
Distinguished Scientist
University of Wisconsin-Madison School of Medicine and Public Health
Disclosure information not submitted.
Paul M. Sondel, MD, PhD
Professor
University of Wisconsin-Madison School of Public Health
Disclosure information not submitted.
Suzanne M. Ponik, PhD
Assistant Professor
University of Wisconsin-Madison School of Medicine and Public Health
Disclosure information not submitted.
Paul F. Laeseke, MD, PhD
Assistant Professor
University of Wisconsin
Disclosure information not submitted.
John-Paul J. Yu, MD, PhD
Assistant Professor
University of Wisconsin-Madison
Disclosure information not submitted.
The high acoustic energies used in focused ultrasound (FUS) for tissue ablation are well characterized; however, less understood are the biological effects of non-ablative acoustic energies. Here, we introduce a novel non-ablative FUS technique we term histoplasty (HP) and demonstrate its ability to alter the tumor microenvironment (TME).
Materials and Methods:
In the (4T1) murine model of breast cancer [1], a clinical grade histotripsy device (HistoSonics) was used to deliver 15 second sub-cavitation non-ablative acoustic pulses at a single spherical focal point to ex vivo tumors. Tumor collagen morphology was quantified pre- and post-HP with second harmonic generation (SHG). Separately, mice bearing bilateral 4T1 tumors were IV injected with liposomal doxorubicin (Doxil; 16 mg/kg) and the right flank tumor was HP treated. Mice were fluorescently imaged to detect Doxil uptake following HP treatment. In a separate experiment, 4T1 tumor-bearing mice were randomized into 2 treatment groups (sham vs HP, n=3/group) and 48 hours following sham/HP treatment, tumors were harvested and analyzed via flow cytometry. Lastly, a murine survival experiment post-HP was conducted as previously described [1]. Tumor fluorescence data were analyzed via two-way ANOVA with Tukey’s correction for multiple comparisons. Flow cytometry comparisons were made using unpaired t-tests. Survival data were analyzed via log-rank comparison.
Results:
HP alters the TME by decreasing tumor collagen length and density by nearly 30% as measured by SHG imaging. This allows for significantly increased Doxil uptake, quantified as fold change in fluorescent flux, in HP-treated tumors compared to non-HP-treated tumors two days after treatment (2.12 vs 1.66, p< 0.01). Compared to control tumors (n=3), flow cytometry on HP treated tumors (n=3) demonstrated a significant increase in tumor macrophage frequency (42% of CD45 vs 33%, p < 0.05) and a significant decrease in myeloid derived suppressive cell frequency (7.1% of CD45 vs 10.3%, p < 0.05). HP treated tumors demonstrated trends towards increased CD8+ (5.1 % of CD45 vs 3.1%, p = 0.117) and CD4+ (14.1% of CD45 vs 11.8%, p = 0.075) T cell frequency. Finally, HP treated mice (n=5, median survival 33 days) demonstrated a positive trend towards prolonged survival over untreated mice (n=4, median survival 26.5 days) (p=0.17).
Conclusion: HP is a conceptually innovative non-ablative FUS approach to non-invasively modify the tumor extracellular matrix by decreasing stromal collagen density, increasing chemotherapeutic uptake, and altering the tumor immune microenvironment.