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Background <p>To evaluate contrast-enhanced ultrasound (CEUS) with VEGFR2-targeted microbubbles for longitudinal monitoring of early treatment effects during combined anti-PD-L1/anti-CTLA-4 immunotherapy in a murine colorectal cancer model.</p> Methods <p>Murine colorectal cancer allografts (CT26) were established subcutaneously in 29 female Balb/c mice (therapy <i>n</i> = 15; control <i>n</i> = 14). Baseline CEUS with VEGFR2-targeted microbubbles was performed on day 7. The therapy group received intraperitoneal anti-PD-L1 and anti-CTLA-4 antibodies between days 7–15; controls received sham treatment. Follow-up CEUS was performed on days 14 and 21. Tumor perfusion (WiAUC) and VEGFR2 binding (SI<sub>8min</sub>, SI<sub>10min</sub>) were quantified, and immunohistochemistry assessed CD8, Ki-67, TUNEL, CD31, and VEGFR2.</p> Results <p>At FU1, WiAUC was significantly lower in the therapy group compared with controls (4,029 ± 61 vs. 6,391 ± 412; <i>p</i> &lt; 0.001), and remained significantly lower at FU2 (1,028 ± 27 vs. 2,049 ± 39; <i>p</i> &lt; 0.001). VEGFR2-targeted microbubble binding was consistently lower under therapy. At FU1, SI<sub>8min</sub> was 407 ± 11 vs. 626 ± 13 and SI<sub>10min</sub> was 409 ± 10 vs. 634 ± 28 (both <i>p</i> &lt; 0.001). At FU2, SI<sub>8min</sub> was 106 ± 6 vs. 207 ± 4 and SI<sub>10min</sub> was 107 ± 5 vs. 207 ± 4 (both <i>p</i> &lt; 0.001). Immunohistochemistry confirmed higher apoptosis and tumor-infiltrating lymphocytes, and lower proliferation, microvascular density, and VEGFR2 expression in treated tumors (all <i>p</i> &lt; 0.05).</p> Conclusions <p>VEGFR2-targeted CEUS enabled longitudinal monitoring of early response to dual anti-PD-L1/anti-CTLA-4 immunotherapy in colorectal cancer. Treated tumors showed lower perfusion and VEGFR2-targeted binding, paralleled by reduced vessel density and VEGFR2 expression as well as increased CD8 infiltration and apoptosis. These findings support VEGFR2-targeted CEUS as a promising noninvasive imaging biomarker for monitoring early immunotherapy-associated vascular changes.</p>

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CEUS with VEGFR2-targeted microbubbles for monitoring of early immunotherapy effects in a colorectal cancer model

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月31日

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  • Felix L. Herr,
  • Jonathan K. Stock,
  • Verena Gräfin zu Solms-Baruth,
  • Larissa V. Blume,
  • Sandra Kloiber-Langhorst,
  • Heidrun Hirner-Eppeneder,
  • Jennifer Stueckl,
  • Barbara Akla,
  • Jens Ricke,
  • Thomas Geyer,
  • Wolfgang Kunz,
  • Maurice M. Heimer,
  • Dirk-Andre Clevert,
  • Melissa J. Antons,
  • Clemens C. Cyran

摘要

Background

To evaluate contrast-enhanced ultrasound (CEUS) with VEGFR2-targeted microbubbles for longitudinal monitoring of early treatment effects during combined anti-PD-L1/anti-CTLA-4 immunotherapy in a murine colorectal cancer model.

Methods

Murine colorectal cancer allografts (CT26) were established subcutaneously in 29 female Balb/c mice (therapy n = 15; control n = 14). Baseline CEUS with VEGFR2-targeted microbubbles was performed on day 7. The therapy group received intraperitoneal anti-PD-L1 and anti-CTLA-4 antibodies between days 7–15; controls received sham treatment. Follow-up CEUS was performed on days 14 and 21. Tumor perfusion (WiAUC) and VEGFR2 binding (SI8min, SI10min) were quantified, and immunohistochemistry assessed CD8, Ki-67, TUNEL, CD31, and VEGFR2.

Results

At FU1, WiAUC was significantly lower in the therapy group compared with controls (4,029 ± 61 vs. 6,391 ± 412; p < 0.001), and remained significantly lower at FU2 (1,028 ± 27 vs. 2,049 ± 39; p < 0.001). VEGFR2-targeted microbubble binding was consistently lower under therapy. At FU1, SI8min was 407 ± 11 vs. 626 ± 13 and SI10min was 409 ± 10 vs. 634 ± 28 (both p < 0.001). At FU2, SI8min was 106 ± 6 vs. 207 ± 4 and SI10min was 107 ± 5 vs. 207 ± 4 (both p < 0.001). Immunohistochemistry confirmed higher apoptosis and tumor-infiltrating lymphocytes, and lower proliferation, microvascular density, and VEGFR2 expression in treated tumors (all p < 0.05).

Conclusions

VEGFR2-targeted CEUS enabled longitudinal monitoring of early response to dual anti-PD-L1/anti-CTLA-4 immunotherapy in colorectal cancer. Treated tumors showed lower perfusion and VEGFR2-targeted binding, paralleled by reduced vessel density and VEGFR2 expression as well as increased CD8 infiltration and apoptosis. These findings support VEGFR2-targeted CEUS as a promising noninvasive imaging biomarker for monitoring early immunotherapy-associated vascular changes.