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Purpose <p>Immune checkpoint inhibition has shown promising results in malignant melanoma, but not all patients respond equally well, necessitating early, accurate monitoring of immunotherapy response. [<sup>18</sup>F]FDG-PET/CT aids in characterising therapy response beyond morphology, but validated imaging biomarkers for immunotherapy response remain scarce. This study investigated three-time point [<sup>18</sup>F]FDG-PET/CT to monitor combined anti-PD-L1/anti-CTLA-4 immunotherapy in murine melanoma allografts and compared quantitative <i>in vivo</i> imaging biomarkers with <i>ex vivo</i> biomarkers from multiparametric immunohistochemistry at each time point.</p> Procedures <p>Melanoma cells (B16-F10) were injected subcutaneously into C57BL/6 mice (<i>n</i> = 40). Seven days post-inoculation, baseline [<sup>18</sup>F]FDG-PET/CT was conducted. Animals were randomized into two groups; the therapy group received 5 i.p.-injections of anti-PD-L1/anti-CTLA-4 (20&#xa0;µg/kg) on days 7, 9, 11, 13 and 15 after tumor&#xa0;cell inoculation. The control group received sham treatment. PET/CT was performed at baseline (day 7 post&#xa0;inoculation), follow-up 1(day 13;&#xa0;FU-1) and follow-up 2 (day 19;&#xa0;FU-2). Tumor allografts were harvested at each time point for immunohistochemistry (CD8, Ki-67, TUNEL) to validate imaging parameters (MTV, SUVmax).</p> Results <p>At FU-1, the therapy group exhibited significantly lower MTV than the control group (<i>p</i> = 0.004). At FU-2, MTV and SUVmax were significantly lower (MTV: <i>p</i> = 0.008; SUVmax: <i>p</i> = 0.0003) compared to controls. <i>Ex vivo</i> analysis revealed significant anti-tumor effects in the therapy group, with higher apoptosis rates (FU-1: <i>p</i> = 0.012; FU-2: <i>p</i> = 0.001), more CD8-positive T-cells (FU-2: <i>p</i> = 0.003) and lower tumor cell proliferation (FU-1: <i>p</i> = 0.012; FU-2: <i>p</i> = 0.012).</p> Conclusions <p>Multi-time point [<sup>18</sup>F]FDG-PET/CT allowed for early non-invasive monitoring of combined anti-PD-L1/anti-CTLA-4 immunotherapy in experimental melanomas, validated by multiparametric immunohistochemistry with significant pro-immunogenic, pro-apoptotic and anti-proliferative effects.</p>

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[18F]FDG-PET/CT Imaging for Response Characterisation of Experimental Melanomas to Anti-PD-L1/Anti-CTLA-4 Immunotherapy

  • 期刊论文

  • 发表日期：

    2025年10月16日

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  • Melissa J. Antons,
  • Sandra Kloiber-Langhorst,
  • Heidrun Hirner-Eppeneder,
  • Rebecca Schaefer,
  • Jennifer Stueckl,
  • Giovanna Palumbo,
  • Rosel Oos,
  • Felix L. Herr,
  • Simon Lindner,
  • Sibylle Ziegler,
  • Matthias Brendel,
  • Jens Ricke,
  • Rudolf A. Werner,
  • Maurice M. Heimer,
  • Clemens C. Cyran

摘要

Purpose

Immune checkpoint inhibition has shown promising results in malignant melanoma, but not all patients respond equally well, necessitating early, accurate monitoring of immunotherapy response. [18F]FDG-PET/CT aids in characterising therapy response beyond morphology, but validated imaging biomarkers for immunotherapy response remain scarce. This study investigated three-time point [18F]FDG-PET/CT to monitor combined anti-PD-L1/anti-CTLA-4 immunotherapy in murine melanoma allografts and compared quantitative in vivo imaging biomarkers with ex vivo biomarkers from multiparametric immunohistochemistry at each time point.

Procedures

Melanoma cells (B16-F10) were injected subcutaneously into C57BL/6 mice (n = 40). Seven days post-inoculation, baseline [18F]FDG-PET/CT was conducted. Animals were randomized into two groups; the therapy group received 5 i.p.-injections of anti-PD-L1/anti-CTLA-4 (20 µg/kg) on days 7, 9, 11, 13 and 15 after tumor cell inoculation. The control group received sham treatment. PET/CT was performed at baseline (day 7 post inoculation), follow-up 1(day 13; FU-1) and follow-up 2 (day 19; FU-2). Tumor allografts were harvested at each time point for immunohistochemistry (CD8, Ki-67, TUNEL) to validate imaging parameters (MTV, SUVmax).

Results

At FU-1, the therapy group exhibited significantly lower MTV than the control group (p = 0.004). At FU-2, MTV and SUVmax were significantly lower (MTV: p = 0.008; SUVmax: p = 0.0003) compared to controls. Ex vivo analysis revealed significant anti-tumor effects in the therapy group, with higher apoptosis rates (FU-1: p = 0.012; FU-2: p = 0.001), more CD8-positive T-cells (FU-2: p = 0.003) and lower tumor cell proliferation (FU-1: p = 0.012; FU-2: p = 0.012).

Conclusions

Multi-time point [18F]FDG-PET/CT allowed for early non-invasive monitoring of combined anti-PD-L1/anti-CTLA-4 immunotherapy in experimental melanomas, validated by multiparametric immunohistochemistry with significant pro-immunogenic, pro-apoptotic and anti-proliferative effects.