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

IF 2.5 4区医学 Q2 RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING

Molecular Imaging and Biology Pub Date : 2025-12-01 Epub Date: 2025-10-16 DOI:10.1007/s11307-025-02056-7

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

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Abstract

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.

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[18]FDG-PET/CT成像对实验性黑色素瘤抗pd - l1 /抗ctla -4免疫治疗的反应特征。

目的：免疫检查点抑制在恶性黑色素瘤中显示出有希望的结果，但并非所有患者的反应都一样好，因此需要早期，准确地监测免疫治疗反应。[18F]FDG-PET/CT有助于表征超越形态学的治疗反应，但有效的免疫治疗反应成像生物标志物仍然很少。本研究通过三个时间点[18F]FDG-PET/CT监测抗pd - l1 /抗ctla -4联合免疫治疗小鼠同种异体黑色素瘤移植物，并在每个时间点比较定量体内成像生物标志物与多参数免疫组织化学体外生物标志物。方法：将黑色素瘤细胞（B16-F10）皮下注射到C57BL/6小鼠（n = 40）。接种后7天，进行基线[18F]FDG-PET/CT检查。动物随机分为两组；治疗组分别于肿瘤细胞接种后第7、9、11、13、15天5次ig注射抗pd - l1 /抗ctla -4（20µg/kg）。对照组接受假治疗。在基线（接种后第7天）、随访1（第13天；FU-1）和随访2（第19天；FU-2）进行PET/CT检查。在每个时间点采集肿瘤同种异体移植物进行免疫组化（CD8, Ki-67， TUNEL）以验证成像参数（MTV, SUVmax）。结果：在FU-1时，治疗组MTV明显低于对照组（p = 0.004）。在FU-2时，MTV和SUVmax与对照组相比显著降低（MTV: p = 0.008; SUVmax: p = 0.0003）。体外分析显示，治疗组具有显著的抗肿瘤作用，细胞凋亡率较高（FU-1: p = 0.012; FU-2: p = 0.001）， cd8阳性t细胞较多（FU-2: p = 0.003），肿瘤细胞增殖较低（FU-1: p = 0.012; FU-2: p = 0.012）。结论：多时间点[18F]FDG-PET/CT可用于实验性黑色素瘤联合抗pd - l1 /抗ctla -4免疫治疗的早期无创监测，多参数免疫组化证实其具有显著的促免疫原性、促凋亡和抗增殖作用。

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来源期刊

Molecular Imaging and Biology 医学-核医学

CiteScore

6.90

自引率

3.20%

发文量

审稿时长

3 months

期刊介绍： Molecular Imaging and Biology (MIB) invites original contributions (research articles, review articles, commentaries, etc.) on the utilization of molecular imaging (i.e., nuclear imaging, optical imaging, autoradiography and pathology, MRI, MPI, ultrasound imaging, radiomics/genomics etc.) to investigate questions related to biology and health. The objective of MIB is to provide a forum to the discovery of molecular mechanisms of disease through the use of imaging techniques. We aim to investigate the biological nature of disease in patients and establish new molecular imaging diagnostic and therapy procedures. Some areas that are covered are: Preclinical and clinical imaging of macromolecular targets (e.g., genes, receptors, enzymes) involved in significant biological processes. The design, characterization, and study of new molecular imaging probes and contrast agents for the functional interrogation of macromolecular targets. Development and evaluation of imaging systems including instrumentation, image reconstruction algorithms, image analysis, and display. Development of molecular assay approaches leading to quantification of the biological information obtained in molecular imaging. Study of in vivo animal models of disease for the development of new molecular diagnostics and therapeutics. Extension of in vitro and in vivo discoveries using disease models, into well designed clinical research investigations. Clinical molecular imaging involving clinical investigations, clinical trials and medical management or cost-effectiveness studies.