Kleinendorst Simone C, Hooijmans Carlijn R, Muselaers Stijn, Oosterwijk Egbert, Konijnenberg Mark, Heskamp Sandra, van Lith Sanne A M
Department of Medical Imaging, Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
Department of Anesthesiology, Pain and Palliative Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
Eur J Nucl Med Mol Imaging. 2025 Apr 26. doi: 10.1007/s00259-025-07293-0.
Given radiation's immunomodulatory effects and the complementary anti-cancer mechanisms of targeted radionuclide therapy (TRT) and immune checkpoint inhibition (ICI), their combination holds promise as a cancer treatment. This systematic review and meta-analysis summarize the literature on the therapeutic efficacy of combined TRT/ICI in animal tumour models.
A systematic search in MEDLINE-PubMed and Embase-OVID was performed. Study characteristics and risk of bias were assessed. Outcome parameters included normalized area under the tumour growth curve and restricted mean survival time, of which ratios between combined treatment and untreated and monotherapy groups were analysed in a random-effects meta-analyses. Predefined subgroup analyses explored potential moderators of treatment efficacy.
In total, 31 studies were included. Study characteristics such as animal sex and age, cancer type, TRT target, and radionuclides, varied considerably across studies. The quality of the included studies could not always be assessed due to poor reporting. All meta-analyses indicated significantly improved survival and tumour growth of combination treatment over untreated, TRT and ICI monotherapy controls (RMST ratio 1.96 [1.72-2.23], 1.44 [ 1.34-1.55], 1.54 [1.38-1.72], and nAUC ratio 0.32 [0.25-0.42], 0.49 [0.41-0.59], 0.41 [0.31-0.55], respectively), with high between-study heterogeneity (I = 76.7-98.2%). The specific mode of action of ICI emerged as a potential moderator of treatment efficacy in subgroup analyses.
This systematic review highlights the therapeutic potential of combined TRT/ICI treatment, demonstrating preclinical proof-of-concept and supporting its further evaluation in clinical trials. However, the current literature remains insufficient to determine optimal treatment parameters like TRT tumour-absorbed dose and ICI type for clinical translation. Further research with improved reporting standards should systematically evaluate the impact of such parameters to enable robust comparisons.
鉴于辐射的免疫调节作用以及靶向放射性核素治疗（TRT）和免疫检查点抑制（ICI）的互补抗癌机制，它们的联合应用有望成为一种癌症治疗方法。本系统综述和荟萃分析总结了关于TRT/ICI联合治疗在动物肿瘤模型中治疗效果的文献。
在MEDLINE-PubMed和Embase-OVID中进行了系统检索。评估了研究特征和偏倚风险。结局参数包括肿瘤生长曲线下的标准化面积和受限平均生存时间，在随机效应荟萃分析中分析了联合治疗组与未治疗组和单药治疗组之间的比率。预定义的亚组分析探讨了治疗效果的潜在调节因素。
总共纳入了31项研究。研究特征，如动物性别和年龄、癌症类型、TRT靶点和放射性核素，在各研究中差异很大。由于报告不佳，并非总能评估所纳入研究的质量。所有荟萃分析均表明，联合治疗组的生存率和肿瘤生长情况明显优于未治疗组、TRT和ICI单药治疗对照组（RMST比率分别为1.96[1.72-2.23]、1.44[1.34-1.55]、1.54[1.38-1.72]，nAUC比率分别为0.32[0.25-0.42]、0.49[0.41-0.59]、0.41[0.31-0.55]），研究间异质性较高（I=76.7-98.2%）。在亚组分析中，ICI的具体作用方式成为治疗效果的潜在调节因素。
本系统综述突出了TRT/ICI联合治疗的治疗潜力，证明了临床前概念验证，并支持其在临床试验中的进一步评估。然而，目前的文献仍不足以确定临床转化所需的最佳治疗参数，如TRT肿瘤吸收剂量和ICI类型。采用改进报告标准的进一步研究应系统评估这些参数的影响，以便进行有力的比较。
