Efficacy of combined targeted radionuclide therapy and immune checkpoint Inhibition in animal tumour models: a systematic review and meta-analysis of the literature

Abstract Purpose 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. Methods 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. Results 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 2 = 76.7–98.2%). The specific mode of action of ICI emerged as a potential moderator of treatment efficacy in subgroup analyses. Conclusion 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.