Response assessment or prediction to checkpoint inhibitor therapy (CIT) is an unsolved problem in current routine diagnostics of patients with melanoma. Here, we evaluated very early changes of primary and secondary lymphoid organs under CIT in multiparametric [18F]-labeled fluorodeoxyglucose-positron emission tomography (18F-FDG-PET)/MRI as possible predictors of treatment response and investigated their correlation with baseline blood immune biomarkers. Between October 2014 and November 2017, 17 patients with unresectable melanoma (8 females; 65±11 years) undergoing CIT were prospectively evaluated using whole-body 18F-FDG-PET/MRI before CIT start (t0), 2 weeks (t1) and 3 months after CIT initiation (t2). At each time point, the volume, the 18F-FDG-uptake and the mean apparent diffusion coefficient (ADC) of the spleen as well as the 18F-FDG uptake of the bone marrow were assessed. Relative lymphocyte count (RLC), relative eosinophil count (REC) and neutrophil-lymphocyte ratio (NLR) were assessed at baseline. Response Evaluation Criteria in Solid Tumours modified for immune-based therapeutics (iRECIST) and decisions from an interdisciplinary tumor board were used for treatment response evaluation at t2 iRECIST was compared with PET response criteria in solid tumors for image-based response evaluation at different time points. Comparative analysis was conducted with Mann-Whitney U test with false discovery rate correction for multiple testing and correlation coefficients were computed. In lymphoid organs, significant differences (p<0.05) between responders (9/17) and non-responders were found for the 18F-FDG-uptake in the spleen at t1 and the increase of the uptake t1-t0 (responders/non-responders: standardized uptake value lean body mass 1.19/0.93; +49%/-1%). The best correlation coefficients to baseline biomarkers were found for the 18F-FDG-uptake in the spleen at t1: NLR, r=-0.46; RLC, r=0.43; REC, r=0.58 (p<0.05), respectively. Compared with the non-responder group, the responder group showed marked increases also in the volume of the spleen (+22%/+10%), the 18F-FDG-uptake of bone marrow (+31%/-9%) at t1 and the ADCmean at t2 (+46%/+15%) compared with t0, however, not reaching significance. Our findings indicate that an effective systemic immune response in patients undergoing CIT can be detected as a significantly increased spleen activity in 18F-FDG-PET as early as 2 weeks after treatment initiation. TRIAL REGISTRATION NUMBER: NCT03132090, DRKS00013925.
Keywords: CTLA-4 antigen; melanoma; programmed cell death 1 receptor.
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