Citation Information: JCI Insight. 2025. https://doi.org/10.1172/jci.insight.186062.
Abstract
BACKGROUND. Previously, we demonstrated that changes in circulating tumor DNA (ctDNA) are promising biomarkers for early response prediction (ERP) to immune checkpoint inhibitors (ICI) in metastatic urothelial cancer (mUC). In this study, we investigated the value of whole blood immunotranscriptomics for ERP-ICI and integrated both biomarkers into a multimodal model to boost accuracy. METHODS. Blood samples of 93 patients were collected at baseline and after 2-6 weeks of ICI for ctDNA (N=88) and immunotranscriptome (N=79) analyses. ctDNA changes were dichotomized into increase or no increase, the latter including patients with undetectable ctDNA. For RNA model development, the cohort was split into a discovery (N=29), test (N=29) and validation set (N=21). Finally, RNA- and ctDNA-based predictions were integrated in a multimodal model. Clinical benefit (CB) was defined as progression-free survival beyond 6 months. RESULTS. Sensitivity (SN) and specificity (SP) of ctDNA increase for predicting non-CB (N-CB) was 59% and 92%, respectively. Immunotranscriptome analysis revealed upregulation of T-cell activation, proliferation and interferon signalling during treatment in the CB group, contrary to N-CB patients. Based on these differences a 10-gene RNA model was generated, reaching a SN and SP of 73% and 79% in the test and 67% and 67% in the validation set for predicting N-CB. Multimodal model integration led to superior performance with a SN and SP of 79% and 100% in the validation cohort. CONCLUSION. The combination of whole blood immunotranscriptome and ctDNA in a multimodal model showed promise for ERP-ICI in mUC and accurately identified patients with N-CB. TRIAL REGISTRATION. 2016-3060, 2020-6778 FUNDING. Eurostars grant E! 114908 - PRECISE, Paul Speth Foundation (Bullseye project)
Authors
Sandra van Wilpe, Davide Croci, Sara S. Fonseca Costa, Iris B.A.W. te Paske, Sofie H. Tolmeijer, Jolique van Ipenburg, Leonie I. Kroeze, Simona Pavan, Sylvain Monnier-Benoit, Guido Coccia, Noushin Hadadi, Irma M. Oving, Tineke J. Smilde, Theo van Voorthuizen, Marieke Berends, Mira D. Franken, Marjolijn J.L. Ligtenberg, Sahar Hosseinian Ehrensberger, Laura Ciarloni, Pedro Romero, Niven Mehra
