BackgroundCytomegalovirus (CMV) reactivation occurs in 30−40% of seropositive patients receiving chimeric antigen receptor T-cell (CAR-T) therapy for B-cell lymphoma and is strongly associated with treatment failure. However, the causal immunological mechanism driving this failure whether through direct viral cytopathic effects, T-cell exhaustion, or resource competition remains undefined.
Furthermore, existing predictive models lack the mechanistic insight needed to guide intervention. We developed a privacy-preserving, mechanistic digital twin to test the “cytokine sink” hypothesis, wherein CMV-specific CD8+ T cells compete with CAR-T cells for the limiting homeostatic cytokine IL−15.MethodsWe constructed a system of ordinary differential equations formalizing this competition for IL−15.
The model was trained using a Hierarchical Bayesian Federated Averaging algorithm on multi-institutional data from 414 patients across five academic cancer centres (Sites A-E). without centralizing raw patient data.
An independent sixth centre (Site F, n=89) served exclusively as the prospective validation site and contributed no data to the training process.
Frontiers in Immunology published a clinical update in Infectious Disease on 12 Jun 2026.
The item focuses on A federated digital twin reveals cytomegalovirus reactivation impairs CAR-T cell therapy via IL-15-mediated cytokine competition in B-Cell lymphoma.
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