Integrating C-reactive protein flare and early MRI dynamics for enhanced prediction of immunotherapy response

Abstract

Background: The C-reactive protein (CRP) flare response, an indicator of early immune activation, has emerged as a promising and cost-effective biomarker for predicting response to immune checkpoint inhibitors (ICIs) across various tumor types. This study evaluates the utility of CRP dynamics as a tumor-agnostic biomarker and integrates systemic inflammatory markers with advanced multiparametric MRI metrics to uncover the biological mechanisms underlying the CRP flare phenomenon and its relationship with treatment response.

Methods: Patients were stratified into three groups based on CRP kinetics: (1) flare-responders, characterized by an initial doubling of baseline CRP followed by a decrease below baseline; (2) CRP responders, defined as patients with no flare increase but a CRP reduction of at least 30% below baseline and (3) CRP non-responders. Multiparametric MRI was performed at baseline, early (1-3 weeks), and intermediate (6-8 weeks) time points to assess tumor size and microstructural features, including cell density and vascularization. Clinical benefit and survival outcomes, including progression-free survival (PFS) and overall survival (OS), were analyzed using Kaplan-Meier curves and log-rank tests. Cox regression analyses were performed to identify independent predictors of clinical outcomes, while intergroup differences in MRI metrics were assessed using Wilcoxon rank-sum and Kruskal-Wallis tests.

Results: Among the 121 evaluable patients with solid tumors enrolled in the PREDICT trial, CRP flare-responders demonstrated significantly longer PFS (5.6 months) and OS (12.1 months) compared with responders (PFS: 3.4 months, OS: 8.0 months) and non-responders (PFS: 3.2 months, OS: 6.7 months; p=0.01 and p<0.01, respectively). Additionally, clinical benefit was achieved in 50% of flare-responders, compared with 13% of responders (p=0.05) and 23% of non-responders (p<0.01). Tumor growth was interrupted early after treatment initiation in CRP flare-responders, whereas non-responders exhibited marked increases in tumor size. In the pilot subset of 33 patients with MRI data, diffusion MRI revealed stable or increased apparent diffusion coefficient values in CRP flare-responders, indicative of reduced tumor cellularity just after 1-3 weeks of treatment.

Conclusions: This study highlights the potential of combining early CRP dynamics with non-invasive imaging metrics to identify ICI responders as early as 2 weeks after treatment initiation. By integrating systemic inflammatory biomarkers with MRI-derived insights into tumor size and microstructural changes, these findings optimize therapeutic strategies and advance understanding of immunotherapy-driven tumor dynamics.

Keywords: Biomarker; Immune Checkpoint Inhibitor; Immunotherapy; Tumor Biomarkers; fMRI / PET.