Biomarker identification and potential combination therapy targeting chemokine changes after atezolizumab plus bevacizumab treatment in unresectable hepatocellular carcinoma

Background: Atezolizumab plus bevacizumab (Atezo/Bev) is a first-line therapy for unresectable hepatocellular carcinoma. This study explored predictive biomarkers through plasma analysis and assessed a novel combination therapy in a mouse model.
Methods: We collected plasma samples from 54 patients treated with Atezo/Bev between October 2020 and January 2022. Multiplex assays analyzed changes in 40 chemokines and cytokines before and after one treatment cycle. Logistic regression identified factors associated with progressive disease (PD) or non-PD. Multivariate analysis using the Cox proportional hazards model was conducted for progression-free survival (PFS). We evaluated a CXCR4 inhibitor blocking CXCL12, combined with an anti-PD-L1 and anti-VEGF-A antibody, in MH134-TC subcutaneous tumors in syngeneic C3H mice.
Results: In multivariate analysis for PFS, ΔCXCL12 (HR 2.55, p=0.0061) and ΔCCL3 (HR 0.44, p=0.0369) were independent prognostic factors. Log-rank analysis showed patients with high ΔCXCL12 had significantly shorter overall survival. In the mouse model, triple combination therapy significantly suppressed tumor growth compared to both anti-PD-L1 + anti-VEGF-A and CXCR4 inhibitor alone (p<0.05). Flow cytometry indicated a trend toward an increased CD8/regulatory T cell ratio, and immunohistochemistry showed reduced Ki67-positive tumor cells.
Conclusions: CXCL12 elevation and CCL3 reduction after Atezo/Bev were associated with worse PFS. In the mouse model, adding a CXCR4 inhibitor enhanced the anti-tumor effect, suggesting its potential benefit for patients with increased CXCL12.