Increased CD8+ T-Cell Infiltration and Efficacy for Multikinase Inhibitors after PD-1 Blockade in Hepatocellular Carcinoma
Menée à l'aide de modèles murins de carcinome hépatocellulaire, cette étude met en évidence l'intérêt des inhibiteurs de PD1 pour augmenter l'infiltration intratumorale des lymphocytes T CD8+ et l'efficacité des inhibiteurs multikinase
Immune checkpoint blockade combined with anti-angiogenic therapy induces vascular normalization and anti-tumor immunity and is efficacious in hepatocellular carcinoma (HCC). But whether and how initial immunotherapy affects the efficacy of subsequent anti-angiogenic therapy is unknown. We evaluated a cohort of HCC patients (n = 25) who received the pan-VEGF receptor multi-kinase inhibitor sorafenib after initial therapy with an anti-programmed cell death protein (PD)-1 antibody and found superior outcomes in these patients (12% overall response rate to sorafenib and a median OS of 12.1 months). To understand mechanisms of this benefit, we examined the impact of an anti-PD-1 antibody on response to subsequent sorafenib treatment in orthotopic models of murine HCC. Prior anti-PD-1 antibody treatment amplified HCC response to sorafenib therapy and increased survival (n = 8–9 mice per group, HR = 0.28, 95% CI: 0.09–0.91; p = .04). Anti-PD-1 therapy showed angio-protective effects on HCC vessels to subsequent sorafenib treatment, which enhanced the benefit of this therapy sequence in a CD8+ T-cell-dependent manner. This priming approach using immunotherapy provides an immediately translatable strategy for effective HCC treatment while reducing drug exposure.