Regorafenib combined with PD1 blockade increases CD8 T-cell infiltration by inducing CXCL10 expression in hepatocellular carcinoma.

BACKGROUND AND PURPOSE

Combining inhibitors of vascular endothelial growth factor and the programmed cell death protein 1 (PD1) pathway has shown efficacy in multiple cancers, but the disease-specific and agent-specific mechanisms of benefit remain unclear. We examined the efficacy and defined the mechanisms of benefit when combining regorafenib (a multikinase antivascular endothelial growth factor receptor inhibitor) with PD1 blockade in murine hepatocellular carcinoma (HCC) models.

BASIC PROCEDURES

We used orthotopic models of HCC in mice with liver damage to test the effects of regorafenib-dosed orally at 5, 10 or 20 mg/kg daily-combined with anti-PD1 antibodies (10 mg/kg intraperitoneally thrice weekly). We evaluated the effects of therapy on tumor vasculature and immune microenvironment using immunofluorescence, flow cytometry, RNA-sequencing, ELISA and pharmacokinetic/pharmacodynamic studies in mice and in tissue and blood samples from patients with cancer.

MAIN FINDINGS

Regorafenib/anti-PD1 combination therapy increased survival compared with regofarenib or anti-PD1 alone in a regorafenib dose-dependent manner. Combination therapy increased regorafenib uptake into the tumor tissues by normalizing the HCC vasculature and increasing CD8 T-cell infiltration and activation at an intermediate regorafenib dose. The efficacy of regorafenib/anti-PD1 therapy was compromised in mice lacking functional T cells (

PRINCIPAL CONCLUSIONS

Judicious regorafenib/anti-PD1 combination therapy can inhibit tumor growth and increase survival by normalizing tumor vasculature and increasing intratumoral CXCR3+CD8 T-cell infiltration through elevated CXCL10 expression in HCC cells.

Informations de copyright

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.

Déclaration de conflit d'intérêts

Competing interests: LG reports personal fees from Agios Pharmaceuticals, Alentis Therapeutics, QED Therapeutics, H3 Biomedicine, Taiho Pharmaceuticals, Debiopharm, Incyte Corporation, SIRTEX and AstraZeneca. AXZ is a consultant/advisory board member for Bayer. RKJ received honorarium from Amgen and consultant fees from Chugai, Ophthotech, Merck, SPARC, SynDevRx and XTuit. Dr Jain owns equity in XTuit, Enlight, SPARC, SynDevRx and Accurius Therapeutics and serves as a paid member of the boards of trustees of Tekla Healthcare Investors, Tekla Life Sciences Investors, Tekla Healthcare Opportunities Fund and Tekla World Healthcare Fund. He is a member of the scientific advisory board of Accurius Therapeutics. DZ, LF and the spouse of LLM are Bayer employees. MC is an AstraZeneca employee. DGD received consultant fees from Bayer, Simcere, Surface Oncology and Bristol Myers Squibb, and research grants from Bayer, Exelixis and Bristol Myers Squibb. No potential conflicts of interest were disclosed by other authors.