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

• DOI: 10.1136/jitc-2020-001435
• Publication Date: 2020-11-24T22:01:07Z
• Authors: Kohei Shigeta; Aya Matsui; Hiroto Kikuchi; Sebastian Klein; Emilie Mamessier; Ivy X Chen; Shuichi Aoki; Shuji Kitahara; Koetsu Inoue; Ayako Shigeta; Tai Hato; Rakesh R Ramjiawan; Daniel Staiculescu; Dieter Zopf; Lukas Fiebig; Gabriela S Hobbs; Alexander Quaas; Simona Dima; Irinel Popescu; Peigen Huang; Lance L Munn; Mark Cobbold; Lipika Goyal; Andrew X Zhu; Rakesh K Jain; Dan G Duda
• Keywords: Regorafenib; CXCR3

Background and purpose Combining inhibitors of vascular endothelial growth factor the programmed cell death protein 1 (PD1) pathway has shown efficacy in multiple cancers, but disease-specific agent-specific mechanisms benefit remain unclear. We examined defined when combining regorafenib (a multikinase antivascular receptor inhibitor) with PD1 blockade murine hepatocellular carcinoma (HCC) models. Basic procedures used orthotopic models HCC mice liver damage to test effects regorafenib—dosed orally at 5, 10 or 20 mg/kg daily—combined anti-PD1 antibodies (10 intraperitoneally thrice weekly). evaluated therapy on tumor vasculature immune microenvironment using immunofluorescence, flow cytometry, RNA-sequencing, ELISA pharmacokinetic/pharmacodynamic studies tissue blood samples from patients cancer. Main findings Regorafenib/anti-PD1 combination increased survival compared regofarenib alone a dose-dependent manner. Combination uptake into tissues by normalizing increasing CD8 T-cell infiltration activation an intermediate dose. The regorafenib/anti-PD1 was compromised lacking functional T cells ( Rag1 -deficient mice). Regorafenib treatment transcription expression CXCL10—a ligand for CXCR3 expressed tumor-infiltrating lymphocytes—in HCC. Using Cxcr3 mice, we demonstrate that mediated intratumoral added combined therapy. Principal conclusions Judicious can inhibit increase CXCR3+CD8 through elevated CXCL10 cells.