Increased CD8+ T-cell Infiltration and Efficacy for Multikinase Inhibitors After PD-1 Blockade in Hepatocellular Carcinoma.

Abstract

Immune checkpoint blockade combined with antiangiogenic therapy induces vascular normalization and antitumor immunity and is efficacious in hepatocellular carcinoma (HCC); but whether and how initial immunotherapy affects the efficacy of subsequent antiangiogenic therapy are unknown. We evaluated a cohort of HCC patients (n = 25) who received the pan-vascular endothelial growth factor receptor multikinase inhibitor sorafenib after initial therapy with an antiprogrammed cell death protein (PD)-1 antibody and found superior outcomes in these patients (12% overall response rate to sorafenib and a median overall survival of 12.1 months). To prove this potential 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, hazard ratio = 0.28, 95% confidence interval = 0.09 to 0.91; 2-sided P = .04). Anti-PD-1 therapy showed angioprotective 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.

• Authors: Hiroto Kikuchi, Aya Matsui, Satoru Morita, Zohreh Amoozgar, Koetsu Inoue, Zhiping Ruan, Daniel Staiculescu, Jeffrey Sum-Lung Wong, Peigen Huang, Thomas Yau, Rakesh K Jain, Dan G Duda
• Journal: Journal of the National Cancer Institute (J Natl Cancer Inst) Vol. 114 Issue 9 Pg. 1301-1305 (09 09 2022) ISSN: 1460-2105 [Electronic] United States
• PMID: 35288743 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please email: [email protected].

Chemical References

• Angiogenesis Inhibitors
• Programmed Cell Death 1 Receptor
• Vascular Endothelial Growth Factor A
• Sorafenib

Topics

• Angiogenesis Inhibitors (therapeutic use)
• Animals
• CD8-Positive T-Lymphocytes
• Carcinoma, Hepatocellular (drug therapy, pathology)
• Humans
• Liver Neoplasms (pathology)
• Mice
• Programmed Cell Death 1 Receptor
• Sorafenib (therapeutic use)
• Vascular Endothelial Growth Factor A (metabolism)