Anti-PD-1/PD-L1 Blockade Immunotherapy Employed in Treating Hepatitis B Virus Infection-Related Advanced Hepatocellular Carcinoma: A Literature Review.

Bin Li,Yi Zheng,Qihan Fu,Weiqin Jiang,Cong Yan,Hangyu Zhang,Jiamin Zhu,Peng Zhao,Zhou Tong,Xiaobing Chen,Lulu Liu,Weijia Fang

doi:10.3389/fimmu.2020.01037

Abstract

Hepatitis B virus (HBV) infection is regarded as the main etiological risk factor in the process of hepatocellular carcinoma (HCC), as it promotes an immunosuppressive microenvironment that is partially mediated by the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) signaling pathway. The tumor microenvironment (TME) of HBV–related HCC is indeed more immunosuppressive than microenvironments not associated with viruses. And compared to TME in hepatitis C virus (HCV) infected HCC, TME of HBV-related HCC is less vascularized and presents different immune components resulting in similar immunosuppression. However, few studies are focusing on the specific side effects and efficacy of PD-1/PD-L1 blockade immunotherapy in HBV-related HCC patients, as well as on the underlying mechanism. Herein, we reviewed the basic research focusing on potential TME alteration caused by HBV infection, especially in HCC patients. Moreover, we reviewed PD-1/PD-L1 blockade immunotherapy clinical trials to clarify the safety and efficacy of this newly developed treatment in the particular circumstances of HBV infection. We found that patients with HBV-related HCC displayed an acceptable safety profile similar to those of non-infected HCC patients. However, we could not determine the antiviral activity of PD-1/PD-L1 blockade because standard anti-viral therapies were conducted in all of the current clinical trials, which made it difficult to distinguish the potential influence of PD-1/PD-L1 blockade on HBV infection. Generally, the objective response rates (ORRs) of PD-1/PD-L1 blockade immunotherapy did not differ significantly between virus-positive and virus-negative patients, except that disease control rates (DCRs) were obviously lower in HBV-infected HCC patients.

Highlights

Liver cancer was predicted to be the sixth most commonly diagnosed cancer and the fourth-leading cause of cancer death in 2018, with about 841,000 new cases and 782,000 deaths annually [1]
One study showed that adefovir monotherapy could control hepatitis B virus (HBV) viremia but HBV surface antigen (HBsAg) seroconversion was not achieved in patients with chronic hepatitis B, while the decreased but remaining number of peripheral Tregs still expressed high levels of PD-1 [76]
We evaluated the safety and efficacy of PD-1/PDL1 blockade immunotherapy, and summarized the general differences between HBV related hepatocellular carcinoma (HCC) and virus unrelated HCC (Table 3)

Summary

Introduction

Liver cancer was predicted to be the sixth most commonly diagnosed cancer and the fourth-leading cause of cancer death in 2018, with about 841,000 new cases and 782,000 deaths annually [1]. Higher expression of PD1 and lymphocyte-activation gene 3 (LAG3), as well as lower expression of CD28 and CD127, were commonly found in tumor-infiltrating CD8+ T cells of HBV-related HCC patients [30,31,32]. In a phase Ib study of unresectable or advanced HCC, 31% HBV-infected patients treated with atezolizumab + bevacizumab achieved objective response, compared with 32% in the overall study population.

Results

Conclusion