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

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.

<p>ADORA1 Promotes Hepatocellular Carcinoma Progression via PI3K/AKT Pathway</p>

“…More recently, ADORA1 has been shown to participate in the PD-1 based checkpoint anti-cancer strategy in non-small cell lung cancer (NSCLC). 21 Given the complexity and etiology of viral hepatitis with HCC in China, 22 plus the success exploration on anti-PD-1/PD-L1 blockade immunotherapy in treating Hepatitis B Virus infection-related advanced hepatocellular carcinoma, 23 development of FDA-approved ADORA1 antagonists could light up a bright light in HCC, as well as cancer patient outcome, especially with current PD-1-based multiple immune therapies. 24 submit your manuscript | www.dovepress.com…”

Immunotherapy for Hepatocellular Carcinoma: A 2021 Update

“…In the dose-expansion phase, 6- and 9-month OS rates were 84% and 70% in HBV+ patients, 85% and 81% in HCV+, while for the entire population of the study, 83% and 74%, respectively [ 52 ]. In the CheckMate 459 study (nivolumab vs. sorafenib), a consistent effect on OS was also observed in advanced HCC with nivolumab, and benefit was noted for patients with HBV infection [ 53 , 177 ].…”

“…In the phase 3 KEYNOTE-240 study, ORR in the whole population was 18% for pembrolizumab vs. 4% for placebo, while HBV+ patients achieved improved OS in comparison to placebo [HR 0.57 (CI: 0.35–0.94)], while no significant benefit appeared in HCV+ patients [ 55 ]. In the phase III, IMbrave150 study, combination of atezolizumab and bevacizumab prolonged median PFS of HBV+ HCC compared to sorafenib, but this phenomenon did not appear in the population of HCC of non-viral etiology (median PFS, HBV+ HCC: 6.7 vs. 2.8 months; non-viral HCC: 7.1 vs. 5.6 months) [ 177 ].…”

“…HBV+ patients were also compared with HCV+ in the same studies, and no significant difference was in ORRs and DCRs between those two subgroups. Interestingly, combinations of anti–PD-1/PD-L1 and anti-VEGF therapy showed similar ORRs and DCRs in all HCCs, regardless of HBV status [ 177 ].…”

Immunotherapy of hepatocellular carcinoma with infection of hepatitis B or C virus

“…It remains unknown whether virally-induced HCC is more prone to immune attack either secondary to the presence of foreign viral antigens or an immune response to the virus, compared to non-viral associated HCC. A recent pooled analysis assessed the efficacy of anti-PD1 or PDL1 in HBV infected HCC patients in comparison to non HBV infected HCC patients [ 86 ] . The results indicated that patients with HBV infection achieved ORRs similar to their non-infected counterparts, and this was seen with single and multi-agent treatment regimens.…”