Immune checkpoint inhibitors for hepatocellular carcinoma

Abstract

The position of immunotherapy as a pillar of systemic cancer treatment has been firmly established over the past decade. Immune checkpoint inhibitors are a welcome option for patients with different malignancies. This is in part because they offer the possibility of durable benefit, even for patients who have failed other treatment modalities. The recent demonstration that immunotherapy is effective for patients with hepatocellular carcinoma (HCC) is a milestone in the history of this recalcitrant disease. The treatment of HCC has been a challenge, and for many years was limited to the tyrosine kinase inhibitor sorafenib and to several novel tyrosine kinase inhibitors that have shown efficacy and have been approved. The current role of immune checkpoint inhibitors in the management of HCC, and how this role is likely to evolve in the years ahead, are key. Other than efforts evaluating single checkpoint inhibitors, potential combination strategies, including combinations with existing local and systemic approaches, including novel therapies are evolving. This is understandably of special interest considering the potential unique immune system of the liver, which may impact the use of immunotherapy in patients with HCC going forward, and how can it be enhanced further. Cancer 2019;125:3312-3319.

<p>Programmed Cell Death Protein-1 (PD-1)-Targeted Immunotherapy for Advanced Hepatocellular Carcinoma in Real World</p>

“…To the best of our knowledge, one of the earliest immunotherapy trials that established promising activity was a Phase 2 study of the anti-CTLA-4 monoclonal antibody tremelimumab in patients with advanced HCC and HCVrelated cirrhosis who developed disease progression while receiving sorafenib. 4 class A. 15 Overall response rate was 23% in sorafenib-naive and 19% in sorafenib-pretreated patients.…”

“…Similarly, a phase ⅠB trial of lenvatinib with pembrolizumab currently is underway (ClinicalTrials.gov identifier NCT03006926). 4 The CheckMate-040 and the KEYNOTE-224 study only included Child-Pugh A patients. However, in our study, nearly 40% of patients were Child-Pugh B or C. There was no significant increase in the number of patients with any grade and high-grade adverse events, suggesting that immunotherapy is safe enough even in patients with advanced liver function impairment.…”

“…2 Its incidence is increasing worldwide due to the dissemination of hepatitis B infection in Africa and Middle East 3 and increased incidence of HCV infection and nonalcoholic steatohepatitis-related HCC in Europe, and North America. 4 About 80% of victims are distributed in Asian countries. Among them, over 50% of the patients are distributed in China.…”

RNA N6-Methyladenosine-Related Gene Contribute to Clinical Prognostic Impact on Patients With Liver Cancer

“…Immune checkpoint proteins including the programmed cell death protein 1 (PD-1/PDCD1), programmed death-ligand-1 (PD-L1/CD274), and cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) are established prognostic markers for LC patients (Cariani and Missale, 2019;El Dika et al, 2019;Johnston and Khakoo, 2019). Recent studies showed that tumor mutation burden (TMB) is also significantly associated with the susceptibility to anti-tumor immunotherapy, and a higher TMB indicates better prognosis in many cancer types (Peng et al, 2019;Wang and Li, 2019).…”

Gene Therapy for Liver Cancers: Current Status from Basic to Clinics

“…However, these MTAs also have limitations owing to the heterogeneity of HCC, and signaling pathway-specific inhibitors, such as those inhibiting fibroblast growth factor (FGF) 19-FGFR4 signaling pathways, are used in clinical trials [13]. Immune checkpoint inhibitors have also been tested [14], but have shown low efficacy in HCC as a current strategy, and further modification of the immune environment is essential [15][16][17]. Overall, HCC is characterized by heterogeneity [18][19][20][21], high risk of recurrence, and drug resistance.…”