Immunotherapeutic Approaches for Treating Hepatocellular Carcinoma

SIMPLE SUMMARY: The incidence of liver cancer is increasing worldwide. When detected early, the most common form of primary liver cancer (hepatocellular carcinoma, or HCC) can be treated with surgery and organ transplantation (when feasible). However, in most cases, HCC is detected at advanced stages, and the survival benefit of current treatments (e.g., systemic therapy with kinase inhibitors) is very limited. The advent of immune checkpoint inhibitors (ICIs) has changed the treatment paradigm for multiple types of cancer, including HCC. The success of ICIs, especially in combination with anti-angiogenic drugs, has extended survival times for a subset of patients with HCC and has stimulated further preclinical and clinical development of immunotherapies, not just ICIs, but also T cell therapy and oncolytic immunotherapy. Because the immunosuppressive tumor microenvironment in HCC often allows cancer cells to escape destruction by the immune system and develop resistance to immunotherapy, combinations with other agents that could sensitize HCC to immunotherapy are actively pursued. ABSTRACT: Liver cancer is a life-threatening disease, and its incidence is increasing globally. The most common form of liver cancer is hepatocellular carcinoma (HCC). Approximately half of patients with HCC, especially those at advanced disease stages, receive systemic therapies, including the tyrosine kinase inhibitors sorafenib and lenvatinib. Over the past few years, immune checkpoint inhibitors (ICIs) have changed the landscape of HCC treatment. In particular, the combination therapy with atezolizumab (an anti-PD-L1 antibody) and bevacizumab (an anti-VEGF antibody) significantly improved survival benefits compared with sorafenib as a single agent, a finding that has stimulated further preclinical and clinical development of immunotherapeutic approaches for treating HCC. In addition to ICIs, oncolytic immunotherapy and adoptive T cell therapy have also emerged as immunotherapeutic strategies. A major challenge is that the tumor microenvironment of HCC is usually immunosuppressive, leading to immune escape and immunotherapy resistance. Hence, combination therapies that could sensitize HCC to immunotherapy have become a growing area of investigation. In this review, we summarize recent advances in HCC immuno-oncology and review immunotherapeutic strategies that are under development for treating HCC.