Immunotherapy of hepatocellular carcinoma: Unique challenges and clinical opportunities

Abstract

Current therapies for advanced hepatocellular carcinoma (HCC) are marginally effective and exacerbate underlying liver disease. The ability of immunotherapy to elicit nontoxic, systemic, long-lived anti-tumor activity makes it particularly well-suited for use in the setting of HCC. While therapeutic benefit has been achieved in early clinical trials, the efficacy of immune-based therapies is limited by several unique properties of HCC, most notably the inherently tolerogenic character of the liver in both healthy and diseased (chronically-infected or tumor-bearing) states. Therapeutic regimens that both counteract these immunosuppressive mechanisms and amplify tumor-specific immunity are expected to profoundly improve clinical outcomes for HCC patients.

Figure 1. Evolving liver immunobiology during HCC development. Numerous tolerogenic factors, many of which are listed here, support immunoregulation in both the steady-state and diseased (chronically-infected or tumor-bearing) liver. These immunosuppressive mechanisms likely accumulate during HBV/HCV-mediated hepatocarcinogenesis and coexist in patients with advanced HCC lesions. See text for all associated references.

Figure 2. Future therapeutic strategies for HCC. (1) Several vaccine approaches have been tested in HCC, including strategies to target AFP and other antigens by DNA, virus, peptide and DC-based vaccines. (2) Sorafenib has been licensed for HCC and other next-generation TKIs are in clinical testing, while bevacizumab (anti-VEGF) is under investigation in HCC as well. (3) Immunomodulatory agents, including those to release immune suppression and boost T cell function, are promising. While more technically challenging, adoptive transfer of antigen-specific T cells, such as tumor-infiltrating lymphocytes (TIL), are nearing clinical translation at more sites around the globe. (4) Rationally designed combinations of standard-of-care ablation approaches (i.e., chemotherapy, RFA, TAE) with immunotherapy strategies will likely work synergistically to improve clinical outcomes for HCC patients.