In recent years, knowledge of hepatocellular carcinoma (HCC)-specific tumor-associated antigens and the development of immune checkpoint blockade therapy has offered a positive outlook for patients with HCC.
Immunotherapy has been investigated in patients with hepatocellular carcinoma (HCC) for decades. However, initial clinical trials that tested various immune-based therapies showed little clinical efficacy in HCC, despite eliciting tumor-specific immune responses. In recent years, knowledge of HCC-specific tumor-associated antigens (TAAs) and the development of immune checkpoint blockade therapy has offered a positive outlook for patients with HCC, according to a review by Gaetano Bertino, MD, with the University of Catania in Catania, Italy.1
Immunotherapies offer great promise, as the search for a second-line therapy continues. Currently, sorafenib, an oral kinase inhibitor, is the only US Food and Drug Administration (FDA)-approved agent available to treat metastatic HCC. No suitable second-line therapies are available for patients who relapse or who are refractory to sorafenib treatment.2Additionally, the recently published results from a double-blind, phase III study indicate that sorafenib is not an effective therapeutic strategy in the adjuvant setting following surgical resection or ablation for patients with HCC, further limiting options.3
Given that most patients with HCC do not receive a diagnosis until the disease is at an advanced stage, and only liver resection and transplantation are considered curative, there is an urgent clinical need to improve the therapy landscape. Although the inherent immune tolerance associated with the liver makes immune-based strategies challenging, the immune system can be utilized in multiple ways. For example, the immune response can be enhanced indirectly with either tumor vaccines or immunomodulators, or directly by introducing effective immune cells with adoptive immunotherapy.4
Bertino et al1describe 7 TAAs that are recognized by the adaptive immune system, elicit a T-cell response, and show HCC specificity. The TAAs described are alpha-fetoprotein (AFP), glypican-3 (GPC3), NY-ESO-1, SSX-2, melanoma antigen gene-A (MAGE-A), telomerase reverse transcriptase (TERT), and HCCassociated antigen-519/targeting protein for Xklp-2 (HCA519/TPX2). These antigens may provide suitable targets for vaccine-based immunotherapies for patients with HCC (Table).
10 to 15 AFP-derived epitopes in development5
Heparan sulphate proteoglycan
Two in development for HLA-A2 and -246
Multiple epitopes but very little activity7
Efficacy in small patient cohort8
Epitopes in development for 1, 3, 109
Telomerase associated enzyme
Multiple epitopes in development10
Two agents inin vitrosudies11
TAA, tumor-associated antigens
When considering the choice of peptide for an immune-based vaccine, several factors must be evaluated. Weak immune responses from native TAAs might be limiting; Hong and colleagues12used an in silicoguided method for optimizing epitopes and engineered a highly immunogenic AFP. An additional method for amplifying immune response is the use of fusion peptides. One example of such a peptide is the full-length hepatitis B virus (HBV) core protein fused with epitopes from HBx, AFP, and MAGE-3.13
Some have argued that the use of HBV antigens alone does not make a sufficient target for an HCC vaccine therapy, as they have not been shown to be expressed stably on HBV-associated HCC cells, and therefore pose some additional risk in cases of liver-sparing treatment.14As such, the fusion peptide approach may pose a suitable comparable strategy. Alternatively, strategies that combine the use of vaccine-activated, TAA-specific T cells with a blockade against inhibitory receptors or immunoregulatory cell types may also provide effective antitumor suppression in HCC.
Despite the heightened antitumor immune response that may be mounted against HCC-specific antigens, overexpression of co-inhibitory signals, such as programmed cell death-1 (PD-1) or cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) checkpoint molecules, may dampen the antitumor response. As such, a focused research effort has been placed on developing clinically effective therapies that target and modulate the immune checkpoint blockade. Two monoclonal antibodies (mAbs) that are currently in clinical development and have shown some clinical efficacy in HCC are tremelimumab and nivolumab.
The anti-CTLA-4 antibody, tremelimumab, prevents the binding between CTLA-4 and its ligands on antigen-presenting cells, and subsequently inhibits the suppression of T-cell activation. In a phase I pilot study of 18 patients with HCC, the safety and feasibility of 2 dose levels of tremelimumab were evaluated when used in combination with either transcatheter arterial chemoembolization (TACE) or radiofrequency ablation (RFA), which have shown poor clinical efficacy on their own.15The results were recently presented at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting. The most common adverse event (AE) associated with tremelimumab was pruritus. Of those patients evaluable for a response, 40% showed a partial response (PR) and all showed immune cell infiltration with possible reductions in HCV viral load. The median progression-free survival (PFS) time was 7.4 months.15
Ongoing phase I and phase I/II studies of tremelimumab in combination with other therapeutic approaches are currently under exploration. In a phase I study currently recruiting participants, tremelimumab will be combined with chemoembolization or ablation in patients with advanced HCC who have not responded to other treatments.16The primary outcome of the study will be the safety and feasibility of treatments.
In a phase I/II study, tremelimumab will be studied alone or in combination with MEDI4736, an anti-programmed cell death ligand-1 (PD-L1) antibody.17The primary outcomes will be determining the number of patients reporting AEs and the number of patients experiencing dose-limiting toxicities. A similar phase I study performed in patients with advanced non-small cell lung cancer (NSCLC) showed tolerable safety with high levels of clinical activity in patients with PD-L1-positive and PD-L1-negative tumors.18A phase III study is currently under way.18Tremelimumab has already been granted an orphan drug designation by the FDA for the treatment of malignant melanoma.
Nivolumab, an anti-PD-1 mAb, blocks the interaction between PD-1 and its ligand, PD-L1, enhancing the antitumor immune response. PD-L1 is highly expressed in many tumor types and is associated with a poor prognosis because of its immunosuppressive properties. Early clinical trials of nivolumab in patients with HCC are promising. In a phase I/II study presented at the 2015 ASCO Annual Meeting, the safety and preliminary efficacy of nivolumab was evaluated in 41 patients with advanced HCC.19In this dose escalation study, patients received nivolumab intravenously for up to 2 years. The most common drug-related AEs were increases in the levels of aspartate aminotransferase, alanine aminotransferase, lipase, and amylase. Grade 3/4 AEs occurred in 17% of patients. Of those patients with an evaluable response, 5% had a complete response (CR; response duration, 14-17 months) and 18% had a PR (response duration, 1-8 months). The overall survival (OS) at 6 months was 72%.19
The results of the phase I/II trial are encouraging for patients with advanced HCC, who currently have very limited therapeutic options. Treatment responses with nivolumab were durable, and the results compared favorably with existing treatment options. The safety profile of nivolumab in this study was consistent with that previously reported with nivolumab in other types of tumors.20Nivolumab is currently approved for use in patients with unresectable or metastatic melanoma and metastatic squamous NSCLC.21
Trials of nivolumab in HCC are ongoing. An expansion, dose-escalating, phase I trial will determine the safety of nivolumab in patients with HCC from 3 different cohorts: uninfected HCC subjects, HBV-infected patients, and hepatitis C virus (HCV)-infected subjects.22The primary outcomes of the study will determine the incidence of worst AEs and hematology and serum chemistry abnormalities, with secondary outcomes evaluating the objective response and disease control rates.
Other immune-based therapeutic approaches still under investigation include the use of immunomodulators and adoptive immunotherapy. Interferon (IFN), a cytokine well known for its immunomodulatory properties, is known to induce HCC apoptosis and autophagy.23As such, IFN-alpha therapy is currently being evaluated in ongoing clinical trials. In one multicenter study currently recruiting participants, IFN-alpha will be analyzed as an adjuvant therapy after surgical resection in patients with HCC who express low levels of miR-26.24A phase II study will compare the combination of IFN-alpha plus fluorouracil (5-FU) versus cisplatin plus 5-FU in patients with HCC to determine OS and PFS rates.25
Adoptive immunotherapy strategies also are being investigated as potential alternatives for patients who are refractory to conventional therapies. Notably, strategies using cytokine-induced killer (CIK) cells are furthest along in clinical development in studies of patients with HCC. These cells have some distinct advantages over other immune cell types, including strong cytolytic activity against tumor cells of both autologous and allogeneic origins, minimal toxicity, and high proliferation rate. At this time, there are numerous phase III trials exploring CIK cells in patients with radical resection of HCC.23
Overall, numerous translational studies and early-stage clinical trials have shown that immunotherapy is safe and well tolerated by patients with a variety of cancers. Clinical studies of immune-based therapies, such as peptide-based vaccines and immune checkpoint blockade therapy, are in their infancy in HCC, but offer hope to patients with advanced disease. Although more randomized, controlled trials in HCC patients are needed, the incorporation of immunotherapy with standard antitumor approaches likely will provide patients with effective alternatives. The future outlook for immunotherapy in HCC is bright.