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Novel Immunotherapies on the Horizon in HCC

Published Online: Oct 09,2015

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.2 Additionally, 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

Multiple TAAs Under Exploration

Bertino et al1 describe 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 HCC–associated antigen-519/targeting protein for Xklp-2 (HCA519/TPX2). These antigens may provide suitable targets for vaccine-based immunotherapies for patients with HCC (Table).

Table. Targetable TAAs in Hepatocellular Carcinoma

Antigen

Type

Therapeutic Potential

AFP

Fetal oncoprotein

10 to 15 AFP-derived epitopes in development5

GPC3

Heparan sulphate proteoglycan

Two in development for HLA-A2 and -246

NY-ESO-1

Cancer/testis antigens

Multiple epitopes but very little activity7

SSX-2

Cancer/testis antigens

Efficacy in small patient cohort8

MAGE-A

Cancer/testis antigens

Epitopes in development for 1, 3, 109

TERT

Telomerase associated enzyme

Multiple epitopes in development10

HCA519/TPX2

Microtubule-associated protein

Two agents in in vitro sudies11

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 colleagues12 used an in silico–guided 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.14 As 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.

Immune Checkpoint Inhibitors

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.15 The 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.16 The 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.17 The 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.18 A phase III study is currently under way.18 Tremelimumab 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.19 In 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.20 Nivolumab 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.22 The 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.

Adoptive Immunotherapy and Immunomodulation

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.23 As 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-26.24 A 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.

References

  1. Bertino G, Demma S, Ardiri A, et al. The immune system in hepatocellular carcinoma and potential new immunotherapeutic strategies. BioMed Res Int. 2015(2015). Article ID 731469. doi:10.1155/2015/731469.
  2. Nobuoka D, Yoshikawa T, Sawada Y, et al. Peptide vaccines for hepatocellular carcinoma. Hum Vaccin Immunother. 2013;9(1):210-212.
  3. Bruix J, Takayama T, Mazzaferro V, et al; STORM investigators. Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial [published online September 8, 2015]. Lancet Oncol. pii: S1470-2045(15)00198-9. doi: 10.1016/S1470-2045(15)00198-9.
  4. Miamen AG, Dong H, Roberts LR. Immunotherapeutic approaches to hepatocellular carcinoma treatment. Liver Cancer. 2012;1(3-4):226-237.
  5. Butterfield LH, Ribas A, Meng WS, et al. T-Cell responses to HLA-A*0201 immunodominant peptides derived from alpha-fetoprotein in patients with hepatocellular cancer. Clin Cancer Res. 2003;9(16 Pt 1):5902-5908.
  6. Komori H, Nakatsura T, Senju S, et al. Identification of HLA-A2- or HLA-A24-restricted CTL epitopes possibly useful for glypican-3-specific immunotherapy of hepatocellular carcinoma. Clin Cancer Res. 2006;12(9):2689-2697.
  7. Korangy F, Ormandy LA, Bleck JS, et al. Spontaneous tumor-specific humoral and cellular immune responses to NY-ESO-1 in hepatocellular carcinoma. Clin Cancer Res. 2004;10(13):4332-4341.
  8. Liang J, Ding T, Guo Z-W, et al. Expression pattern of tumour-associated antigens in hepatocellular carcinoma: association with immune infiltration and disease progression. Br J Cancer. 2013;109(4):1031-1039.
  9. Zerbini A, Pilli M, Soliani P, et al. Ex vivo characterization of tumor-derived melanoma antigen encoding gene-specific CD8+cells in patients with hepatocellular carcinoma. J Hepatol. 2004;40(1):102-109.
  10. Mizukoshi E, Nakamoto Y, Marukawa Y, et al. Cytotoxic T cell responses to human telomerase reverse transcriptase in patients with hepatocellular carcinoma. Hepatology. 2006;43(6):1284-1294.
  11. Aref AM, Hoa NT, Ge L, et al. HCA519/TPX2: a potential T-cell tumor-associated antigen for human hepatocellular carcinoma. Onco Targets Ther. 2014;7:1061-1070.
  12. Hong Y, Peng Y, Guo ZS, et al. Epitope-optimized alpha-fetoprotein genetic vaccines prevent carcinogen-induced murine autochthonous hepatocellular carcinoma. Hepatology. 2014;59(4):1448-1458.
  13. Chen Y, Yang D, Li S, et al. Development of a Listeria monocytogenes-based vaccine against hepatocellular carcinoma. Oncogene. 2012;31(17):2140-2152.
  14. Buschow SI, Sprengers D, Woltman AM [letter to the editor] To target or not to target viral antigens in HBV related HCC? J Hepatol. 2015;62(6):1449-1450.
  15. Duffy A, Makarova-Rusher O, Kerker S, et al. A pilot study of tremelimumab – a monoclonal antibody against CTLA-4 – in combination with either trans catheter arterial chemoembolization (TACE) or radiofrequency ablation (RFA) in patients with hepatocellular carcinoma (HCC). J Clin Oncol. 2015;33(suppl; abstr 4081).
  16. ClinicalTrials.gov. Tremelimumab With Chemoembolization or Ablation for Liver Cancer. https://clinicaltrials.gov/ct2/show/NCT01853618. Accessed September 16, 2015.
  17. ClinicalTrials.gov. A Study of MEDI4736 With Tremelimumab, MEDI4736 or Tremelimumab Monotherapy in Unresectable Hepatocellular Carcinoma.  https://clinicaltrials.gov/ct2/show/NCT02519348. Accessed September 16, 2015.
  18. Antonia SJ, Goldberg SB, Balmanoukian AS, et al. Phase Ib study of MEDI4736, a programmed cell death ligand-1 (PD-L1) antibody, in combination with tremelimumab, a cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) antibody, in patients (pts) with advanced NSCLC. J Clin Oncol. 2015;33(suppl; abstr 3014).
  19. El-Khoueiry AB, Melero I, Crocenzi TS, et al. Phase I/II safety and antitumor activity of nivolumab in patients with advanced hepatocellular carcinoma (HCC): CA209-040. J Clin Oncol. 2015;33(suppl; abstr LBA101).
  20. Shaffer A. Study Opens Door for Nivolumab in HCC. May 2015. http://www.onclive.com/conference-coverage/asco-2015/Study-Opens-Door-for-Nivolumab-in-HCC. Accessed September 16, 2015.
  21. U.S. Food and Drug Administration. FDA expands approved use of Opdivo to treat lung cancer. March 4, 2015. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm436534.htm. Accessed September 16, 2015.
  22. ClinicalTrials.gov. Study to Evaluate the Effectiveness, Safety and Tolerability of Nivolumab in Subjects With Advanced Liver Cancer Anti-PD-1 HCC (Anti-Programmed-Death-1 Hepatocellular Carcinoma). https://clinicaltrials.gov/show/NCT01658878. Accessed September 16, 2015.
  23. Hong Y-P, Li Z-D, Prasoon P, Zhang Q. Immunotherapy for hepatocellular carcinoma: From basic research to clinical use. World J Hepatol. 2015;7(7):980-992.
  24. ClinicalTrials.gov. The Effect of Postoperative Interferon- Alpha Treatment in Low miR-26 Expression Patients With HCC. https://clinicaltrials.gov/ct2/show/NCT01681446. Accessed September 16, 2015.
  25. ClinicalTrials.gov. P2 Study of Postoperative Interferon/Fluorouracil vs Cisplatin/Fluorouracil for Hepatocellular Carcinoma.  https://clinicaltrials.gov/ct2/show/NCT01834963. Accessed September 16, 2015.



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Novel Immunotherapies on the Horizon in HCC
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