Facing the dawn of immunotherapy for hepatocellular carcinoma
Authors: Martin F. Sprinzl, Peter R. Galle
Journal: Journal of Hepatology (2013)

A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis CJournal of HepatologyVol. 59Issue 1PreviewTremelimumab is a monoclonal antibody that blocks cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), an inhibitory co-receptor that interferes with T cell activation and proliferation. The purpose of this pilot clinical trial was to test the antitumor and antiviral effect of tremelimumab in patients with hepatocellular carcinoma (HCC) and chronic hepatitis C virus (HCV) infection; and to study the safety of its administration to cirrhotic patients. Full-Text PDF The local tumor environment promotes T-cell exhaustion and impairs immunological tumor surveillance hence efforts to improve T-cell responses were made to establish immunotherapy for solid tumors. Intensive research for immunotherapy has eventually made substantial progress, particularly as clinical trials have confirmed the efficacy of T-cell stimulation in patients suffering from malignant melanoma [[1]Hodi F.S. O'Day S.J. McDermott D.F. Weber R.W. Sosman J.A. Haanen J.B. et al.Improved survival with ipilimumab in patients with metastatic melanoma.N Engl J Med. 2010; 363: 711-723Crossref PubMed Scopus (11496) Google Scholar] and renal cell carcinoma [[2]Yang J.C. Hughes M. Kammula U. Royal R. Sherry R.M. Topalian S.L. et al.Ipilimumab (anti-CTLA4 antibody) causes regression of metastatic renal cell cancer associated with enteritis and hypophysitis.J Immunother. 2007; 30: 825-830Crossref PubMed Scopus (598) Google Scholar]. Therapeutic antibodies, such as ipilimumab [[1]Hodi F.S. O'Day S.J. McDermott D.F. Weber R.W. Sosman J.A. Haanen J.B. et al.Improved survival with ipilimumab in patients with metastatic melanoma.N Engl J Med. 2010; 363: 711-723Crossref PubMed Scopus (11496) Google Scholar] and tremelimumab [[3]Ribas A. Kefford R. Marshall M.A. Punt C.J. Haanen J.B. Marmol M. et al.Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma.J Clin Oncol. 2013; 31: 616-622Crossref PubMed Scopus (644) Google Scholar], targeting cytotoxic T-cell antigen 4 (CTLA-4) expressed on exhausted T cells stand out among immunotherapeutic concepts and may also be applied to hepatocellular carcinoma (HCC). HCC was considered a potential candidate for immunotherapy for many years, as it commonly expresses tumor-associated antigens (TAA), which could serve as therapeutic T-cell target [4Breous E. Thimme R. Potential of immunotherapy for hepatocellular carcinoma.J Hepatol. 2011; 54: 830-834Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar, 5Gehring A.J. Ho Z.Z. Tan A.T. Aung M.O. Lee K.H. Tan K.C. et al.Profile of tumor antigen-specific CD8 T cells in patients with hepatitis B virus-related hepatocellular carcinoma.Gastroenterology. 2009; 137: 682-690Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar]. However, the indigenous hepatic environment provides local immune tolerance and potentially impedes HCC-directed immunotherapy [[6]Thomson A.W. Knolle P.A. Antigen-presenting cell function in the tolerogenic liver environment.Nat Rev Immunol. 2010; 10: 753-766Crossref PubMed Scopus (562) Google Scholar]. In contrast to most other solid tumors, HCC coincides with long-standing hepatic damage, which regularly leads to cirrhosis and end-stage liver disease at time of tumor diagnosis [[7]Llovet J.M. Ducreux M. Lencioni R. Di Bisceglie A.M. Galle P.R. Dufour J.F. et al.EASL–EORTC clinical practice guidelines: management of hepatocellular carcinoma.J Hepatol. 2012; 56: 908-943Abstract Full Text PDF PubMed Google Scholar]. Hepatic toxicity of HCC therapy therefore limits oncologic management as patients are at risk of developing hepatic failure during anticancer treatment. Additional toxicity concerns were discussed for immunotherapy, particularly as underlying chronic hepatitis B and C may develop inflammatory flairs during T-cell stimulation with fatal outcome. Consequently, unspecific immunotherapy of HCC did not hit clinical evaluation despite the fact that clinically approved systemic therapy with sorafenib shows only modest efficacy [[8]Llovet J.M. Ricci S. Mazzaferro V. Hilgard P. Gane E. Blanc J.F. et al.Sorafenib in advanced hepatocellular carcinoma.N Engl J Med. 2008; 359: 378-390Crossref PubMed Scopus (9271) Google Scholar], and innovative therapeutic approaches are desperately needed for HCC. In this issue of the Journal of Hepatology, Sangro et al. evaluated the feasibility of anti CTLA-4 antibodies (tremelimumab) for the treatment of HCC [[9]Sangro B, Gomez -Martin C, de la Mata M, Inarrairaegui M, Garralda E, Barrera P, et al. A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C. J Hepatol 2013;59:81–88.Google Scholar]. HCC patients with liver cirrhosis (Child-Pugh grade A and B) and hepatitis C were studied, which could not receive previous tumor ablation or had experienced failure of standard HCC treatment prior to taking part in the study. Following intravenous administration of tremilimumab, 3 out of 17 patients (17.6%) developed a partial response according to RECIST criteria, and intention-to-treat analysis showed a median survival of 8.2 months. However, the open explorative study design did not allow profound efficacy assessment of this regimen. In this study, administration of tremelimumab was accompanied by a tolerable toxicity profile, most frequently including skin rash (65%), fatigue (55%), and anorexia (50%). During the initial course of tremilimumab, a transient increase of serum transaminase activity was observed. Hepatotoxicity did not impair liver function, even in the context of Child-Pugh B cirrhosis and hepatitis C. Therapy was stopped in 3 patients before tumor response evaluation was completed due to tremilimumab-related diarrhea or clinical deterioration, which was not associated with the treatment regimen. The relevance of this study is strengthened by the inclusion of HCC patients, showing hepatitis C associated cirrhosis, which represents a typical clinical scenario. However, the safety profile outlined above might not apply to HCC in association with other liver diseases. Particularly chronic hepatitis B, which shows higher liver failure rates due to inflammatory flares compared to hepatitis C, might respond differently to CTLA-4 blockage. The authors further monitored surrogate markers of immune activation and observed a suppression of hepatitis C virus (HCV) replication as well as increasing frequencies of HCV specific T cells. HCV specific T-cell responses did not correlate with tumor regression, thus indicating that TAA specific T cells respond differently. Low antigen avidity and alternative homing of TAA-directed T cells might explain this discrepancy [[10]Thimme R. Neagu M. Boettler T. Neumann-Haefelin C. Kersting N. Geissler M. et al.Comprehensive analysis of the alpha-fetoprotein-specific CD8+ T cell responses in patients with hepatocellular carcinoma.Hepatology. 2008; 48: 1821-1833Crossref PubMed Scopus (66) Google Scholar]. Hence, only TAA specific T-cell signatures seem appropriate to predict patient groups with better outcome [11Ayaru L. Pereira S.P. Alisa A. Pathan A.A. Williams R. Davidson B. et al.Unmasking of alpha-fetoprotein-specific CD4(+) T cell responses in hepatocellular carcinoma patients undergoing embolization.J Immunol. 2007; 178: 1914-1922Crossref PubMed Scopus (116) Google Scholar, 12Weide B. Zelba H. Derhovanessian E. Pflugfelder A. Eigentler T.K. Di Giacomo A.M. et al.Functional T cells targeting NY-ESO-1 or Melan-A are predictive for survival of patients with distant melanoma metastasis.J Clin Oncol. 2012; 30: 1835-1841Crossref PubMed Scopus (100) Google Scholar, 13Yuan J. Adamow M. Ginsberg B.A. Rasalan T.S. Ritter E. Gallardo H.F. et al.Integrated NY-ESO-1 antibody and CD8+ T-cell responses correlate with clinical benefit in advanced melanoma patients treated with ipilimumab.Proc Natl Acad Sci U S A. 2011; 108: 16723-16728Crossref PubMed Scopus (278) Google Scholar, 14Hiroishi K. Eguchi J. Baba T. Shimazaki T. Ishii S. Hiraide A. et al.Strong CD8(+) T-cell responses against tumor-associated antigens prolong the recurrence-free interval after tumor treatment in patients with hepatocellular carcinoma.J Gastroenterol. 2010; 45: 451-458Crossref PubMed Scopus (104) Google Scholar]. Based on the acceptable toxicity profile of tremelimumab, Sangro et al. provide the first evidence for the feasibility of CTLA-4 targeted immunotherapy in HCC patients [[9]Sangro B, Gomez -Martin C, de la Mata M, Inarrairaegui M, Garralda E, Barrera P, et al. A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C. J Hepatol 2013;59:81–88.Google Scholar], which should encourage further clinical trials. The proposed CTLA-4 based immunotherapy, aiming at a broad T-cell stimulation, may be extended by antibodies targeting alternative immune-modulatory molecules (Tim-3, PD-1 or LAG-3) to overcome T-cell exhaustion [15Jin H.T. Anderson A.C. Tan W.G. West E.E. Ha S.J. Araki K. et al.Cooperation of Tim-3 and PD-1 in CD8 T-cell exhaustion during chronic viral infection.Proc Natl Acad Sci U S A. 2010; 107: 14733-14738Crossref PubMed Scopus (588) Google Scholar, 16Blackburn S.D. Shin H. Haining W.N. Zou T. Workman C.J. Polley A. et al.Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection.Nat Immunol. 2009; 10: 29-37Crossref PubMed Scopus (1479) Google Scholar]. More specific approaches, such as TAA-pulsed dendritic cell vaccines or transduction of engineered TAA-directed T cells, could further improve efficacy of immunotherapy. The latter approach requires laborious cell preparations or is restricted to selected HLA-matched patient subgroups, which could delay its broad clinical introduction. Cell free vaccine strategies do not face the same methodological restrictions and have entered clinical assessment of HCC treatment [[17]Sawada Y. Yoshikawa T. Nobuoka D. Shirakawa H. Kuronuma T. Motomura Y. et al.Phase I trial of a glypican-3-derived peptide vaccine for advanced hepatocellular carcinoma: immunologic evidence and potential for improving overall survival.Clin Cancer Res. 2012; 18: 3686-3696Crossref PubMed Scopus (220) Google Scholar]. Combination of conventional HCC therapy with immune stimulation seems to be a very promising approach. This includes immune stimulation in the context of local HCC therapy by percutaneous alcohol injection, radiofrequency ablation or transarterial chemoembolisation. Synergistic effects may evolve from necrotizing tumor tissue and TAA release into the blood circulation, which eventually leads to antigen specific T-cell priming. T-cell responses directed against HCC following tumor ablation support this hypothesis [11Ayaru L. Pereira S.P. Alisa A. Pathan A.A. Williams R. Davidson B. et al.Unmasking of alpha-fetoprotein-specific CD4(+) T cell responses in hepatocellular carcinoma patients undergoing embolization.J Immunol. 2007; 178: 1914-1922Crossref PubMed Scopus (116) Google Scholar, 18Mizukoshi E. Yamashita T. Arai K. Sunagozaka H. Ueda T. Arihara F. et al.Enhancement of tumor-associated antigen-specific T cell responses by radiofrequency ablation of hepatocellular carcinoma.Hepatology. 2012; ([Epub ahead of print])Google Scholar]. HCC directed T cells recognize different antigens, such as α-fetoprotein, NY-ESO-1 or MAGE-1, and therefore cover a broad range of targets. Addition of CTLA-4 or PD-1/PD-L1 blocking antibodies might further promote T-cell expansion and recovery of T-cell effector functions, as shown for tumor specific T cells ex vivo [5Gehring A.J. Ho Z.Z. Tan A.T. Aung M.O. Lee K.H. Tan K.C. et al.Profile of tumor antigen-specific CD8 T cells in patients with hepatitis B virus-related hepatocellular carcinoma.Gastroenterology. 2009; 137: 682-690Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar, 19Mizukoshi E. Nakamoto Y. Arai K. Yamashita T. Sakai A. Sakai Y. et al.Comparative analysis of various tumor-associated antigen-specific t-cell responses in patients with hepatocellular carcinoma.Hepatology. 2011; 53: 1206-1216Crossref PubMed Scopus (145) Google Scholar]. Ideally, localized therapy might therefore induce systemic immune responses, which may also cause regression of extrahepatic HCC manifestations. Even systemic therapy with sorafenib has immune modulatory properties and could act synergistically with immunotherapy. Our own research has recently shown that sorafenib is able to reverse alternative polarization of HCC-associated macrophages, which eventually restored natural killer cell responses directed against malignant target cells [[20]Sprinzl M.F. Reisinger F. Puschnik A. Ringelhan M. Ackermann K. Hartmann D. et al.Sorafenib perpetuates cellular anti-cancer effector functions by modulating the cross talk between macrophages and natural killer cells.Hepatology. 2013; ([Epub ahead of print])PubMed Google Scholar]. Sorafenib treated HCC-associated macrophages also switched from interleukin 10 secretion towards pro-inflammatory interleukin 12 production, which further supports sufficient T-cell priming. In line with this observation, another group has identified regulatory T-cell suppression and effector T-cell induction by sorafenib [[21]Cabrera R. Ararat M. Xu Y. Brusko T. Wasserfall C. Atkinson M.A. et al.Immune modulation of effector CD4+ and regulatory T cell function by sorafenib in patients with hepatocellular carcinoma.Cancer Immunol Immunother. 2012; ([Epub ahead of print])Google Scholar]. Hence, tyrosin kinase inhibitors may be further explored for their immune modulatory properties, as they affect check points of immune response, like mitogen-activated protein kinases, signal transducer and activator of transcription and nuclear factor kappa B. Following a long history of frustrating failures to expand the treatment options for HCC, introduction of tremelimumab opens up a new approach in the field of hepatobiliary oncology. Immunotherapy has high potential either to evolve as independent therapy option or to complement conventional HCC management in combination therapy. Nevertheless, development of HCC immunotherapy should also include monitoring of immune signatures for future patient stratification, to allow a calculated and successful immunotherapy in selected patient subgroups. MFS has nothing to disclose regarding funding or conflict of interest with respect to this manuscript. PRG is an advisory board member for Medimmune.