Research ArticleA clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C☆
Introduction
While hepatocellular carcinoma (HCC) is poorly chemosensitive, sorafenib significantly increases survival [1] and is the standard of care [2] for patients in the advanced stage. Yet, there is an unmet need for new and better systemic therapies for HCC and other targeted agents are on different steps of clinical development [3]. Some clinical observations suggest that HCC may in fact be susceptible to immunotherapy. HCC is the tumor with the highest reported rate of spontaneous regression for which antitumor immunity has been recognized as a leading mechanism [4], and occasional objective tumor responses have been reported after adoptive immunotherapy using dendritic cells pulsed with tumor lysate [5] or lymphokine-activated killer cells plus recombinant interleukin 2 [6].
Tremelimumab (CP-675,206) is a fully human IgG2 monoclonal antibody (mAb) that blocks the binding of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). The main role of CTLA-4 at the immune synapse is to outcompete the binding of the CD28 co-stimulatory receptor to CD80 and CD86 with much superior avidity [7], [8]. In addition, binding of CTLA-4 and B7 has been proposed to send an inhibitory signal that serves as a natural brake for T cell activation [9], [10]. CTLA-4 blockade releases this brake and enhances T cell activation and proliferation through various mechanisms still under intense study [11], [12].
Tremelimumab reportedly induces tumor responses in a subset of patients with metastic melanoma [13], [14] and colorectal cancer [15]. In the field of advanced melanoma, ipilimumab (another CTLA-4-blocking mAb) has demonstrated a survival advantage over a gp100 vaccine [16]. These strategies pioneered the field of immunostimulatory monoclonal antibodies for the therapy of cancer and are being followed by a panoply of targets on immune cells, which are under clinical development [17].
The antiviral effect of CTLA-4 blockade has never been explored in patients with chronic viral infections. The population of HCC patients with chronic hepatitis C virus (HCV) infection provides an exceptional occasion to simultaneously test the antitumoral and antiviral effect of tremelimumab. In the first study of its kind, our results strongly suggest that in fact this CTLA-4-blocking agent may elicit both antitumoral effects against HCC and antiviral effects against HCV infection.
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Study population
Patients 18 years of age or older were enrolled in the study if they had inoperable HCC confirmed by biopsy or non-invasive criteria [18] and chronic HCV infection, their functional status was Child-Pugh class A or B, and the disease was not amenable to percutaneous ablation or transarterial therapy. Patients previously treated with sorafenib, systemic chemotherapy, or recruited into another clinical trial could be enrolled after a washout period of at least 4 weeks. All patients required to have
Patient characteristics
Twenty-one patients were enrolled from January 2009 to November 2010 and their main characteristics are shown in Table 1. One patient was a screening failure due to evolving liver dysfunction and the remaining 20 patients were assessable for safety. The population was mainly constituted of patients with advanced tumors that had relapsed or progressed to at least one previous antitumoral therapy. A relevant 43% of patients had some degree of liver dysfunction (Child-Pugh class B). Seven patients
Discussion
To our knowledge, this is the first time that tremelimumab has been tested against HCC. In a population of patients with advanced tumors, many with impaired liver function, the frequency and severity of AE were acceptable and similar to those reported in non-cirrhotic patients [13], [14], [15]. Only one patient had severe diarrhea probably related to immune-induced colitis, a complication that might have been particularly frightening in cirrhotic patients. While designing the clinical trial,
Financial support
This study was supported by an Independent Investigator Research grant from Pfizer Inc. In addition, this work was supported by “UTE project CIMA” to JIR-B, EL, PA, and JL. CIBEREHD is funded by Instituto de Salud Carlos III. The study was also funded in part by grants from Ministerio de Educación y Ciencia (SAF2010-15060 to JJL and grant SAF2010-15074 to PS). CA is supported by Fundación Científica de la Asociación Española Contra el Cáncer (AECC).
Conflict of interest
IM has served as consultant for Pfizer Inc., Bristol Myers Squibb, and Astra Zeneca. The remaining authors have no conflicts of interest.
Acknowledgments
Authors wish to thank Carmen Fuertes, Virginia Villar, Veronica Arostegui and Edurne Elizalde for their cooperation and technical support. We deeply acknowledge Jesús Gomez-Navarro (Pfizer Inc.New London, CT) for his extraordinary support in the first steps of this project. Enrique Grande, Cecilia Guzman and Maria Victoria Bolos from Pfizer Inc. (Spain) are also acknowledged for their continuous help and support throughout the clinical trial.
References (33)
- et al.
Targeted therapies for hepatocellular carcinoma
Gastroenterology
(2011) - et al.
Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial
Lancet
(2000) - et al.
Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver
J Hepatol
(2001) - et al.
CTLA4 blockade expands FoxP3+ regulatory and activated effector CD4+ T cells in a dose-dependent fashion
Blood
(2008) - et al.
Hepatitis C virus induces the expression of CCL17 and CCL22 chemokines that attract regulatory T cells to the site of infection
J Hepatol
(2011) - et al.
Anti-CTLA-4 antibody therapy: immune monitoring during clinical development of a novel immunotherapy
Semin Oncol
(2010) - et al.
Sorafenib in advanced hepatocellular carcinoma
N Engl J Med
(2008) EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma
J Hepatol
(2012)- et al.
Spontaneous regression of hepatocellular carcinoma: three case reports and a categorized review of the literature
Dig Dis Sci
(2008) - et al.
A phase II study of adoptive immunotherapy using dendritic cells pulsed with tumor lysate in patients with hepatocellular carcinoma
Hepatology
(2008)
CTLA-4-mediated inhibition in regulation of T cell responses: mechanisms and manipulation in tumor immunotherapy
Annu Rev Immunol
The reverse stop-signal model for CTLA4 function
Nat Rev Immunol
Regulation of T cell receptor signaling by tyrosine phosphatase SYP association with CTLA-4
Science
Molecular basis of T cell inactivation by CTLA-4
Science
The blockade of immune checkpoints in cancer immunotherapy
Nat Rev Cancer
The emerging role of CTLA4 as a cell-extrinsic regulator of T cell responses
Nat Rev Immunol
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The trial is registered as NCT01008358 on the National Clinical Trials database (www.clinicaltrials.gov).
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These authors contributed equally to senior authorship.