Immunotherapy for Liver Cancer

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  • Liver Cancer
  • Treatment Options
  • CRI's Impact
  • Clinical Trials

How is Immunotherapy Changing the Outlook for Patients with Liver Cancer?

Reviewed By: Jonathan S. Cebon, Ph.D., FRACP
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Austin Health/Ludwig Cancer Research, Melbourne, Australia
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Primary liver cancer is one of the major cancer types for which new immune-based cancer treatments are currently in development. Cancer can often spread to the liver from other sites such as the breast or lung. These are known as secondary liver cancer.  Information about these cancers is provided within the sections dealing with the site of origin for those cancers. This page features information on liver cancer and immunotherapy clinical trials for liver cancer patients, and highlights the Cancer Research Institute’s role in working to bring effective immune-based cancer treatments to liver cancer patients.

The liver is a large organ that lies beneath the right lung that performs many important physiological functions, including breaking down nutrients absorbed from the intestine; filtering the blood of toxins; and producing blood clotting factors. You cannot live without a functioning liver.

Brief Statistics

In 2016, there will be roughly 39,230 new cases of primary liver cancer in the U.S., and 27,170 deaths. Most (80%) of these cases are hepatocellular carcinoma (HCC), a type of cancer that begins in liver cells called hepatocytes. The majority of other cancers arise from cells of the bile ducts and include cholangiocarcinoma. More men than women are diagnosed with liver cancer.

Risk factors for liver cancer include alcohol-related cirrhosis, obesity and diabetes, and chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. Rates of liver cancer appear to be on the rise in both men and women. In Western countries this is largely because of HCV and obesity. A vaccine that protects against HBV has been available since 1982; in fact, the HBV vaccine was the first preventative cancer vaccine in existence. There is currently no vaccine to prevent HCV infection. For patients with advanced liver cancer, nivolumab (Opdivo®), an anti-PD-1 checkpoint inhibitor, has been approved for those previously treated with sorafenib.

The overall 5-year relative survival rate for patients with liver cancer is 17%. Less than half of patients with liver cancer are diagnosed at an early stage, when the 5-year survival is 31%. For patients with regional and metastatic disease, survival rates drop to 11% and 3%, respectively. Better therapies to treat liver cancer are badly needed.

CRI Contributions and Impact

Liver cancer was the first cancer recognized as having a viral cause. Chronic inflammation resulting from infections with hepatitis B virus (HBV) and hepatitis C virus (HCV) promote the development of liver tumors. CRI scientists have been studying liver cancer for more than three decades. In recent years, funding has gone to scientists who are working to understand the inflammation that is known to cause liver cancer.

  • Gabriel A. Rabinovich, Ph.D., a CRI investigator from 2006-2010 at the University of Buenos Aires, Buenos Aires, Argentina, provided the first demonstration that galectin-1, a protein expressed by various normal and pathological tissues and that is thought to be a master regulator of certain immune responses, plays a role in modulating cell adhesion and tumor growth in liver cancer, suggesting that it could be a promising target to prevent or slow liver cancer progression.
  • Paul Klenerman, M.D., Ph.D., a 2014-2016 Clinic and Laboratory Integration Program (CLIP) grantee and a professor at the University of Oxford, United Kingdom, is studying a novel set of immune cells called mucosal-associated invariant T (MAIT) cells and their association with inflammation as a cause of liver cancer. Klenerman proposes to investigate the ability of liver cancer to activate MAIT cells, as well as the ability of MAIT cells to recognize and kill liver cancer cells. The laboratory then aims to modulate the MAIT cells so that the recognition, targeting, and killing of liver cancer cells are improved. These studies will help us understand the mechanisms by which MAIT cells interact with liver tissue during cancer development, which could lead to the potential for an immunotherapy for liver cancer.
  • In 2013, Thomas Chia Ting Fung, a graduate student at the University of Pennsylvania School of Medicine, was awarded a STaRT grant to study the role of innate lymphoid cell-controlled intestinal barrier function in hepatocellular carcinoma. Liver cancers commonly develop as a result of long-term, chronic liver injury due to viral infection or alcoholism. Many studies indicate that individuals with chronic liver disease not only exhibit impaired liver function but also damage to the intestinal wall, which is associated with excessive inflammation caused by the translocation of beneficial intestinal bacteria to the liver. These conditions are believed to accelerate the development and progression of liver cancer from chronic liver disease. Fung’s goal is to investigate how the immune system regulates intestinal damage and translocation of harmless bacteria during chronic liver injury and liver cancer development. These studies may identify novel and therapeutic targets for the prevention or treatment of liver cancer aimed at reducing intestinal bacteria-driven inflammation.
  • More than 60% of adults in the United States are overweight or obese. Obesity is a risk factor for several cancers including and especially hepatocellular carcinoma (HCC), the dominant form of primary liver cancer. How immune homeostasis is maintained at a steady state in the liver and, more importantly, how such balance is breached by obesity remain poorly understood. Zhenyu Zhong, Ph.D., a 2014-2017 postdoctoral fellow at the University of California, San Diego, aims to identify the key regulator for maintaining immune homeostasis in the liver and delineating how obesity compromises immune homeostasis to drive inflammation and promote liver disease progression. This research will provide mechanistic insights into how obesity-induced liver damage and subsequent inflammation drive liver disease progression, and will likely promote the development of novel therapies for liver cancer.
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Liver Cancer Statistics

80% Are hepatocellular carcinoma (HCC)
17% Relative 5-year survival rate for liver cancer
4 Types of immunotherapy clinical trials
1st Cancer recognized as having a viral cause

Clinical Trials for Liver Cancer

Several approaches to immunotherapy for liver cancer have shown promise in early clinical trials. These treatments can be broken into 4 main categories: checkpoint inhibitors/immune modulators, monoclonal antibodies, adoptive cell transfer, and oncolytic virus therapy.

Therapies
  • Checkpoint Inhibitors/Immune Modulators
  • Monoclonal Antibodies
  • Adoptive Cell Therapy
  • Oncolytic Virus Therapies

A promising avenue of clinical research in liver cancer is the use of immune checkpoint inhibitors. These treatments work by targeting molecules that serve as checks and balances in the regulation of immune responses. By blocking inhibitory molecules or, alternatively, activating stimulatory molecules, these treatments are designed to unleash or enhance pre-existing anti-cancer immune responses. Several checkpoint inhibitors, targeting multiple different checkpoints, are currently in development.  These trials may not be available for patients who have past or present hepatitis due to viral infection.  This is because activation of the immune system in the presence of viral hepatitis may cause damage to normal liver cells.  

  • A phase III trial testing nivolumuab (Opdivo®) versus sorafenib (Nexavar®) as a first-line treatment for patients with advanced liver cancer (NCT02576509).
  • A phase I/II study testing nivolumab (Opdivo®) and/or ipilimumab (Yervoy®) in advanced liver cancer with or without chronic hepatitis (NCT01658878).
  • A phase I/II trial of nivolumab (Opdivo®) and galunisertib, a TGF-beta receptor 1 kinase inhibitor, in patients with advanced cancers, including liver cancer (NCT02423343).
  • Tremelimumab, an antibody targeting the CTLA-4 molecule, is being tested along with chemoembolization or ablation in a phase I clinical trial for patients with liver cancer (NCT01853618).
  • MEDI4736, a PD-L1-targeting antibody, and/or tremelimumab are being tested in a phase I/II trial for patients with unresectable liver cancers (NCT02519348).
  • A phase I trial of BMS-986016 (an anti-LAG-3 antibody) with or without nivolumab (Opdivo®) for patients with solid tumors, including liver cancer (NCT01968109).

Monoclonal antibodies (mAbs) are molecules, generated in the lab, that target specific antigens on tumors. Many antibodies are currently used in cancer treatment, and some appear to generate an immune response. Several antibodies are currently being tested in clinical trials:

  • A phase III trial testing ramucirumab (Cyramza®), an antibody targeting epidermal growth factor receptor (EGFR), a molecule that often appears in high amounts on the surface of cancer cells and helps them grow, in patients with liver cancer following first-line therapy with sorafenib (Nexavar®) (NCT02435433).
  • A phase I/II trial testing IMMU-132, an antibody-drug conjugate targeting Τrop-2, in patients with liver and other cancers, and without hepatitis B or C (NCT01631552).
  • A phase I/II trial of TRC105, a monoclonal antibody to CD105/endoglin, which is essential for angiogenesis, in patients with liver cancer (NCT01306058NCT02560779).

Another major avenue of immunotherapy for liver cancer is adoptive T cell transfer. In this approach, T cells are removed from a patient, genetically modified or treated with chemicals to enhance their activity, and then re-introduced into the patient with the goal of improving the immune system’s anti-cancer response.

  • A phase II trial taking enriched tumor-infiltrating immune cells and re-infusing them in patients with metastatic digestive tract cancers, including liver cancer without hepatitis B or C (NCT01174121).

Oncolytic virus therapy uses a modified virus that can cause tumor cells to self-destruct and generate a greater immune response against the cancer.

  • A phase III trial of pexastimogene devacirepvec (Pexa-Vec), a vaccina virus-based oncolytic immunotherapy designed to stimulate the immune system following infection and replication within tumor cells, followed by sorafenib (Nexavar®) in patients with advanced liver cancer who have not received prior systemic therapy (NCT02562755).

Go to our Clinical Trial Finder to find clinical trials of immunotherapies for liver cancer that are currently enrolling patients.

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Sources: ACS Facts and Figures 2016, Cancer.net, ClinicalTrials.gov, CRI documents

Updated March 2016

*Immunotherapy results may vary from patient to patient.

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