For Liver Cancer

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

Reviewed by:

Ignacio Melero, MD, PhD
Foundation for Applied Medical Research (FIMA, Spain)

Immunotherapy for liver cancer can enhance cancer-fighting immune system responses, but may not always be available or viable for patients with a history of hepatitis infection.

The liver performs many vital functions involved in detoxification, drug processing, and metabolism of fat and sugars. Cancers of the liver often spread to other organs, such as the breasts or lungs. Approximately 80% of liver cancers start in a type of liver cell called the hepatocytes. The majority of other liver cancers arise from cells of the bile ducts. Types of liver cancer include:

  • Hepatocellular carcinoma (HCC)
  • Cholangiocarcinoma (bile duct cancer)
  • Hepatoblastoma, the most common type of childhood liver cancer

A major cause of liver cancer is the hepatitis virus, which is responsible for roughly 80% of all cases. Inflammation in liver, resulting from untreated hepatitis B and hepatitis C, can lead to scarring (cirrhosis). As the liver attempts to repair and replace the damaged tissue, there is a greater chance for error in DNA replication, which can lead to cancer.

Fortunately, it is possible to prevent hepatitis via vaccination; the hepatitis B vaccine (below) was the first preventive cancer vaccine developed (in 1982). While there is currently no vaccine to prevent hepatitis C virus (HCV) infection, there are direct-acting antivirals that seem to be effective at reducing the incidence of liver cancer.

Preventive Vaccine

  • Hepatitis B (HBV) vaccine (HEPLISAV-B®): a preventive cancer vaccine that protects against infection by the hepatitis B virus; can help prevent the development of HBV-related liver cancer

Other risk factors for liver cancer include alcohol-related cirrhosis, obesity, and diabetes.

More men than women are diagnosed with liver cancer, although rates of liver cancer appear to be on the rise in both. Globally, in 2018, there were an estimated 840,000 new cases of liver cancer along with 780,000 deaths. In the United States alone, 41,000 people new cases of liver cancer will be diagnosed in 2023, and roughly 29,000 will die from the disease. 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. 

Since the human body cannot survive without a functioning liver, this cancer presents an urgent need for more effective treatments.

Liver Cancer Treatment Options

Standard liver cancer treatments include surveillance, surgery, liver transplant, ablation therapy, embolization therapy, targeted therapy, and radiation therapy. For advanced HCC, the standard of care is the immunotherapy combination of the checkpoint inhibitor atezolizumab and the targeted antibody bevacizumab.

Immunotherapy is class of treatments that take advantage of a person’s own immune system to help kill cancer cells. There are currently six FDA-approved immunotherapy options for liver cancer.


  • Atezolizumab (Tecentriq®): a checkpoint inhibitor that targets the PD-L1 pathway; approved, in combination with bevacizumab, as a first-line treatment for subsets of patients with advanced liver cancer
  • Dostarlimab (Jemperli): a checkpoint inhibitor that targets the PD-1/PD-L1 pathway; approved for subsets of patients with advanced liver cancer that has DNA mismatch repair deficiency (dMMR)
  • Ipilimumab (Yervoy®): a checkpoint inhibitor that targets the CTLA-4 pathway; approved, in combination with nivolumab, for patients with advanced, previously treated liver cancer
  • Nivolumab (Opdivo®): a checkpoint inhibitor that targets the PD-1/PD-L1 pathway; approved for subsets of patients with advanced liver cancer, including in combination with ipilimumab
  • Pembrolizumab (Keytruda®): a checkpoint inhibitor that targets the PD-1/PD-L1 pathway; approved for subsets of patients with advanced liver cancer, including those with high microsatellite instability (MSI-H), DNA mismatch repair deficiency (dMMR), or high tumor mutational burden (TMB-H)

Targeted Antibodies

  • Bevacizumab (Avastin®): a targeted antibody that targets the VEGF-A pathway; approved, in combination with atezolizumab, as a first-line treatment for subsets of patients with advanced liver cancer

Immunotherapy treatments can enhance cancer-fighting immune system responses, but may not always be available or viable for patients with a history of hepatitis infection, as this type of immune system activity can damage normal, functioning liver cells.

Several other immunotherapies are currently being tested in clinical trials, including oncolytic viruses and adoptive cell therapy.

CRI’s Impact in Liver Cancer

At the Cancer Research Institute, we’re dedicated to supporting scientific research for liver cancer, working to advance immunotherapy as a viable treatment for people affected by this disease. The scientists we fund have studied liver cancer—and the chronic inflammation from hepatitis B and hepatitis C viruses that causes it—for more than 30 years.

  • Gabriel A. Rabinovich, PhD, a CRI investigator from 2006-2010 at the University of Buenos Aires, Buenos Aires, Argentina, provided the first demonstration that galectin-1 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, MD, PhD, a Clinic and Laboratory Integration Program (CLIP) grantee from 2014-2016 and a professor at the University of Oxford, United Kingdom, studied a novel set of immune cells called mucosal-associated invariant T (MAIT) cells and their association with inflammation as a cause of 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.
  • Zhenyu Zhong, PhD, a postdoctoral fellow at the University of California, San Diego from 2014-2017, identified a key regulator of liver inflammation that appears to play a role in obesity-associated liver cancer. He also developed a strategy capable of preventing this cancer-promoting inflammation in mice.
  • The CRI Anna-Maria Kellen Clinical Accelerator is funding a clinical study that seeks to determine the effectiveness of combining the CTLA-4 inhibitor tremelimumab with the PD-L1 inhibitor durvalumab in patients diagnosed with various advanced solid tumors who have failed standard therapy.

Explore CRI’s current funding for liver cancer research in our funding directory.

Related Links

Liver Cancer Statistics

840K Newly diagnosed patients each year globally

17% Relative 5-year survival rate for liver cancer

1st Cancer recognized as having a viral cause

Liver Cancer Clinical Trial Targets

Discover the different proteins, pathways, and platforms that scientists and physicians are pursuing to develop new cancer treatments. Use this information to consider your clinical trial options.

Targeted antibodies are proteins produced by the immune system that can be customized to target specific markers on cancer cells in order to disrupt cancerous activity, especially unrestrained growth. Antibody-drug conjugates (ADCs) are equipped with anti-cancer drugs that they can deliver to tumors. Bi-specific T cell-engaging antibodies (BiTEs) bind both cancer cells and T cells in order to help the immune system respond more quickly and effectively. Antibody targets under evaluation in liver cancer clinical trials include:

  • cMET: a growth-related pathway that is often abnormally activated in cancer
  • DLL/Notch: a pathway that can promote cell growth
  • EGFR: a pathway that controls cell growth and is often mutated in cancer
  • FGF/FGF-R: a pathway that controls cell growth, death, and migration
  • HER2: a pathway that controls cell growth and is commonly overexpressed in cancer and  associated with metastasis
  • Mesothelin: a protein that’s commonly overexpressed in cancer and may aid metastasis
  • TROP2: a protein that’s commonly overexpressed in cancer and appears to aid  cancer cell self-renewal, proliferation, invasion, and survival
  • VEGF/VEGF-R: a pathway that can promote blood vessel formation in tumors

Cancer vaccines are designed to elicit an immune response against tumor-specific or tumor-associated antigens, encouraging the immune system to attack cancer cells bearing these antigens. Cancer vaccines can be made from a variety of components, including cells, proteins, DNA, viruses, bacteria, and small molecules. Cancer vaccine targets under evaluation in liver cancer clinical trials include:

  • P53: a tumor suppressor protein that is often mutated, nonfunctional, and overexpressed in cancer
  • Telomerase: an enzyme that helps maintain the health of cellular DNA; exploited by cancer cells to achieve immortality
  • Tumor-associated antigens (TAAs): proteins often expressed at abnormally high levels on tumor cells that can be used to target them; also found on normal cells at lower levels

Adoptive cell therapy takes a patient’s own immune cells, expands or otherwise modifies them, and then reintroduces them to the patient, where they can seek out and eliminate cancer cells. In CAR T cell therapy, T cells are modified and equipped with chimeric antigen receptors (CARs) that enable superior anti-cancer activity. Natural killer cells (NKs) and tumor infiltrating lymphocytes (TILs) can also be enhanced and reinfused in patients. Cell-based immunotherapy targets under evaluation in liver cancer clinical trials include:

  • GPC3: a cell surface protein thought to be involved in regulating growth and cell division
  • Mesothelin: a protein that’s commonly overexpressed in cancer and may aid metastasis
  • NY-ESO-1: a protein that’s normally produced only before birth, but is often abnormally expressed in cancer

Immunomodulators manipulate the “brakes” and “gas pedals” of the immune system. Checkpoint inhibitors target molecules on immune cells to unleash new or enhance existing immune responses against cancer. Cytokines regulate immune cell maturation, growth, and responsiveness. Adjuvants can stimulate pathways to provide longer protection or produce more antibodies. Immunomodulator targets under evaluation in liver cancer clinical trials include:

  • CD40: activating this co-stimulatory pathway can kick-start adaptive immune responses
  • CD137 (also known as 4-1BB): activating this co-stimulatory pathway can help promote the growth, survival, and activity of cancer-fighting T cells
  • CTLA-4: blocking this pathway can help promote expansion and diversification of cancer-fighting T cells
  • GITR: activating this pathway can help prevent immunosuppression and increase the survival of cancer-fighting T cells
  • IDO: blocking this enzyme’s activity can help prevent cancer-fighting T cells from being suppressed
  • OX40: activating this co-stimulatory pathway can help promote T cell survival after activation
  • PD-1/PD-L1: blocking this pathway can help prevent cancer-fighting T cells from becoming “exhausted,” and can restore the activity of already-exhausted T cells
  • STAT3: activating this intracellular signaling protein can help stimulate adaptive immune responses
  • Toll-like receptors (TLRs): activation of these innate immune receptors can help stimulate vaccine-like responses against tumors

Oncolytic virus therapy uses viruses that are often, but not always, modified in order to infect tumor cells and cause them to self-destruct. This can attract the attention of immune cells to eliminate the main tumor and potentially other tumors throughout the body. Viral platforms under evaluation in liver cancer clinical trials include:

  • Adenovirus: a family of common viruses that can cause a wide range of typically mild effects including sore throat, fatigue, and cold-like symptoms
  • Herpes simplex virus: a virus that can cause the formation of sores on the mouth and genitals
  • Vaccinia virus: the virus that was used to help vaccinate against and eliminate smallpox; rarely causes illness in humans and is associated with a rash covering the body

Find an Immunotherapy Clinical Trial

Create a profile and fill out a questionnaire to identify immunotherapy clinical trials for which you may be eligible.

Need more information? Learn more about clinical trials.

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