Leaders in Pharmaceutical Business Intelligence (LPBI) Group

Immunotherapy in Cancer

Larry H. Bernstein, MD, FCAP, Curator

LPBI

Liver Cancer

Jonathan S. Cebon, Ph.D., FRACP
Austin Health/Ludwig Cancer Research, Melbourne, Australia

http://www.cancerresearch.org/cancer-immunotherapy/impacting-all-cancers/liver-cancer#sthash.E1y4Wv0P.dpuf

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 2014, there will be roughly 33,190 new cases of primary liver cancer in the U.S., and 23,000 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.

When diagnosed early, liver cancer can be treated successfully with surgery—provided the tumor is small and has not spread beyond the liver. In some cases, a liver transplant may also be an option, but liver donors are rare and the waitlist can be long. Few treatment options exist for patients with advanced liver cancer. There is one targeted therapy, sorafenib (Nexavar^®), FDA approved for the treatment of patients with HCC for whom surgery is not an option. Nexavar works by inhibiting the growth of new blood vessels in the tumor, thereby starving it of nutrients, as well as by inhibiting growth signaling pathways in the cancer cells.

The overall 5-year relative survival rate for patients with liver cancer is 16%. Less than half of patients with liver cancer are diagnosed at an early stage, when the 5-year survival is 29%. For patients with regional and metastatic disease, survival rates drop to 10% and 3%, respectively. Better therapies to treat liver cancer are badly needed.

IMMUNOTHERAPY FOR LIVER CANCER

Several approaches to immunotherapy for liver cancer have shown promise in early clinical trials. These treatments can be broken into 6 main categories: checkpoint inhibitors/immune modulators, therapeutic vaccines, adoptive T cell transfer, monoclonal antibodies, cytokines, and oncolytic virus therapy.

Checkpoint Inhibitors / Immune Modulators

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.

• Tremelimumab, an antibody targeting the CTLA-4 molecule, and being developed by MedImmune/AstraZeneca, 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 made by MedImmune/AstraZeneca, is being tested in a phase I/II trial for patients with advanced solid tumors (NCT01693562).
• Pembrolizumab (Keytruda®, MK-3475) is an anti-PD-1 antibody being developed by Merck that is in a phase I trial for patients with advanced, biomarker-positive solid tumors without hepatitis B or C (NCT02054806).
• MPDL3280A, an anti-PD-L1 antibody being developed by Roche/Genentech, is being tested in numerous cancers in a phase I trial in patients without hepatitis B or C (NCT01375842).
• A phase I trial of MPDL3280A in combination with bevacizumab (Avastin) or chemotherapy is enrolling patients with advanced cancer without a history of hepatitis C infection; history of hepatitis B is allowed if infection has resolved (NCT01633970).
• Urelumab (BMS-663513, anti-4-1BB/CD137), made by Bristol-Myers Squibb, is being tested in a phase I trial in patients with advanced cancers without hepatitis B or C infection (NCT01471210).
• PF-05082566 is an anti-4-1BB/CD137 antibody developed by Pfizer that is being tested in a phase I trial for patients with solid tumors (NCT01307267).

Combination checkpoint trials include:

• A phase I study of lirilumab (anti-KIR antibody; Bristol-Myers Squibb) in combination with nivolumab (anti-PD-1 antibody; BMS) in patients with advanced solid tumors (NCT01714739).
• A phase I trial of ipilimumab (Yervoy®), an anti-CTLA-4 antibody, plus Gleevec (imatinib mesylate), a c-Kit inhibitor, for patients with advanced cancer without hepatitis B or C (NCT01738139).
• A phase I trial of BMS-986016 (an anti-LAG-3 antibody) with or without nivolumab (Opdivo®) for patients with solid tumors (NCT01968109).

Therapeutic Vaccines

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. Several trials of vaccines, given alone or with other therapies, are currently enrolling patients:

•  A phase II trial of a vaccine that targets the NY-ESO-1 protein in patients with advanced cancer whose cancers express NY-ESO-1, without hepatitis B or C with evidence of ongoing liver damage (NCT01697527).
• A phase I/II trial of DCVax in patients with solid tumors, including liver cancer (NCT01882946).
• A phase I trial of a vaccine (FANG) that blocks furin protein production, plus GM-CSF, for advanced cancer (NCT01061840).
• A phase I trial of NY-ESO-1 fusion protein vaccine in patients with advanced cancer whose cancers express NY-ESO-1 and without hepatitis B or C (NCT01522820).
• A phase I trial testing a tumor cell vaccine and the adjuvant ISCOMATRIX with chemotherapy in patients with advanced cancer after tumor removal and without hepatitis B or C (NCT01341496).

Adoptive T Cell Therapy

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. Several trials of adoptive T cell transfer techniques are currently under way for patients with liver cancer, including:

• 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).
• A phase II study of T cells genetically reengineered to target the NY-ESO-1 antigen in patients with NY-ESO-1-positive cancers and without hepatitis B or C (NCT01967823).
• A phase I/II trial of T cells genetically reengineered to target the anti-MAGE-A3-DP4 protein in advanced cancer and without hepatitis B or C (NCT02111850).
• A phase I/II study of chimeric antigen receptor (CAR) T cells which are designed to target VEGFR2 and without hepatitis B or C (NCT01218867).

Monoclonal Antibodies

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

• 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 (NCT01306058).
• A phase I trial of ontuxizumab (MORAb-004), an antibody targeting endosialin/TEM1, in young patients with solid tumors and without hepatitis B or C (NCT01748721).
• A phase I trial of OMP-52M51, anti-Notch-1 monoclonal antibody, in patients with solid tumors (NCT01778439).
• A phase I trial of ABT-700, an anti-C-met antibody, in patients with solid tumors (NCT01472016).
• A phase I trial of MM-151, an antibody designed to bind and inhibit signaling from EGFR, in patients with solid tumors (NCT01520389).
• A phase I trial of CEP-37250/KHK2804, an antibody targeting glycolipids, in patients with advanced solid tumors (NCT01447732).

Cytokines

Cytokines are messenger molecules that help control the growth and activity of immune system cells.

• A phase I trial testing interleukin 15 (IL-15) in patients with advanced cancer, without hepatitis B or C (NCT01572493).
• A phase I trial to test interleukin 12 (IL-12) in patients with solid tumors, without hepatitis B or C infection (NCT01417546).

Oncolytic Virus Therapy

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 I trial of rRp450, a Herpes simplex virus 1 (HSV) specially altered to target and kill cancer cells, in patients with liver tumors and liver metastases and without hepatitis C infection or chronic infection with hepatitis B (NCT01071941).

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

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.

Sources: ACS Facts and Figures 2014, Cancer.net, ClinicalTrials.gov, CRI documents

http://www.cancerresearch.org/cancer-immunotherapy/impacting-all-cancers/liver-cancer#sthash.E1y4Wv0P.dpuf