Immunotherapy for Liver Cancer Treatment

Your immune system comprises a wide network of white blood cells, organs and tissues. Under normal circumstances, it is able to recognize and destroy any components that are abnormal or foreign to the body, such as bacteria and viruses. This allows your immune system to protect you from all kinds of infections and diseases.

Your immune system is also capable of preventing or slowing cancer growth. However, sometimes, the immune response triggered against cancer cells may not be strong enough to kill them. Cancer cells also have the ability to evade your immune system in various ways. This includes:

• Developing mutations that make them less recognizable to your immune system
• Having proteins on the surface of their cells that deactivate immune cells and prevent your immune system from attacking them
• Altering surrounding healthy cells so that they interfere with your immune response to the cancer cells

Immunotherapy is a type of cancer treatment that aims to overcome these problems. It works by boosting the ability of your immune system to identify and attack cancer cells, thereby strengthening your body’s immune response to cancer.

To prevent itself from attacking normal and healthy cells in the body, your immune system uses immune checkpoint proteins found on the surface of immune cells. When immune checkpoint proteins attach to partner proteins on other cells, this interaction sends an ‘off’ signal to the immune cells and switches off the immune response, ensuring that healthy cells are not altered.

Some cancer cells are able to use these checkpoints to avoid detection and attack from immune cells. Immune checkpoint inhibitors (ICIs) are a class of drugs that are able to target checkpoint proteins and trigger an immune response towards cancer cells. There are two types of ICIs currently used in liver cancer immunotherapy: PD-1/PD-L1 inhibitors and CTLA-4 inhibitors.

PD-1/PD-L1 inhibitors

Some liver cancer cells produce a protein called programmed death-ligand 1 (PD-L1) on the surface of their cells. PD-L1 attaches to another molecule called programmed cell death protein 1 (PD-1) found on the surface of immune cells called T cells. This interaction signals the T cells not to kill the cancer cells, thereby suppressing the immune response.

ICIs targeting either PD-1 or PD-L1 counteract that process by preventing the interaction between the two proteins, enabling the T cells to kill the liver cancer cells and thus shrinking the tumor or slowing cancer growth.

Two ICIs targeting PD-L1 are:

• Atezolizumab: This ICI is typically used together with bevacizumab (a targeted drug) as first-line treatment for liver cancers that cannot be treated with surgery or have spread to other bodily organs
• Durvalumab: This ICI can be used together with another immunotherapy drug, tremelimumab (see below), as first-line treatment for liver cancers that cannot be treated with surgery (unresectable)

Both atezolizumab and durvalumab are given as an infusion into your vein (intravenous), usually once every two to four weeks. However, atezolizumab can also be administered as an injection under your skin (subcutaneous).

Meanwhile, two ICIs targeting PD-1 are:

• Pembrolizumab: This drug can be used on its own for people with liver cancer who are unable to take sorafenib (a targeted drug) or whose cancer has progressed despite treatment with it, and
• Nivolumab: This ICI is typically used together with another immunotherapy drug called ipilimumab (see below) for liver cancers that have been treated previously (with other therapies)

These PD-1 inhibitors are administered every two to six weeks as an intravenous infusion.

CTLA-4 inhibitors

Cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) is a protein found on the surface of T cells. When bound to another protein called B7, it prevents the T cells from destroying other cells. In normal circumstances, this interaction helps keep the T cells in check. However, in the context of cancer, it prevents the T cells from attacking the cancer cells, thereby suppressing the body’s immune response. CTLA-4 inhibitors that block CTLA-4 can therefore keep the protein from limiting the immune response, increasing the ability of T cells to kill cancer cells.

Two FDA-approved CTLA-4 inhibitors used in immunotherapy for liver cancer are:

• Ipilimumab: This inhibitor can be used together with nivolumab (see above) to treat liver cancers that have been treated previously (with other therapies)
• Tremelimumab: This drug can be used in conjunction with durvalumab (see above) as a first-line treatment for liver cancers that cannot be removed surgically

Both ipilimumab and tremelimumab are given as intravenous infusion, but the duration of treatment varies. Ipilimumab is usually administered once every three weeks, while tremelimumab is given once every four weeks.

Many other cancer immunotherapies are being tested in clinical trials, including those studying potential ICIs, combination therapies and the use of oncolytic viruses and adoptive cell therapy.

Like other types of cancer treatment, immunotherapy for liver cancer also comes with its share of side effects, including:

• Fatigue or weakness
• Fever
• Cough
• Nausea
• Constipation or diarrhea
• Skin problems, like rashes or itching
• Loss of appetite
• Muscle or joint pain

Other side effects that are rarer but more severe are:

• Infusion reactions: These occur during administration of the immunotherapeutics and are similar to allergic reactions. They are characterized by fever, chills, flushing of the face, rashes, itchy skin, dizziness, wheezing and breathing difficulties.
• Autoimmune reactions: Immunotherapeutics work by removing natural checks on the body’s immune system. For that reason, your immune system may start attacking other cells in the body in some instances. This can lead to serious or life-threatening problems in the lungs, intestines, liver, kidneys and other organs. In the event of autoimmune reactions, you may need to cease treatment and be treated with immunosuppressive drugs.

Your doctor(s) will usually provide you with medication to manage some of the more common side effects. But if these problems grow more severe or if they do not resolve, do inform your healthcare providers.

Liver cancer can be challenging to treat with immunotherapy because of its unique microenvironment that is designed to tolerate benign substances like food and microbes. This tolerance, however, also extends to cancer cells, which in turn supports tumor growth and makes it more difficult to attack the tumor effectively. On top of that, the interaction between cancer cells and certain immune cells, such as macrophages and neutrophils, in the liver can trigger immune-suppressing mechanisms. This can inhibit the efficacy of current therapies, like ICIs, and thereby complicate immunotherapy. Furthermore, response to ICIs is limited to 20–30% of patients, and currently, no biomarker has been validated for the prediction of immunotherapy.

Scientists are studying how to overcome this challenge by boosting the body’s immune response against liver cancer. Prospective strategies include:

• Combining immunotherapy with other treatment types
• Targeting specific immune cells within the liver microenvironment
• Modifying the liver microenvironment to reduce immune suppression
• Developing new agents that can bypass or counteract the inhibitory mechanisms in the liver

While these approaches hold promise for improving outcomes in liver cancer treatment, it is important that they strike a balance between enhancing anti-cancer immunity and maintaining the liver’s critical functions.

Your doctors will take into account several factors when deciding whether you should receive immunotherapy as part of your treatment plan. These include the type of liver cancer you have, the cancer stage and other factors, like your overall health. In general, immunotherapy is used to treat advanced or unresectable liver cancer, but success rates vary. While it may not be able to cure the cancer, immunotherapeutics can help control tumor growth, slow cancer progression and alleviate any symptoms.

However, keep in mind that it may not be suitable for those with a history of hepatitis infection or other liver damage. This is because of the immune system activity involved, which could potentially damage healthy, functioning liver tissue.

If you have any questions regarding cancer immunotherapies, please consult your doctors and cancer care team for support and resources.