Immunotherapy for Melanoma Skin Cancer

Immunotherapy is the use of medicines to help a person’s own immune system recognize and destroy cancer cells more effectively. Several types of immunotherapy can be used to treat melanoma.

Immune checkpoint inhibitors

An important part of the immune system is its ability to keep itself from attacking normal cells in the body. To do this, it uses “checkpoints,” which are proteins on immune cells that need to be turned on (or off) to start an immune response. Melanoma cells sometimes use these checkpoints to avoid being attacked by the immune system. But these drugs target the checkpoint proteins, helping to restore the immune response against melanoma cells.

PD-1 inhibitors

Pembrolizumab (Keytruda) and nivolumab (Opdivo) are drugs that target PD-1, a protein on immune system cells called T cells that normally help keep these cells from attacking other cells in the body. By blocking PD-1, these drugs boost the immune response against melanoma cells. This can often shrink tumors and help people live longer.

They can be used to treat melanomas:

• That can’t be removed by surgery
• That have spread to other parts of the body
• After surgery (as adjuvant treatment) for certain stage II or III melanomas to try to lower the risk of the cancer coming back

These drugs are given as an intravenous (IV) infusion, typically every 2 to 6 weeks, depending on the drug and why it's being given. 

PD-L1 inhibitor

Atezolizumab (Tecentriq) is a drug that targets PD-L1, a protein related to PD-1 that is found on some tumor cells and immune cells. Blocking this protein can help boost the immune response against melanoma cells.

This drug can be used along with cobimetinib and vemurafenib in people with melanoma that has the BRAF gene mutation, when the cancer can’t be removed by surgery or has spread to other parts of the body.

This drug is given as an intravenous (IV) infusion every 2 to 4 weeks.

CTLA-4 inhibitor

Ipilimumab (Yervoy) is another drug that boosts the immune response, but it has a different target. It blocks CTLA-4, another protein on T cells that normally helps keep them in check.

It can be used to treat melanomas that can’t be removed by surgery or that have spread to other parts of the body. It might also be used for less advanced melanomas after surgery (as an adjuvant treatment) in some situations, to try to lower the risk of the cancer coming back.

When used alone, this drug doesn’t seem to shrink as many tumors as the PD-1 inhibitors, and it tends to have more serious side effects, so usually one of those other drugs is used first. Another option in some situations might be to combine this drug with one of the PD-1 inhibitors. This can increase the chance of shrinking the tumors (slightly more than a PD-1 inhibitor alone), but it can also increase the risk of side effects.

This drug is given as an intravenous (IV) infusion, usually once every 3 weeks for 4 treatments (although it may be given for longer when used as an adjuvant treatment). 

LAG-3 inhibitor

Relatlimab targets LAG-3, another checkpoint protein on certain immune cells that normally helps keep the immune system in check.

This drug is given along with the PD-1 inhibitor nivolumab (in a combination known as Opdualag). It can be used to treat melanomas that can’t be removed by surgery or that have spread to other parts of the body. 

This drug is given as an intravenous (IV) infusion, typically once every 4 weeks.

Possible side effects of immune checkpoint inhibitors

Some of the more common side effects of these drugs can include fatigue, cough, nausea, skin rash, poor appetite, constipation, joint pain, and diarrhea.

Other, more serious side effects occur less often.

Infusion reactions: Some people might have an infusion reaction while getting these drugs. This is like an allergic reaction, and can include fever, chills, flushing of the face, rash, itchy skin, feeling dizzy, wheezing, and trouble breathing. It’s important to tell your doctor or nurse right away if you have any of these symptoms while getting these drugs.

Autoimmune reactions: These drugs remove one of the safeguards on the body's immune system. Sometimes the immune system responds by attacking other parts of the body, which can cause serious or even life-threatening problems in the lungs, intestines, liver, hormone-making glands, kidneys, or other organs.

It’s very important to report any new side effects to someone on your health care team as soon as possible. If serious side effects do occur, treatment may need to be stopped and you might be given high doses of corticosteroids to suppress your immune system.

Interleukin-2 (IL-2)

Interleukins are proteins that certain cells in the body make to boost the immune system in a general way. Lab-made versions of interleukin-2 (IL-2) are sometimes used to treat melanoma. They are given as intravenous (IV) infusions, at least at first. Some patients or caregivers may be able to learn how to give injections under the skin at home.

For advanced melanomas: IL-2 can sometimes shrink advanced melanomas when used alone. It is not used as much as in the past, because the immune checkpoint inhibitors are more likely to help people and tend to have fewer side effects. But IL-2 might be an option if these drugs are no longer working.

Side effects of IL-2 can include flu-like symptoms such as fever, chills, aches, severe tiredness, drowsiness, and low blood cell counts. In high doses, IL-2 can cause fluid to build up in the body so that the person swells up and can feel quite sick. Because of this and other possible serious side effects, high-dose IL-2 is given only in the hospital, in centers that have experience with this type of treatment.

For some earlier-stage melanomas: Melanomas that have reached the nearby lymph nodes are more likely to come back in another part of the body, even if all of the cancer is thought to have been removed. IL-2 can sometimes be injected into the tumors (known as intralesional therapy) to try to prevent this. Side effects are similar but tend to be milder when IL-2 is injected directly into the tumor.

When deciding whether to use IL-2, patients and their doctors need to take into account the potential benefits and side effects of this treatment.

Oncolytic virus therapy

Viruses are a type of germ that can infect and kill cells. Some viruses can be altered in the lab so that they infect and kill mainly cancer cells. These are known as oncolytic viruses. Along with killing the cells directly, the viruses can also alert the immune system to attack the cancer cells.

Talimogene laherparepvec (Imlygic), also known as T-VEC, is an oncolytic virus that can be used to treat melanomas in the skin or lymph nodes that can’t be removed with surgery. The virus is injected directly into the tumors, typically every 2 weeks. This treatment can sometimes shrink these tumors, and might also shrink tumors in other parts of the body.

Side effects can include flu-like symptoms and pain at the injection site.

Bacille Calmette-Guerin (BCG) vaccine

BCG is a germ related to the one that causes tuberculosis. BCG doesn’t cause serious disease in humans, but it does activate the immune system. The BCG vaccine can be used to help treat stage III melanomas by injecting it directly into tumors, although it isn't used very often.

Imiquimod cream

Imiquimod (Zyclara) is a drug that is put on the skin as a cream. It stimulates a local immune response against skin cancer cells. For very early (stage 0) melanomas in sensitive areas on the face, some doctors may use imiquimod if surgery might be disfiguring. It might also be an option for some melanomas that have spread along the skin.

The cream is usually applied 2 to 5 times a week for around 3 months. Some people have serious skin reactions to this drug. Imiquimod is not used for more advanced melanomas.

Newer treatments

Some other types of immunotherapy have shown promise in treating melanoma in early studies. Other studies are now looking at combining different types of immunotherapy to see if it might help them work better. (See What’s New in Melanoma Skin Cancer Research?)