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 “checkpoint” proteins on immune cells, which act like switches 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 drugs that target checkpoint proteins, called checkpoint inhibitors, can help the immune system find and attack 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 helps keep these cells from attacking other cells in the body. By blocking PD-1, these drugs boost the immune response against melanoma cells.

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, III, or IV melanomas that have been removed completely, 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 the targeted drugs 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 can be given as an intravenous (IV) infusion, typically every 2 to 4 weeks. It can also be given (as Tecentriq Hybreza) as an injection under the skin (subcutaneously) over several minutes, typically once every 3 weeks.

CTLA-4 inhibitor

Ipilimumab (Yervoy) is another checkpoint inhibitor, 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 is less likely to shrink tumors than the PD-1 inhibitors, and it tends to have more serious side effects, so usually one of those other drugs is tried first. Another option is to combine ipilimumab 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), such as aldesleukin, are sometimes used to treat melanoma.

For advanced melanomas: IL-2 in high doses 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.

When treating advanced melanoma, IL-2 is 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.

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 help lower this risk. Side effects tend to be milder when IL-2 is injected directly into the tumor.

When deciding whether to use IL-2, it’s important to consider the potential benefits and side effects of this treatment. Because of the risk of serious side effects, high-dose IL-2 is not usually a good option for people who have other serious health problems.

Tumor-infiltrating lymphocyte (TIL) therapy

TILs are immune system cells called T cells that have entered (infiltrated) a tumor to attack the cancer cells. Treatments that use these cells can help shrink some melanomas. This type of treatment is also known as tumor-derived autologous T cell immunotherapy.

Lifileucel (Amtagvi) is a type of TIL therapy that can be used to treat people with advanced melanomas, after other treatments have been tried.

For this treatment, a melanoma tumor is removed with surgery and is sent to a lab, where the TILs are separated out and then multiplied over a few weeks. They are then sent back to be given to the person as an infusion into a vein (IV). Once in the body, the TILs seek out and attack the melanoma cells.

People getting this treatment are first given chemotherapy for about a week to help the body accept the TILs. After getting the TILs, the person is also given IL-2 (see above), which helps these immune cells attack the cancer.

This treatment can cause serious or even life-threatening side effects, so it needs to be given in a hospital. Serious side effects can include:

• Very low blood cell counts, which can increase the risk of serious bleeding and infections
• Internal bleeding
• Serious infections
• Heart problems
• Lung problems
• Kidney problems
• Infusion reactions

Other side effects are also possible, including fever, chills, feeling very tired, skin rash, low blood pressure, and diarrhea.

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 it 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 vaccine that contains 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 anymore.

Imiquimod cream

Imiquimod (Zyclara) is a topical 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 isn’t able to remove all of the tumor.

Imiquimod might also be an option to treat some melanomas that have spread along the skin, especially if surgery can’t be done for some reason.

The cream is usually applied 2 to 5 times a week for around 3 months. Some people have serious skin reactions to this drug, and some might develop flu-like symptoms during treatment.

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. To learn more, see What’s New in Melanoma Skin Cancer Research?