Immunotherapy for melanoma, explained

Melanoma is one of the deadliest forms of skin cancer. This is primarily because it spreads more aggressively than other skin cancers. Although melanomas only account for 1% of skin cancers, they are responsible for a high number of cancer deaths.

Because melanoma can grow so quickly, it is difficult to treat it effectively once it has spread to the lymph nodes or other organs throughout the body.

Early-stage melanomas are usually treated with surgery to remove the cancer cells. However, treatment for advanced cases of melanoma may include immunotherapy, a treatment that activates your immune system to fight the cancer cells.

Here’s what you need to know about immunotherapy for melanoma.

How immunotherapy affects the immune system

Immunotherapy helps the body’s immune system better recognize and fight off cancer cells. Immunotherapy can work on melanoma in several ways:

By strengthening the overall function of the immune system to destroy cancer cells
By specifically attacking certain types of cancer and immune cells, called immune checkpoint inhibitors
With cell therapy in which the patient’s own tumor cells are used to boost the immune system
With viral therapy, in which viruses modified in the laboratory are used to attack cancer cells

Here’s a closer look at each type of immunotherapy for melanoma.

General immunotherapy

In theory, the body’s immune system can recognize and attack cancer cells to prevent them from growing. But sometimes cancer cells can grow too quickly for the immune system to keep up, or the cells can even hide from or attack the immune system. General immunotherapy uses medications that can help improve the overall function of the immune system. For example, interleukins are proteins that can strengthen the immune system so that it can better recognize and attack melanoma cells. Melanoma treatment uses laboratory-made versions of the protein interleukin-2 (IL-2).

IL-2s are no longer used as widely as they once were because they can have serious side effects and usually don’t work as well as immune checkpoint inhibitors.

Immune checkpoint inhibitors

Immune checkpoint inhibitors (ICIs) are a targeted form of immunotherapy. A key way immunotherapy works for melanoma is to “turn off” certain proteins in immune cells that prevent the cells from attacking the cancer.

In a healthy person, the immune system has built-in “checkpoints” that prevent immune cells from destroying healthy cells. Unfortunately, melanoma cells use these checkpoints against the body and can bind to them, allowing cancer to grow. Immune checkpoint inhibitors are drugs that “turn off” these specific checkpoints, allowing immune cells to recognize the melanoma and work to destroy it.

PD-1 inhibitors: PD-1 inhibitors target an immune cell protein called PD-1. PD-1s normally function to prevent immune cells from destroying other cells. Blocking PD-1 releases these immune cells to better fight cancerous melanoma cells. PD-1 inhibitors are called pembrolizumab (brand name: Keytruda) and nivolumab (brand name: Opdivo) and are given as IV infusions. They can only be used for melanomas that have spread and cannot be removed surgically. They can also be used as secondary treatment (called adjuvant) and preventive treatment to reduce the risk of the cancer coming back.
PD-L1 inhibitors: PD-L1 inhibitors, atezolizumab (brand name: Tecentriq), work in the same way by blocking the PD-L1 protein on immune cells, which normally prevents the cells from attacking. This type of immunotherapy can be used specifically in people who have metastatic melanoma with the BRAF gene mutation. It can be administered intravenously or by injection.
CLTA-4 inhibitors: This type of checkpoint inhibitor targets the CTLA-4 proteins that are found on T cells in the immune system. When used alone, CLTA-4 inhibitors are less effective and have more serious side effects than other immunotherapy drugs, but can be given with a PD-1 inhibitor. Ipilimumab (brand name: Yervoy) is given as an intravenous infusion.
LAG-3 inhibitors: LAG-3 inhibitors (called relatlimab) block the LAG-3 checkpoint protein. Relatlimab is typically given as an infusion in combination with a PD-1 inhibitor called nivolumab. (Together, relatlimab and nivolumab have the brand name Opdualag.)

Checkpoint inhibitors are a promising development in melanoma treatment. Before treatment with ICIs, the average survival rate for advanced melanoma was only six months. However, survival rates are now well above the six-month rate.

Therapy with tumor infiltrating lymphocytes (TIL).

T cells are a special type of immune cell that the body uses to fight cancer. When they invade a tumor, they are called tumor-infiltrating lymphocytes (TILs). TIL therapy is a newer cancer treatment in which TILs are removed from a tumor, grown in the laboratory, and returned to the body in the form of an infusion. TIL may be effective in advanced melanoma because the T cells taken from the cancer cells have “learned” to specifically recognize melanoma.

The treatment is complex and takes place in several steps in the hospital. In 2024, the US Food and Drug Administration (FDA) approved lifileucel (brand name: Amtagvi) as the first FDA-approved tumor T-cell immunotherapy.

Oncolytic virus therapy

Oncolytic virus therapy involves “hijacking” viruses to target cancer cells. Viruses are known for their ability to hide from the immune system and attack healthy cells. So scientists have found a way to put this ability to good use by engineering viruses (called oncolytic viruses) in a laboratory so that they attack cancer cells instead.

In addition to directly destroying cancer cells, oncolytic viruses can also alert the rest of the immune system to attack the cancer cells. For melanoma, talimogene laherparepvec (brand name: Imlygic), also known as T-VEC, is an oncolytic virus that can be used to try to shrink tumors that cannot be removed surgically. Currently, the main purpose of oncolytic virus therapy for melanoma is to shrink tumor size, and some data show that it may help increase survival rates.

Many of the immunotherapy treatment options for melanoma can be combined with each other, providing more opportunities for effective treatment. Expanded immunotherapy options offer new hope for a very difficult type of cancer.

The best treatment results are always achieved with an earlier diagnosis. Therefore, in the fight against melanoma, it is very important to know the signs of skin cancer and carry out regular skin examinations.

This educational resource was created with support from Merck.

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