The body has a built-in defense: the immune system, which consists of white blood cells, lymph system tissues and organs that work together to identify and destroy infections and abnormal cells. However, cancer cells use genetic changes to hide their abnormality or interfere with the immune system's ability to detect and destroy them. Immunotherapy helps the immune system overcome these defenses.

"We're working with what the body naturally does but has not done perfectly, as it has allowed cancer to develop. We're trying to reinforce the body's natural defenses," says Svetomir Markovic, M.D., Ph.D., a Mayo Clinic Comprehensive Cancer Center medical oncologist who researches immunotherapy for melanoma and non-Hodgkin lymphoma.

"Immunotherapy leverages the patient's immune system to fight cancer. It activates and pushes it to find the tumors and kill them," says Haidong Dong, M.D., Ph.D., a Mayo Clinic Comprehensive Cancer Center cancer immunologist. "You can use different tools — T cells, vaccines, targeted drugs — but they all use the patient's immune cells to fight their tumors."

Dr. Markovic and Dr. Dong discuss the history of cancer immunotherapy at Mayo Clinic, how it works, its benefits and risks, and its future:

The roots of cancer immunotherapy at Mayo Clinic

In the late '90s, Dr. Dong and his colleagues at Mayo Clinic discovered that a protein called PD-L1 regulates the immune system's response to cancer cells and other threats. PD-L1 acts as a check or brake by binding to another protein in T cells called PD-1. This discovery led them to develop an antibody that blocks PD-L1's function.

"Using the antibody to block PD-L1 restores the immune system's ability to kill the tumor," says Dr. Dong, the Iris and Winston Clement Professor of Research. "This breakthrough laid the foundation for immunotherapy drugs that target the PD-L1 pathway."

In 2002, Dr. Dong and his team reported their findings, paving the way for the development of new immunotherapy drugs called immune checkpoint inhibitors. In 2014, the Food and Drug Administration approved pembrolizumab as the first immune checkpoint inhibitor to treat melanoma. Today, pembrolizumab is approved to treat 18 types of cancer.

How does cancer immunotherapy work?

Cancer immunotherapy drugs don't directly target cancer cells. Instead, they enhance the body's immune cells, improving their ability to recognize and destroy cancer cells.

"Immunotherapy helps the immune system see where the tumor is in the body. The immune system can see a single cancer cell. That's powerful," says Dr. Dong.

"Immunotherapy helps the immune system see where the tumor is in the body. The immune system can see a single cancer cell. That's powerful."Dr. Haidong Dong

"It's almost like cancer therapy by proxy," says Dr. Markovic, the Charles F. Mathy Professor of Melanoma Research. "We're engaging the body to do its job in ways that make it uniquely effective."

Some of the most common immunotherapies used in cancer treatment include:

Immune checkpoint inhibitors

Immune checkpoint inhibitors are immunotherapy drugs that block checkpoint proteins, such as PD-L1, on cancer cells from binding to their partner proteins on immune cells (T cells). This allows the immune system to destroy cancer cells. Pembrolizumab is one example of an immune checkpoint inhibitor. Eleven immune checkpoint inhibitors have now been approved to treat cancer.

Most of these drugs are used for advanced cancer or cancer that has spread (metastasized). However, some immune checkpoint inhibitors are now being used in earlier stages of cancer to prevent its spread and recurrence. Clinical trials are also investigating combinations of these drugs with other treatments and new immune checkpoint inhibitors.

Learn about immune checkpoint inhibitors and related research at Mayo Clinic:

• Immune checkpoint inhibitors: Immunotherapy for people with triple-negative breast cancer
• From molecule to melanoma: A foundation of research brings new cancer immunotherapies to patients

Oncolytic viruses

Oncolytic viruses use naturally occurring or lab-made viruses to infect cancer cells, causing them to rupture. This stimulates the immune system to attack the remaining cancer cells.

Most oncolytic virus treatments for cancer are still in clinical trials. A weakened form of herpes simplex virus type 1 given by injection is approved to treat melanoma on the skin or in lymph glands.

Learn about oncolytic virus research at Mayo Clinic:

• Novel oncolytic immunotherapy shows promise for patients with bladder cancer
• Unleashing viruses aimed at killing cancer
• Mayo Clinic researchers load CAR-T cells with oncolytic virus to treat solid cancer tumors

Personalized cancer vaccines

Personalized cancer vaccines train the immune system to recognize a specific cancer-related protein from a person's tumor. As the immune system learns to recognize the protein, it can fight it. This treatment is still being studied in clinical trials.

Learn about personalized cancer vaccine research at Mayo Clinic:

• Mayo Clinic Minute: How personalized vaccines target cancer tumors
• Vaccines: The next frontier of lung cancer treatment and prevention
• Tomorrow's Cure: How personalized vaccines combat cancer
• Mayo Clinic researchers design personalized vaccines to fight cancer
• Harnessing the immune system to fight ovarian cancer

Cellular therapies

Cellular therapies involve collecting cells from blood and modifying them to attack cancer cells. These include chimeric antigen receptor (CAR)-T cell therapy and tumor-infiltrating lymphocyte (TIL) therapy.

• CAR-T cell therapy: For this therapy, white blood cells called T cells are removed from a person's blood and genetically modified to produce chimeric antigen receptors. CARs allow T cells to recognize markers on the surface of cancer cells, activating the T cells to kill them. The modified CAR-T cells are then infused into the patient's body to identify and destroy their cancer. The FDA has approved CAR-T cell therapy to treat several types of blood cancer, and clinical trials are exploring its use for solid tumor cancers.
• TIL therapy: This therapy involves surgically removing a person's cancerous tumor, extracting immune cells (lymphocytes) from it, and enriching them. During this process, the patient receives chemotherapy to prepare to receive the enriched immune cells, which are later infused into their body to target any remaining cancer. "The first treatment the patient receives warms up the immune system — improves it to a degree ­— but not enough to kill the tumor. TIL therapy gives the immune cells more power to finish the job," says Dr. Dong. In 2024, the FDA approved the first TIL therapy, lifileucel, for people with melanoma that has spread or cannot be removed by surgery.

Learn about cellular therapy research at Mayo Clinic:

• What is CAR-T cell therapy?
• Understanding CAR-T cell therapy for cancer: Mayo Clinic expert explains how it works
• Unleashing CAR-T cell therapy to destroy solid tumors in thyroid cancer
• Using molecular scissors to improve CAR-T cell therapy
• Preparing to biomanufacture a new CAR-T cell therapy for B-cell cancers

Cytokines

Cytokines are proteins made by white blood cells that signal the immune system to either activate or slow down. Cytokines used as immunotherapy drugs include interleukins and interferons:

• Interleukins: These act as chemical signals between white blood cells. Aldesleukin is a lab-made interleukin (IL-2) that increases the growth and activity of certain white blood cells. It is used to treat melanoma and kidney cancer that has spread throughout the body.
• Interferons: These help the body resist viruses and cancer cells. Interferon alfa-2b is a type of interferon (IFN-alpha) used to treat hairy cell leukemia, melanoma, follicular lymphoma and AIDS-related Kaposi sarcoma.

Bispecific antibodies

When the immune system detects cancer cells or other abnormal cells, it produces immune cells called antibodies to attack them. Bispecific antibodies are lab-made antibodies that can bind to both cancer and immune cells simultaneously, bringing them close together to enhance the immune system’s ability to destroy cancer cells.

The FDA has approved seven immunotherapy drugs that use bispecific antibodies to treat cancer.

Learn about bispecific antibody research at Mayo Clinic: "New research discovers a new combination of therapy for people with a type of leukemia, leading them to live longer."

What are the benefits and risks of immunotherapy?

Immunotherapy is effective against many types of cancer because it uses the immune system to recognize and attack cancer cells. "We don't yet know which immunotherapy best suits all malignancies. As we learn the biology of all this, as our intervention tools become more sophisticated, the number of cancers we can treat increases," says Dr. Markovic.

"We don't yet know which immunotherapy best suits all malignancies. As we learn the biology of all this, as our intervention tools become more sophisticated, the number of cancers we can treat increases."Dr. svetomir Markovic

Immunotherapy can also produce long-lasting responses to treatment by training the immune system to recognize cancer and respond quickly if it returns.

However, immunotherapy can cause side effects. "That’s the price we pay," says Dr. Markovic. "When turned on, the immune system attacks the cancer but may also attack noncancerous tissue, producing side effects similar to autoimmune disease symptoms. They mimic allergic reactions."

Side effects vary based on the type of immunotherapy. Some can be serious, but most can be managed, treated and resolved. Common side effects include redness, itching or blistering of the skin, flu-like symptoms, diarrhea, swelling and weight gain.

Mayo Clinic scientists and colleagues worldwide are researching how to reduce immunotherapy's side effects and increase its benefits. "As we get better with cancer immunotherapy, our treatments become more effective, less toxic and help more people," says Dr. Markovic.

The future of cancer immunotherapy

Scientists are researching ways to improve immunotherapy outcomes and reduce its limitations. Dr. Dong says research is exploring these key areas:

• Understanding why the responses vary from person to person.
• Combining immunotherapy with other treatments, such as chemotherapy, radiation therapy, or targeted drug therapy, to produce the best outcomes.
• Reducing side effects.
• Identifying biomarkers to help predict which people will respond to immunotherapy.

Dr. Dong says this research could improve the effectiveness of immunotherapy and patients’ quality of life. It will also help care teams make more informed treatment decisions and may decrease the financial burden of cancer treatment.

"Immunotherapy has fundamentally changed cancer medicine with the possibility of a cure for cancers that have been considered completely incurable," says Dr. Markovic. "It was once unheard of for patients with metastatic, advanced melanoma to be cured of their disease. Today, a person with this diagnosis has a one in three chance of being cured. That’s a dramatic improvement in outcomes."

Learn more

Drs. Dong and Markovic encourage you to ask your care team specific questions about your treatment. Other trusted sources of information about immunotherapy include:

• American Cancer Society
• Cancer Research Institute
• National Cancer Institute
• National Comprehensive Cancer Network

Find a clinical trial at Mayo Clinic.

Join a support group on Mayo Clinic Connect, an online community moderated by Mayo Clinic for patients and caregivers.

This article first published on the Mayo Clinic Comprehensive Cancer Center blog.

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