Immunotherapy

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Immunotherapy medicines use the power of your body’s immune system to attack cancer cells.

There are several immunotherapy medicines approved by the U.S. Food and Drug Administration (FDA) to treat breast cancer.

Immune checkpoint inhibitors to treat breast cancer are:

Tecentriq is used in combination with the chemotherapy medicine Abraxane (chemical name: albumin-bound or nab-paclitaxel) as a first treatment for unresectable locally advanced or metastatic triple-negative, PD-L1-positive breast cancer. Unresectable means that it can’t be removed with surgery.

Targeted immunotherapy medicines to treat breast cancer are:

  • Herceptin (chemical name: trastuzumab)
  • Perjeta (chemical name: pertuzumab)
  • Kadcyla (chemical name: T-DM1 or ado-trastuzumab emtansine)

These three targeted therapy medicines treat HER2-positive breast cancer by targeting the HER2 receptors on breast cancer cells. In addition to blocking HER2 receptors, these medicines can also help fight breast cancer by alerting the immune system to destroy cancer cells. Because of this, they are sometimes called “immune targeted therapies.”

Learn more about immunotherapy:

What is immunotherapy?

Cancer immunotherapy medicines work by helping your immune system work harder or more efficiently to fight cancer cells.

Your immune system is made up of a number of organs, tissues, and cells that work together to protect you from foreign invaders that can cause disease. When a disease- or infection-causing agent, such as a bacterium, virus, or fungus, gets into your body, your immune system reacts and works to kill the invaders. This self-defense system works to keep you from getting sick.

Immunotherapy uses substances — either made naturally by your body or man-made in a lab — to boost the immune system to:

  • stop or slow cancer cell growth
  • stop cancer cells from spreading to other parts of the body
  • be better at killing cancer cells

To start an immune system response to a foreign invader, the immune system has to be able to tell the difference between cells or substances that are “self” (part of you) vs. “non-self” (not part of you and possibly harmful). Your body’s cells have proteins on their surfaces or inside them that help the immune system recognize them as “self.” This is part of the reason the immune system usually doesn’t attack your body’s own tissues. (Autoimmune disorders happen when the immune system mistakenly attacks your own tissues, such as the thyroid gland, joints, connective tissue, or other organs.)

“Non-self” cells have proteins and other substances on their surfaces and inside them that the body doesn’t recognize, called antigens. Foreign antigens trigger the immune system to attack them and the cells they are in or on, whether viruses, bacteria, or infected cells. This response either destroys the foreign invaders or keeps them in check so they can’t harm the body.

So why doesn’t your immune system attack breast cancer cells on its own, without the help of immunotherapy medicines? There are two main reasons:

  • A breast cancer cell starts out as a normal, healthy cell. A cancerous growth is a collection of cells that were once normal and healthy. Precancerous and even early breast cancer cells don’t look that much different from normal cells. They don’t shout “non-self” in the way that bacteria, viruses, and other foreign materials do — which makes things more challenging for the immune system. But as cells transform into cancer, they do create proteins that the immune system sees as “foreign” antigens. In some cases, the immune system is able to recognize some cancer cells as harmful and stop the process before a cancer can grow further.
  • As a cancer develops, the cancerous cells develop the ability to avoid the immune system. Breast cancer doesn’t happen overnight; it develops over a period of time. As healthy cells gradually change into cancer cells, the genetic information inside them is constantly changing. Some of these genetic changes allow the cancer cells to avoid detection by the immune system. Other changes allow cancer cells to speed up their growth rate and multiply much more quickly than normal cells do. This process can overwhelm the immune system and allow the breast cancer to grow unchecked.

In general, immunotherapy medicines can be divided into two main groups:

  • Active immunotherapies, which stimulate your immune system to respond to the cancer. Cells from a cancer are examined in the lab to find antigens specific to that tumor. Then an immunotherapy treatment is created that makes the immune system target those antigens. Cancer vaccines and adoptive cell therapy are examples of active immunotherapies.
  • Passive immunotherapies, which give the body man-made immune system components to help it fight cancer. Passive immunotherapies don’t stimulate your immune system to actively respond the way active immunotherapies do. Immune checkpoint inhibitors and cytokines are examples of passive immunotherapies.

Because immunotherapy medicines help your immune system to kill cancer, the process can take a long time. Right now, it’s not clear how long someone should be treated with immunotherapy. Many experts believe that combining immunotherapies — for example, a vaccine with a checkpoint inhibitor — may be a good way to jump start a strong immune response to cancer. It’s also likely that immunotherapies will be combined with other cancer treatments, such as targeted therapies.

Scientists are studying the immunogenicity of breast cancer — how to provoke the immune system to respond to breast cancer — as well as specific immunotherapies. Stay tuned to Breastcancer.org for the latest updates.

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Is immunotherapy right for you?

Immunotherapy medicines are relatively new and have not been studied as long as surgery, chemotherapy, radiation therapy, and hormonal therapy.

It’s difficult right now to say who will benefit from available immunotherapies or those that are currently under investigation, such as vaccines. Much of the research looking at immunotherapies to treat breast cancer is focusing on metastatic disease, especially triple-negative breast cancer (breast cancer that is estrogen-receptor-negative, progesterone-receptor-negative, and HER2-receptor negative).

“We know that not all tumor types are the same, and also that every patient's tumor is going to be unique,” said Leisha Emens, M.D., Ph. D, professor of medicine in hematology/oncology at the University of Pittsburgh Medical Center Hillman Cancer Center. Dr. Emens specializes in cancer immunotherapy. Her research focuses on the development and implementation of breast cancer immunotherapies (including vaccines and immune checkpoint inhibitors) in combination with traditional cancer treatments and other drugs that activate the immune system.

“One reason that triple-negative breast cancer is more susceptible to immune therapy is that these tumors may have more genetic mutations, referred to as mutational load,” she continued. “These mutations cause the tumor cells to produce unique antigens that look foreign to the immune system. It might be that a personalized vaccine composed of these unique antigens could work well to induce or amplify T cells in patients with triple-negative breast cancer who do not have sufficient T cells in the tumor immune microenvironment at diagnosis.

“We still need to learn a lot to be able to predict which patients may respond to immunotherapy,” Dr. Emens continued. “For some breast tumors, the mutational load may be important, and for others that may not be the case. Also, the presence of PD-L1 [a checkpoint protein that helps the immune system recognize cells as part of the body, rather than a foreign invader] in the tumor makes it more likely that a patient will respond to an immune checkpoint blockade that targets the checkpoint proteins PD-1 and PD-L1 — but it is not perfect. Small numbers of patients without PD-L1 in their tumors can also respond to immunotherapy, so we need to know more about what is driving their tumor immunity.”

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Immune checkpoint inhibitors

To start an immune system response to a foreign invader, the immune system has to be able to tell the difference between cells or substances that are “self” (part of you) vs. “non-self” (not part of you and possibly harmful). Your body’s cells have proteins on their surfaces or inside them that help the immune system recognize them as “self.”

Some of these proteins that help your immune system recognize “self” cells are called immune checkpoints. Cancer cells sometimes find ways to use these immune checkpoint proteins as a shield to avoid being identified and attacked by the immune system.

Immune system cells called T cells roam throughout the body looking for signs of disease or infection. When T cells meet another cell, they analyze certain proteins on the cell’s surface, which helps the T cell identify the cell. If the surface proteins signal that the cell is normal and healthy, the T cell leaves it alone. If the surface proteins suggest the cell is cancerous or unhealthy in another way, the T cell starts an attack against it. Once T cells start an attack, the immune system begins to make more specialized proteins that prevent this attack from damaging normal cells and tissues in the body. These specialized proteins that keep healthy cells and tissues safe are called immune checkpoints.

Immune checkpoint inhibitors target these immune checkpoint proteins and help the immune system recognize and attack cancer cells. Immune checkpoint inhibitors essentially take the brakes off the immune system by blocking checkpoint inhibitor proteins on cancer cells or on the T cells that respond to them.

PD-1 and PD-L1 inhibitors

PD-1 is a type of checkpoint protein found on T cells. PD-L1 is another checkpoint protein found on many healthy cells in the body. When PD-1 binds to PD-L1, it stops T cells from killing a cell.

Still, some cancer cells have a lot of PD-L1 on their surface, which stops T cells from killing these cancer cells. An immune checkpoint inhibitor medicine that stops PD-1 from binding to PD-L1 allows T cells to attack the cancer cells.

Tecentriq (chemical name: atezolizumab) is a PD-L1 inhibitor approved by the FDA to be used in combination with the chemotherapy medicine Abraxane (chemical name: albumin-bound or nab-paclitaxel) as a first treatment for unresectable locally advanced or metastatic triple-negative, PD-L1-positive breast cancer.

Other PD-1 and PD-L1 inhibitors that have been approved by the FDA to treat cancers other than breast cancer are:

  • Keytruda (chemical name: pembrolizumab), used to treat advanced-stage skin cancer, certain types of non-small cell lung cancer, advanced-stage head and neck squamous cell cancer, Hodgkin lymphoma, advanced-stage urothelial cancer, and advanced-stage cancers with microsatellite instability-high or mismatch repair deficient, a specific type of genetic marker
  • Opdivo (chemical name: nivolumab), used to treat metastatic non-small cell lung cancer, Hodgkin lymphoma, advanced-stage renal cell cancer, advanced-stage urothelial cancer, advanced-stage head and neck squamous cell cancer, and metastatic skin cancer
  • Bavencio (chemical name: avelumab), used to treat a rare type of metastatic skin cancer called Merkel cell carcinoma and advanced-stage urothelial cancer
  • Imfinzi (chemical name: durvalumab), used to treat advanced-stage urothelial cancer

Clinical trials are studying these and other PD-1/PD-L1 inhibitors to treat breast cancer.

CTLA-4 inhibitors

CTLA-4 is another checkpoint protein on some T cells. When CTLA-4 binds to the B7 protein on another cell, it stops the T cell from killing the cell.

The CTLA-4 inhibitor medicine Yervoy (chemical name: ipilimumab) targets the CTLA-4 protein and stops it from binding to B7 on other immune cells. This pushes the T cells to become activated to attack cancer cells. Yervoy has been approved by the FDA to treat advanced-stage skin cancer. It is also being studied to treat breast and other cancers.

Side effects

One big concern about immune checkpoint inhibitor medicines is that they may allow the immune system to attack some healthy cells and organs. Because the medicines essentially take the brakes off the immune system, T cells may start attacking cells other than cancer cells. Some serious side effects include problems with the lungs, liver, intestines, pancreas, and kidneys.

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Immune targeted therapies

Targeted cancer therapies are treatments that target specific characteristics of cancer cells, such as a protein that allows cancer cells to grow in a rapid or abnormal way. Some targeted therapies work like the antibodies made naturally by the immune system. These types of targeted therapies can help the immune system recognize the cancer.

One way the immune system defends the body against foreign invaders is by making large numbers of antibodies. An antibody is a protein that sticks to an antigen. Antigens are proteins and other substances on the surface of and inside foreign cells that the body doesn’t recognize. Antigens trigger the immune system to attack them and the cells they are in or on, whether viruses, bacteria, or something else. Antibodies circulate throughout your body until they find and attach to the antigen. Once attached, antibodies can recruit other immune system cells to destroy the cells containing the antigen.

Researchers have designed antibodies that specifically target a certain antigen, such as one found on specific cancer cells. These are known as monoclonal antibodies.

Some monoclonal antibodies recognize specific proteins on the surface of cancer cells, called target proteins, and then bind to those target proteins. When the monoclonal antibody binds to the target protein, it blocks the target protein’s function and kills the cancer cell. Monoclonal antibodies that work like this and are approved by the FDA to treat breast cancer are:

  • Herceptin (chemical name: trastuzumab), which kills HER2-positive breast cancer cells by binding to the HER2 receptor and blocking cancer cells’ ability to receive growth signals
  • Perjeta (chemical name: pertuzumab), which, like Herceptin, kills HER2-positive breast cancer cells by binding to the HER2 receptor and blocking cancer cells’ ability to receive growth signals
  • Kadcyla (chemical name: T-DM1 or ado-trastuzumab emtansine), a combination of Herceptin and the chemotherapy medicine emtansine. Kadcyla delivers emtansine to HER2-positive cancer cells in a targeted way by attaching emtansine to Herceptin, which binds to the HER2 receptors in the cancer cells and delivers the emtansine directly to the tumor

Visit the links above to learn more about how Herceptin, Perjeta, and Kadcyla work, as well as their side effects.

When Herceptin, Perjeta, Kadcyla, and other monoclonal antibodies bind to cancer cells, they can act as a marker so the immune system can now recognize the cancer cells and kill them. Rituxan (chemical name: rituximab) is another similar antibody used to treat non-Hodgkin lymphoma, chronic lymphocytic leukemia, and autoimmune diseases such as rheumatoid arthritis and Wegener’s granulomatosis (an autoimmune disorder that causes inflammation in blood vessels). Rituxan binds to the CD20 protein on healthy and diseased B cells, a type of white blood cell. When Rituxan binds to the B cells, it attracts immune cells to destroy both the cancerous B cells and the normal B cells.

Still other monoclonal antibodies bind to specific immune cells, such as T cells, to boost the ability of those cells to kill cancer cells. Tecentriq, approved by the FDA to treat certain PD-L1-positive, advanced-stage, triple-negative breast cancers, is an immune checkpoint inhibitor that is a monoclonal antibodies. Immune checkpoint inhibitors bind to proteins on T cells and other immune cells.

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Cancer vaccines

You’re probably familiar with traditional vaccines for diphtheria, mumps, whooping cough, polio, rubella, tetanus, tuberculosis, and other diseases that have been nearly eliminated in the United States because so many people have been vaccinated. For these diseases, a killed or weakened version of the organism that causes the disease is given to a healthy person to rev up the immune system and start a response.

There are some cancers that have been linked to viruses. Some strains of the human papilloma virus (HPV), which causes genital warts, have been linked to cervical, anal, throat, and other cancers. HPV vaccines may help protect against some of these cancers. People with long-term hepatitis B infections have a higher risk of liver cancer. So, the hepatitis B vaccine may reduce the risk of liver cancer.

Still, much of the research on vaccines for cancer are on cancer treatment vaccines. Treatment vaccines try to get the immune system to attack cancer cells. Treatment vaccines are different because they don’t prevent disease, they work to stimulate the immune system to kill a disease that is already there. You don’t receive a cancer treatment vaccine until after you’ve been diagnosed.

Cancer treatment vaccines are made up of cancer cells, parts of cells, or antigens, the proteins on a foreign cell — like a cancer cell — that allow the immune system to recognize it as “other.” In some cases, a person’s immune cells are taken from the body and exposed to these substances in the lab to create the vaccine. Once the vaccine is ready, it’s put back into the body to boost the immune system’s response to cancer cells.

Cancer treatment vaccines may take months to produce a noticeable immune system response, so they may be most useful to reduce the risk of the cancer coming back (recurrence) after the main cancer treatments, such as surgery, are done. Doctors call treatments given after surgery “adjuvant” treatments.

Right now, no cancer treatment vaccines have been approved by the FDA to treat breast cancer. Still, there are several clinical trials looking at breast cancer treatment vaccines.

Some of the studies are looking at treatment vaccines in combination with other treatments, such as Herceptin (chemical name: trastuzumab) or chemotherapy.

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Adoptive cell therapy

Adoptive cell therapy tries to boost the natural ability of your immune system’s killer cells, either T cells or natural killer cells, to recognize and kill cancer cells.

During adoptive cell therapy, scientists draw some blood from you and remove T cells from the blood. Doctors may modify your T cells so they can better recognize the cancer cells in your body. These altered T cells are then grown in large batches in the lab. Growing enough altered T cells for a treatment can take 2 weeks to several months.

In some cases, a person having adoptive cell therapy may have other treatments to reduce the number of immune cells in the body because these unaltered immune cells do not recognize the cancer cells. Then, the altered T cells are put back in the body to seek out and destroy the cancer cells.

There are several types of adoptive cell therapy, based on how the T cells are treated in the lab:

  • chimeric antigen receptor (CAR) T-cell therapy genetically alters T cells to have chimeric antigen receptors, or CARs, on their surfaces; CARs may allow the T cells to better recognize cancer cells
  • tumor-infiltrating lymphocyte (TIL) and interleukin-2 (IL-2) T cell therapy removes TILs, a type of T cell found in cancer tumors, and treats them with interleukin (IL-2), a type of protein that can boost the ability of the T cells to recognize cancer cells; IL-2 is also a cytokine and a man-made version of it called Proleukin (chemical name: aldesleukin) has been approved by the FDA to treat metastatic kidney cancer and metastatic skin cancer

No adoptive cell therapies have been approved by the FDA to treat breast or any other cancer yet. Adoptive cell therapy is only available in clinical trials.

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Cytokines

Cytokines are considered non-specific immunotherapy medicines because they don’t respond to a particular target on most cancer cells. Instead, they boost the immune system in a more general way. This general boost can still lead to a better immune response to cancer. In many cases, cytokines are given after or at the same time as another cancer treatment, such as chemotherapy or radiation therapy.

Cytokines are proteins made by some immune system cells. They help control the growth and activity of other immune system cells and blood cells.

Right now, no cytokines are approved by the FDA to treat breast cancer.

There are two main cytokines being studied to treat cancer: interleukins and interferons.

Interleukins are a group of cytokines that help white blood cells, which are immune system cells, talk to each other and help the immune system produce cells that destroy cancer.

A specific interleukin, interleukin-2 (IL-2), helps immune system cells grow and divide more quickly, which means there are more of them to attack foreign cells in the body, such as cancer. A man-made version of IL-2 called Proleukin (chemical name: aldesleukin) has been approved by the FDA to treat metastatic kidney cancer and metastatic skin cancer.

Side effects of IL-2 can include chills, fever, fatigue, weight gain, nausea, vomiting, diarrhea, and low blood pressure. Rare but serious side effects include abnormal heartbeat, chest pain, and other heart problems.

Other interleukins, including IL-7, IL-12, and IL-21 are being studied as medicines to treat cancer.

Interferons are proteins that help the body fight off virus infections and cancers. Some research suggests that interferons may actually slow the growth of cancer cells. There are three types of interferons, which is abbreviated IFN: IFN-alpha, IFN-beta, and IFN-gamma.

Only IFN-alpha is FDA-approved to treat cancer. IFN-alpha boosts the ability of certain immune cells to attack cancer cells and may also slow the growth of the blood vessels that cancer tumors need to grow.

A man-made version of IFN-alpha, called Intron A, is used to treat hairy cell leukemia, non-Hodgkin lymphoma, and skin cancer, as well as hepatitis C and hepatitis B.

Side effects of interferons can include chills, fever, headache, fatigue, loss of appetite, nausea, vomiting, low while blood cell counts, skin rash, and thinning hair. These side effects can be severe and can make it hard for many people to tolerate interferon treatment.

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The medical expert for Immunotherapy is:

Leisha Emens, M.D., Ph.D., professor of medicine in hematology/oncology at the University of Pittsburgh Medical Center Hillman Cancer Center. She is also co-leader of the Hillman Cancer Immunology and Immunotherapy Program, and director of translational immunotherapy for the Women's Cancer Research Center. Dr. Emens specializes in cancer immunotherapy, and her research focuses on the development and implementation of breast cancer immunotherapies (including vaccines and immune checkpoint inhibitors) in combination with traditional cancer treatments and other drugs that activate the immune system. Dr. Emens discloses that she has received research support from Merck, EMD-Serono, AstraZeneca, Genentech-Roche, Corvus, and Aduro. She has received honoraria from Vaccinex, Amgen, Syndax, Peregrine, Bayer, and Gritstone.


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