Immunotherapy is a cancer treatment that helps your immune system fight cancer. It is a type of biological therapy. Biological therapy uses substances that are made from living organisms, or versions of these substances that are made in a lab.

Doctors don't yet use immunotherapy as often as other cancer treatments, such as surgery, chemotherapy, and radiation therapy. But they do use immunotherapy for some types of cancer, and researchers are doing clinical trials to see whether it also works for other types.

When you have cancer, some of your cells begin to multiply without stopping. They spread into the surrounding tissues. One reason that the cancer cells can keep growing and spreading is that they are able to hide from your immune system. Some immunotherapies can "mark" your cancer cells. This makes it easier for your immune system to find and destroy the cells. It is a type of targeted therapy, a treatment that specifically targets cancer cells. Other types of immunotherapies work by boosting your immune system to work better against cancer.

You could get immunotherapy intravenously (by IV), in pills or capsules, or in a cream for your skin. For bladder cancer, they might place it directly into your bladder. You may have treatment every day, week, or month. Some immunotherapies are given in cycles. It depends on your type of cancer, how advanced it is, the type of immunotherapy you get, and how well it is working.

You may have side effects. The most common side effects are skin reactions at the needle site, if you get it by IV. Other side effects may include flu-like symptoms, or rarely, severe reactions.

Cancer can play a cat and mouse game with our immune systems, hiding cells and making it harder to fight off the disease.

One treatment to help combat this is immunotherapy, a type of cancer treatment that helps strengthen patients’ immune systems and fight off cancer.

What is cancer?

Our body usually forms new cells when our old cells die. Sometimes this process goes wrong. With cancer, new cells grow when you don't need them, and old cells don't die when they should. These extra cells can form a mass called a tumor.

How does immunotherapy combat cancer?

Some types of immunotherapy help find extra cancer cells so that they can be destroyed. Others boost your immune system to work better against cancer.

Who could benefit from immunotherapy?

Immunotherapy is not as widely used as surgery, chemotherapy, and radiation therapy. But immunotherapies have treated people with many types of cancer and are being tested in clinical trials.

Ask your health care provider if immunotherapy may be a good option for you or a loved one.

How is immunotherapy given?

Treatment can be given intravenously (in your vein), by taking a pill, or through your bladder. For patients with early skin cancer, there is an immunotherapy cream you can rub on your skin.

Where do you get immunotherapy?

You may get immunotherapy treatment at a doctor’s office, a clinic, or an outpatient unit at a hospital.

What are possible side effects of immunotherapy?

Side effects are unique to each patient and each cancer.

Some common side effects include fever, chills, weakness, dizziness, nausea or vomiting, fatigue, and other flu-like symptoms.

If you had immunotherapy through your vein, you may have pain, swelling, soreness, itchiness, or a rash at the needle site.

Cancer involves a loss of the ability of cells to control their cell cycle, the stages each eukaryotic cell goes through as it grows and then divides. When this control is lost, the affected cells rapidly divide and often lose the ability to differentiate into the cell type appropriate for their location in the body. In addition, they lose contact inhibition and can start to grow on top of each other. This can result in formation of a tumor. It is important to make a distinction here: The term “cancer” is used to describe the diseases resulting from loss of cell-cycle regulation and subsequent cell proliferation. But the term “tumor” is more general. A “tumor” is an abnormal mass of cells, and a tumor can be benign (not cancerous) or malignant (cancerous).

Traditional cancer treatment uses radiation and/or chemotherapy to destroy cancer cells; however, these treatments can have unwanted side effects because they harm normal cells as well as cancer cells. Newer, promising therapies attempt to enlist the patient’s immune system to target cancer cells specifically. It is known that the immune system can recognize and destroy cancerous cells, and some researchers and immunologists also believe, based on the results of their experiments, that many cancers are eliminated by the body’s own defenses before they can become a health problem. This idea is not universally accepted by researchers, however, and needs further investigation for verification.

Using Viruses to Cure Cancer

Viruses typically destroy the cells they infect—a fact responsible for any number of human diseases. But the cell-killing powers of viruses may yet prove to be the cure for some types of cancer, which is generally treated by attempting to rid the body of cancerous cells. Several clinical trials are studying the effects of viruses targeted at cancer cells. Reolysin, a drug currently in testing phases, uses reoviruses (respiratory enteric orphan viruses) that can infect and kill cells that have an activated Ras-signaling pathway, a common mutation in cancerous cells. Viruses such as rubeola (the measles virus) can also be genetically engineered to aggressively attack tumor cells. These modified viruses not only bind more specifically to receptors overexpressed on cancer cells, they also carry genes driven by promoters that are only turned on within cancer cells. Herpesvirus and others have also been modified in this way.

As part of its normal function, the immune system detects and destroys abnormal cells and most likely prevents or curbs the growth of many cancers. For instance, immune cells are sometimes found in and around tumors. These cells, called tumor-infiltrating lymphocytes or TILs, are a sign that the immune system is responding to the tumor. People whose tumors contain TILs often do better than people whose tumors don’t contain them.

Even though the immune system can prevent or slow cancer growth, cancer cells have ways to avoid destruction by the immune system. For example, cancer cells may:

• Have genetic changes that make them less visible to the immune system.
• Have proteins on their surface that turn off immune cells.
• Change the normal cells around the tumor so they interfere with how the immune system responds to the cancer cells.

Immunotherapy helps the immune system to better act against cancer.

Cell-mediated immune responses can be directed against cancer cells, many of which do not have the normal complement of self-proteins, making them a target for elimination. Abnormal cancer cells may also present tumor antigens. These tumor antigens are not a part of the screening process used to eliminate lymphocytes during development; thus, even though they are self-antigens, they can stimulate and drive adaptive immune responses against abnormal cells.

Presentation of tumor antigens can stimulate naïve helper T cells to become activated by cytokines such as IL-12 and differentiate into T_H1cells. T_H1 cells release cytokines that can activate natural killer (NK) cells and enhance the killing of activated cytotoxic T cells. Both NK cells and cytotoxic T cells can recognize and target cancer cells, and induce apoptosis through the action of perforins and granzymes. In addition, activated cytotoxic T cells can bind to cell-surface proteins on abnormal cells and induce apoptosis by a second killing mechanism called the CD95 (Fas) cytotoxic pathway.

Despite these mechanisms for removing cancerous cells from the body, cancer remains a common cause of death. Unfortunately, malignant tumors tend to actively suppress the immune response in various ways. In some cancers, the immune cells themselves are cancerous. In leukemia, lymphocytes that would normally facilitate the immune response become abnormal. In other cancers, the cancerous cells can become resistant to induction of apoptosis. This may occur through the expression of membrane proteins that shut off cytotoxic T cells or that induce regulatory T cells that can shut down immune responses.

The mechanisms by which cancer cells alter immune responses are still not yet fully understood, and this is a very active area of research. As scientists’ understanding of adaptive immunity improves, cancer therapies that harness the body’s immune defenses may someday be more successful in treating and eliminating cancer.

Several types of immunotherapy are used to treat cancer. These include:

• Immune checkpoint inhibitors, which are drugs that block immune checkpoints. These checkpoints are a normal part of the immune system and keep immune responses from being too strong. By blocking them, these drugs allow immune cells to respond more strongly to cancer.

• T-cell transfer therapy, which is a treatment that boosts the natural ability of your T cells to fight cancer. In this treatment, immune cells are taken from your tumor. Those that are most active against your cancer are selected or changed in the lab to better attack your cancer cells, grown in large batches, and put back into your body through a needle in a vein. T-cell transfer therapy may also be called adoptive cell therapy, adoptive immunotherapy, or immune cell therapy.

• Monoclonal antibodies, which are immune system proteins created in the lab that are designed to bind to specific targets on cancer cells. Some monoclonal antibodies mark cancer cells so that they will be better seen and destroyed by the immune system. Such monoclonal antibodies are a type of immunotherapy. Monoclonal antibodies may also be called therapeutic antibodies.

• Treatment vaccines, which work against cancer by boosting your immune system’s response to cancer cells. Treatment vaccines are different from the ones that help prevent disease.

• Immune system modulators, which enhance the body’s immune response against cancer. Some of these agents affect specific parts of the immune system, whereas others affect the immune system in a more general way.

Immune Checkpoint Inhibitors

How do immune checkpoint inhibitors work against cancer?

Immune checkpoints are a normal part of the immune system. Their role is to prevent an immune response from being so strong that it destroys healthy cells in the body.

Immune checkpoints engage when proteins on the surface of immune cells called T cells recognize and bind to partner proteins on other cells, such as some tumor cells. These proteins are called immune checkpoint proteins. When the checkpoint and partner proteins bind together, they send an “off” signal to the T cells. This can prevent the immune system from destroying the cancer.

Immunotherapy drugs called immune checkpoint inhibitors work by blocking checkpoint proteins from binding with their partner proteins. This prevents the “off” signal from being sent, allowing the T cells to kill cancer cells.

One such drug acts against a checkpoint protein called CTLA-4. Other immune checkpoint inhibitors act against a checkpoint protein called PD-1 or its partner protein PD-L1. Some tumors turn down the T cell response by producing lots of PD-L1.

FDA Approves First Immunotherapy to Target LAG-3

Opdualag, a combination of relatlimab and nivolumab, is now an initial treatment option for advanced melanoma.

Which cancers are treated with immune checkpoint inhibitors?

Immune checkpoint inhibitors are approved to treat some people with a variety of cancer types, including:

• breast cancer
• bladder cancer
• cervical cancer
• colon cancer
• head and neck cancer
• Hodgkin lymphoma
• liver cancer
• lung cancer
• renal cell cancer (a type of kidney cancer)
• skin cancer, including melanoma
• stomach cancer
• rectal cancer
• any solid tumor that is not able to repair errors in its DNA that occur when the DNA is copied

What side effects are caused by immune checkpoint inhibitors?

Immune checkpoint inhibitors can cause side effects that affect people in different ways. The side effects you may have and how they make you feel will depend on how healthy you are before treatment, your type of cancer, how advanced it is, the type of immune checkpoint inhibitor you are receiving, and the dose.

Doctors and nurses cannot know for sure when or if side effects will occur or how serious they will be. So, it is important to know which signs to look for and what to do if they occur.

Common side effects of immune checkpoint inhibitors include:

• rash
• diarrhea
• fatigue

Rarer side effects of immune checkpoint inhibitors can include widespread inflammation. Depending on the organ of your body that is affected, inflammation can lead to:

• changes in skin color, rash, and feeling itchy, caused by skin inflammation
• cough and chest pains, caused by inflammation in the lungs
• belly pain and diarrhea, caused by inflammation in the colon
• diabetes, caused by inflammation in the pancreas
• hepatitis (inflammation of the liver)
• hypophysitis (inflammation of the pituitary gland)
• myocarditis (inflammation of the heart muscle)
• nephritis (inflammation of the kidney) and impaired kidney function
• overactive or underactive thyroid
• nervous system problems such as muscle weakness, numbness, and trouble breathing

How do monoclonal antibodies work against cancer?

Monoclonal antibodies are immune system proteins that are created in the lab. Antibodies are produced naturally by your body and help the immune system recognize germs that cause disease, such as bacteria and viruses, and mark them for destruction. Like your body’s own antibodies, monoclonal antibodies recognize specific targets.

Many monoclonal antibodies are used to treat cancer. They are a type of targeted cancer therapy, which means they are designed to interact with specific targets.

Some monoclonal antibodies are also immunotherapy because they help turn the immune system against cancer. For example, some monoclonal antibodies mark cancer cells so that the immune system will better recognize and destroy them. An example is rituximab, which binds to a protein called CD20 on B cells and some types of cancer cells, causing the immune system to kill them. B cells are a type of white blood cell.

Other monoclonal antibodies bring T cells close to cancer cells, helping the immune cells kill the cancer cells. An example is blinatumomab (Blincyto®), which binds to both CD19, a protein found on the surface of leukemia cells, and CD3, a protein on the surface of T cells. This process helps the T cells get close enough to the leukemia cells to respond to and kill them.

Which cancers are treated with monoclonal antibodies?

Many monoclonal antibodies have been approved to treat a wide variety of cancers.

What are the side effects of monoclonal antibodies?

Monoclonal antibodies can cause side effects, which can differ from person to person. The ones you may have and how they make you feel will depend on many factors, such as how healthy you are before treatment, your type of cancer, how advanced it is, the type of monoclonal antibody you are receiving, and the dose.

Doctors and nurses cannot know for sure when or if side effects will occur or how serious they will be. So, it is important to know which signs to look for and what to do if you start to have problems.

Like most types of immunotherapy, monoclonal antibodies can cause skin reactions at the needle site and flu-like symptoms.

Needle site reactions include:

• pain
• swelling
• soreness
• redness
• itchiness
• rash

Flu-like symptoms include:

• chills
• fatigue
• fever
• muscle aches and pains
• nausea
• vomiting
• diarrhea

Monoclonal antibodies can also cause:

• mouth and skin sores that can lead to serious infections
• high blood pressure
• congestive heart failure
• heart attacks
• inflammatory lung disease

Monoclonal antibodies can cause mild to severe allergic reactions while you are receiving the drug. In rare cases, the reaction is severe enough to cause death.

Some monoclonal antibodies can also cause capillary leak syndrome. This syndrome causes fluid and proteins to leak out of tiny blood vessels and flow into surrounding tissues, resulting in dangerously low blood pressure. Capillary leak syndrome may lead to multiple organ failure and shock.

Cytokine release syndrome can sometimes occur with monoclonal antibodies, but it is often mild. Cytokines are immune substances that have many different functions in the body, and a sudden increase in their levels can cause:

• fever
• nausea
• headache
• rash
• rapid heartbeat
• low blood pressure
• trouble breathing

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How does T-cell transfer therapy work against cancer?

T-cell transfer therapy is a type of immunotherapy that makes your own immune cells better able to attack cancer. There are two main types of T-cell transfer therapy: tumor-infiltrating lymphocytes (or TIL) therapy and CAR T-cell therapy. Both involve collecting your own immune cells, growing large numbers of these cells in the lab, and then giving the cells back to you through a needle in your vein. T-cell transfer therapy is also called adoptive cell therapy, adoptive immunotherapy, and immune cell therapy.

The process of growing your T cells in the lab can take 2 to 8 weeks. During this time, you may have treatment with chemotherapy and, maybe, radiation therapy to get rid of other immune cells. Reducing your immune cells helps the transferred T cells to be more effective. After these treatments, the T cells that were grown in the lab will be given back to you via a needle in your vein.

• TIL therapy uses T cells called tumor-infiltrating lymphocytes that are found in your tumor. Doctors test these lymphocytes in the lab to find out which ones best recognize your tumor cells. Then, these selected lymphocytes are treated with substances that make them grow to large numbers quickly.

  The idea behind this approach is that the lymphocytes that are in or near the tumor have already shown the ability to recognize your tumor cells. But there may not be enough of them to kill the tumor or to overcome the signals that the tumor is releasing to suppress the immune system. Giving you large numbers of the lymphocytes that react best with the tumor can help to overcome these barriers.

• CAR T-cell therapy is similar to TIL therapy, but your T cells are changed in the lab so that they make a type of protein known as CAR before they are grown and given back to you. CAR stands for chimeric antigen receptor. CARs are designed to allow the T cells to attach to specific proteins on the surface of the cancer cells, improving their ability to attack the cancer cells.

What cancers are treated with T-cell transfer therapy?

T-cell transfer therapy was first studied for the treatment of metastatic melanoma because melanomas often cause a strong immune response and often have many TILs. The use of TIL therapy has been effective for some people with melanoma and has produced promising findings in other cancers, such as cervical squamous cell carcinoma and cholangiocarcinoma. However, this treatment is still experimental.

Two CAR T-cell therapies have been approved by the Food and Drug Administration, both for blood cancers:

• Tisagenlecleucel (Kymriah™)
• Axicabtagene ciloleucel (Yescarta™)

CAR T-cell therapy has also been studied for the treatment of solid tumors, including breast and brain cancers, but use in such cancers is still experimental.

What are the side effects of T-cell transfer therapy?

T-cell transfer therapy can cause side effects, which people experience in different ways. The side effects you may have and how serious they are will depend on how healthy you are before treatment, your type of cancer, how advanced it is, the type of T-cell transfer therapy you are receiving, and the dose.

Doctors and nurses cannot know for sure when or if side effects will occur or how they will affect you. So, it is important to know which signs to look for and what to do if you start to have problems.

CAR T-cell therapy can cause a serious side effect known as cytokine release syndrome. This syndrome is caused when the transferred T cells, or other immune cells responding to the new T cells, release a large amount of cytokines into the blood.

Cytokines are immune substances that have many different functions in the body. A sudden increase in their levels can cause:

• Fever
• Nausea
• Headache
• Rash
• Rapid heartbeat
• Low blood pressure
• Trouble breathing

Most patients have a mild form of cytokine release syndrome, but in some people it may be severe or life threatening.

Also, although CAR T cells are designed to recognize proteins that are found only on cancer cells, they can also sometimes recognize normal cells. Depending on which normal cells are recognized, this can cause a range of side effects, including organ damage.

TIL therapy can cause capillary leak syndrome. This syndrome causes fluid and proteins to leak out of tiny blood vessels and flow into surrounding tissues, resulting in dangerously low blood pressure. Capillary leak syndrome may lead to multiple organ failure and shock.

There are two types of cancer vaccines: preventive and therapeutic. Preventive vaccines are used to prevent cancer from occurring, whereas therapeutic vaccines are used to treat patients with cancer. Most preventive cancer vaccines target viral infections that are known to lead to cancer. These include vaccines against human papillomavirus (HPV) and hepatitis B, which help prevent cervical and liver cancer, respectively.

Most therapeutic cancer vaccines are in the experimental stage. They exploit tumor-specific antigens to stimulate the immune system to selectively attack cancer cells. Specifically, they aim to enhance T_H1 function and interaction with cytotoxic T cells, which, in turn, results in more effective attack on abnormal tumor cells. In some cases, researchers have used genetic engineering to develop antitumor vaccines in an approach similar to that used for DNA vaccines. The vaccine contains a recombinant plasmid with genes for tumor antigens; theoretically, the tumor gene would not induce new cancer because it is not functional, but it could trick the immune system into targeting the tumor gene product as a foreign invader.

The first FDA-approved therapeutic cancer vaccine was sipuleucel-T (Provenge), approved in 2010 to treat certain cases of prostate cancer. This unconventional vaccine is custom designed using the patient’s own cells. APCs are removed from the patient and cultured with a tumor-specific molecule; the cells are then returned to the patient. This approach appears to enhance the patient’s immune response against the cancer cells. Another therapeutic cancer vaccine (talimogene laherparepvec, also called T-VEC or Imlygic) was approved by the FDA in 2015 for treatment of melanoma, a form of skin cancer. This vaccine contains a virus that is injected into tumors, where it infects and lyses the tumor cells. The virus also induces a response in lesions or tumors besides those into which the vaccine is injected, indicating that it is stimulating a more general (as opposed to local) antitumor immune response in the patient.

How do immune system modulators work against cancer?

Immune-modulating agents are a type of immunotherapy that enhance the body’s immune response against cancer.

Types of immune-modulating agents include:

• Cytokines, which are proteins made by white blood cells. They play important roles in your body’s normal immune responses and in the immune system’s ability to respond to cancer.

  Cytokines that are sometimes used to treat cancer include:

  • Interferons (INFs). Researchers have found that one type of interferon, called INF-alfa, can enhance your immune response to cancer cells by causing certain white blood cells, such as natural killer cells and dendritic cells, to become active. INF-alfa may also slow the growth of cancer cells or promote their death.
  • Interleukins (ILs). There are more than a dozen interleukins, including IL-2, which is also called T-cell growth factor. IL-2 boosts the number of white blood cells in the body, including killer T cells and natural killer cells. Increasing these cells can cause an immune response against the cancer. IL-2 also helps B cells (another type of white blood cell) produce certain substances that can target cancer cells.

  Hematopoietic growth factors are cytokines that are used to reduce side effects from cancer treatment by promoting the growth of blood cells that are damaged by chemotherapy. They include:

  • Erythropoietin, which increases the production of red blood cells
  • IL-11, which increases the production of platelets
  • Granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF), which both increase the number of white blood cells. Boosting white blood cells reduces the risk of infections. G-CSF and GM-CSF can also enhance the immune system response against cancer by increasing the number of cancer-fighting T cells.


• BCG is a weakened form of the bacteria that causes tuberculosis. It does not cause disease in humans. BCG is used to treat bladder cancer. When inserted directly into the bladder with a catheter, BCG causes an immune response against cancer cells. It is also being studied in other types of cancer. BCG stands for Bacillus Calmette-Guérin.


• Immunomodulatory drugs (also called biological response modifiers) stimulate the immune system. They include:
  • Thalidomide (Thalomid®)
  • Lenalidomide (Revlimid®)
  • Pomalidomide(Pomalyst®)
  • Imiquimod (Aldara®, Zyclara®)

  Thalidomide, lenaliodomide, and pomalidomide cause cells to release IL-2. They also stop tumors from forming new blood vessels. Tumors need to form new blood vessels to grow beyond a certain size. These three drugs may also be called angiogenesis inhibitors.

  Imiquimod is a cream that you rub on the skin. It causes cells to release cytokines.

Which cancers are treated with immune system modulators?

Most immune-modulating agents are used to treat advanced cancer. Some are used to help manage side effects.

What are the side effects of immune system modulators?

Immune-modulating agents can cause side effects, which affect people in different ways. The side effects you may have and how they make you feel will depend on how healthy you are before treatment, your type of cancer, how advanced it is, the type of immune-modulating agent you are getting, and the dose.

Doctors and nurses cannot know for sure when or if side effects will occur or how serious they will be. So, it is important to know which signs to look for and what to do if you start to have problems.

Immune-modulating agents can cause flu-like symptoms, which include:

• Fever
• Chills
• Weakness
• Dizziness
• Nausea or vomiting
• Muscle or joint aches
• Fatigue
• Headache

Learn more about flu-like symptoms caused by cancer treatment.

Cytokines can also cause many serious side effects, such as:

• Trouble breathing
• Low or high blood pressure
• Severe allergic reactions
• Lowered blood counts, which can raise the risk of infections and cause bleeding problems
• Blood clots
• Problems with mood, behavior, thinking, and memory
• Skin problems, such as rash, burning at injection site, and ulcers
• Organ damage

BCG can also cause urinary side effects.

Thalidomide, lenalidomide, and pomalidomide can cause:

• Blood clots
• Nerve problems that lead to pain, numbness, tingling, swelling, or muscle weakness in different parts of the body.
• Birth defects, if used during pregnancy

Imiquimod can cause skin reactions.

A new study in mice suggests that for treatment that combines two immunotherapy drugs, the timing and sequence of the drugs’ administration are critical to the treatment’s efficacy and safety.

The study investigators found that treating mice with two different immunotherapy agents at the same time had less of an effect on tumor growth compared with one of the agents alone. But staggering the timing of when the two therapies were given substantially slowed tumor growth and extended survival in the mice. However, this effect was not observed when the therapies were given in the reverse order.

“Studying these mice has given us some insight about how important the schedule [of combination treatment] is,” said the study’s senior investigator Bernard A. Fox, Ph.D., of the Earle A. Chiles Research Institute, Robert W. Franz Cancer Center.

The findings from the study, which was funded in part by NCI and appeared August 28 in Clinical Cancer Research, reinforce that “we need to invest in studying patients more closely, and do really well-controlled clinical trials of immunotherapy combinations,” Dr. Fox added. “I think that’s how we’re going to make greater progress.”

Joining Forces: PD-1 Inhibitors and OX40 Agonists

A T cell is a type of immune cell that has the ability to attack and kill infected or abnormal cells, including cancer cells. This killing ability is carefully controlled by several molecules on the surface of the T cell. For example, PD-1 limits a T cell’s killing ability, while OX40 enhances it.

Targeted therapies that block PD-1 on T cells or its binding partner, PD-L1, on tumor cells lead to increased T-cell activity and a potentially greater antitumor immune response. Several of these so-called immune checkpoint inhibitors have been approved by the Food and Drug Administration to treat certain cancers, including lung cancer and melanoma.

However, PD-1 and PD-L1 inhibitors have demonstrated limited efficacy for patients with many other types of cancer, including breast cancer.

“What we’re struggling with now is figuring out how to take the really deep, durable, and rapid responses we’re seeing with some immunotherapies and broaden the group of patients who have these phenomenal responses,” said James Gulley, M.D., Ph.D., head of the immunotherapy section of NCI’s Center for Cancer Research, who was not involved in the study.

For patients who do not respond to immunotherapy, one problem appears to be that their tumors counteract the immune response induced by these drugs, Dr. Gulley explained. “With a single immunotherapy, the tumor can find a way to shut down the antitumor immune response,” he said.

Dr. Fox and his team wanted to see if, for tumors that do not respond to PD-1 inhibitors, combining the treatment with another type of immunotherapy might be able to overcome these counter measures and generate a more effective antitumor immune response.

They turned to a new class of immunotherapy drugs known as OX40 agonists—drugs that bind to and activate OX40, potently ramping up T-cell activity. Several OX40 agonists are currently being evaluated in clinical trials as potential cancer treatments.

To test their hypothesis, the research team used a mouse model of breast cancer that closely resembles how the disease behaves in humans. After tumors formed in the mice, the researchers left them untreated or treated them with a PD-1 inhibitor, an OX40 agonist, or both immunotherapy agents at the same time.

Compared with untreated mice, PD-1 inhibitor treatment alone had no impact on tumor growth or survival, whereas OX40 agonist treatment alone slowed tumor growth and improved survival, they found.

The combination treatment, however, had less of an effect on tumor growth than the OX40 agonist alone. In addition, the survival benefit observed with OX40 agonist treatment alone was diminished with the combination treatment.

“We were really surprised to see that the addition of those two agents together was significantly less effective” than the OX40 agonist alone, Dr. Fox said.

The researchers also found that mice treated with the combination had very high levels of certain cytokines and exhibited symptoms of cytokine release syndrome (CRS), a side effect of some immunotherapies. CRS is “typically the result of hyperactive T cells that generate massive amounts of cytokines, resulting in symptoms such as low blood pressure, fever, nausea, and rash,” said Dr. Gulley. In some cases, CRS can become severe, resulting in organ failure and even death.

In addition, the combination treatment eventually caused T cells in the mouse tumors to shut down—an effect known as T-cell exhaustion.

The team wondered if sequential treatment with the two drugs might work better to slow tumor growth in the mice. They reasoned that treatment with the OX40 agonist first might provide an initial boost in antitumor T-cell activity, and subsequent treatment with the PD-1 inhibitor might extend it.

Their hunch was accurate: Treatment with the OX40 agonist followed by treatment with the PD-1 inhibitor 2 days later delayed tumor growth and extended the mice’s survival more than treatment with the OX40 agonist alone.

In fact, the sequential combination treatment led to complete tumor regression in 30% of the mice and nearly doubled the group’s survival time compared with concurrent combination treatment. And the sequential treatment did not lead to CRS-like symptoms or T-cell exhaustion.

However, reversing the treatment sequence—treating mice with the PD-1 inhibitor followed by the OX40 agonist—did not slow tumor growth.

Separating the administration of the two drugs “had a profound effect on the biological effects of the drugs,” said Dr. Fox. “The most striking thing was the fact that we could get such long-term survival and apparent cure in some mice if we sequence the therapies,” he added. This kind of response has not been observed in other preclinical studies using the same mouse model, he noted.

Considerations for Immunotherapy Clinical Trials

Dr. Gulley noted that although mouse models are not the perfect surrogate for human biology, they can give good insight into the potential effects of combination treatments in humans.

“This study prompts us to take a step back and say, let’s not just haphazardly combine immunotherapies. Let’s understand the biology of what we’re doing before we do clinical trials,” he said.

Dr. Fox believes combination immunotherapies might be even more effective if a precision medicine approach is incorporated. By examining molecular biomarkers in an individual patient’s tumor, he explained, doctors may better predict which immunotherapies will generate the most effective antitumor immune response in the patient.

“We’re not there yet, but the idea is that we’ll be able to tailor therapy to each individual,” he said.

For example, PD-1 inhibitors and OX40 agonists both strengthen a weak antitumor immune response, so they are best suited for patients with an existing immune response. But patients who have no antitumor immune response at all—which is probably the majority, said Dr. Fox—may require another type of immunotherapy to jump-start their immune systems.

Scientists are testing PD-1 inhibitors and OX40 agonists with other immunotherapies that can trigger an initial antitumor immune response, Dr. Gulley noted.

For example, Dr. Fox and his colleagues are exploring a combination treatment including a cancer vaccine and an OX40 agonist in patients with advanced cancer. In preclinical studies the combination treatment significantly increased antitumor T-cell activity, and the cancer vaccine was recently tested in an NCI-funded phase II trial as adjuvant therapy for patients at high risk of cancer recurrence. They plan to test the vaccine in combination with an OX40 agonist and a PD-1 inhibitor in a subsequent trial.

Immunotherapy drugs have been approved to treat many types of cancer. However, immunotherapy is not yet as widely used as surgery, chemotherapy, or radiation therapy.

Immunotherapy can cause side effects. Many side effects happen when the immune system that is revved-up to act against the cancer also acts against healthy cells and tissues in the body.

Different people have different side effects. The ones you have and how they make you feel will depend on

• how healthy you are before treatment
• your type of cancer
• how advanced your cancer is
• the type and dose of immunotherapy you are getting

You might be on immunotherapy for a long time. And side effects can occur at any point during and after treatment. Doctors and nurses cannot know for certain when or if side effects will occur or how serious they will be. So, it is important to talk with your doctors and nurses about what signs to look for and what to do if you start to have problems.

Some side effects are common with all types of immunotherapy. For instance, you might have skin reactions at the needle site, which include:

• pain
• swelling
• soreness
• redness
• itchiness
• rash

You may have flu-like symptoms, which include:

• fever
• chills
• weakness
• dizziness
• nausea or vomiting
• muscle or joint aches
• fatigue
• headache
• trouble breathing
• low or high blood pressure

Other side effects might include:

• swelling and weight gain from retaining fluid
• heart palpitations
• sinus congestion
• diarrhea
• infection
• organ inflammation

Some types of immunotherapy may cause severe or fatal allergic and inflammation-related reactions. But, these reactions are rare.

Certain side effects might happen depending on the type of immunotherapy you receive. Visit the page for the type of immunotherapy that you are receiving for more details about serious side effects. Types of immunotherapy include:

• immune checkpoint inhibitors
• t-cell transfer therapy
• monoclonal antibodies
• treatment vaccines
• immune system modulators

A growing number of people with cancer have benefited in recent years from immunotherapy—treatments that strengthen the ability of the immune system to detect and destroy cancer.

Some patients have had dramatic and lasting responses to these new treatments, which include immune checkpoint inhibitors and CAR T-cell therapies. In rare cases, patients with advanced cancers have had their tumors disappear completely following treatment with immunotherapy.

But immunotherapy drugs, like all medicines, can cause side effects, including rare complications that, for some patients, may be life threatening.

“Side effects related to immunotherapy drugs occur frequently and can affect almost any organ in the body,” said Sarah Dubbs, M.D., an emergency medicine physician at the University of Maryland School of Medicine who has written about the side effects of cancer immunotherapy.

“Most side effects are mild to moderate in severity and respond to treatments such as steroids,” Dr. Dubbs continued. Doctors caring for patients who are receiving immunotherapy must be vigilant, however, because some patients may develop serious health problems, she added.

As immunotherapy has become a more widely used treatment for cancer, researchers have gained insights into the side effects associated with these treatments, including some complications not previously linked to other cancer treatments.

Building on that work, researchers are now trying to better understand how and why these side effects occur in certain patients and develop strategies for managing them.

An Overly Active Immune System

Drugs that stimulate the immune system to attack tumor cells can, in some patients, cause the immune system to recognize some of the body’s healthy tissues as foreign and attack them.

Some patients receiving immunotherapy develop inflammation of the inner lining of the colon, the lungs, or heart muscle, among other side effects associated with an overly active immune system.

Understanding more about the causes of immunotherapy-related side effects and being able to identify patients most at risk for them could help doctors to select immunotherapy drugs for patients in the future, noted Dr. Dubbs.

To advance research in this area, investigators have been documenting complications associated with immunotherapy drugs, studying the biological mechanisms, modifying immunotherapy drugs to reduce their side effects, and increasing awareness of potential side effects among clinicians and patients.

For example, the side effects of immunotherapy drugs and new ways to manage them were discussed at a recent scientific meeting on emergency medicine for treating patients with cancer, hosted by the University of Texas MD Anderson Cancer Center.

“As emergency room doctors, we are the first line of care, and we need to educate ourselves about new technologies in medicine and be ready to care for our patients,” Dr. Dubbs said.

“When we get a patient’s medical history, we ask what immunotherapy treatment they’re on and it’s important to be specific,” she continued. “With different types of chemotherapy, it was not as important to know exactly which type, because the drugs behave similarly in the body.

“But with immunotherapy drugs it matters, because there are different adverse events associated with different medications, and treatment may vary depending upon which immunotherapy drug a patient had received,” Dr. Dubbs added.

Enhancing the Immune Response

The immune-related side effects of immunotherapy highlight a fundamental difference between these drugs and other cancer treatments: Conventional treatments such as chemotherapy kill tumor cells directly, whereas immunotherapy does not.

Immune checkpoint inhibitors, for example, block proteins that help keep the immune response in check, such as CTLA-4, PD-1, or PD-L1 (a protein that PD-1 attaches to). Blocking one of these proteins “releases the brakes” on the immune system, boosting the ability of immune cells to attack tumor cells.

CAR T-cell therapy uses a different approach to reach the same goal: A patient’s T cells are modified in the laboratory to enhance their ability to recognize and bind to cancer cells and kill them. These modified cells are then expanded in number and infused back into the patient.

Treatment-Related Side Effects Vary

The types of side effects a person receiving immunotherapy experiences will depend on several factors, including the type of immunotherapy, the dose, how healthy the person was before treatment, the type of cancer, and how advanced the cancer is.

For patients receiving immunotherapy drugs that are given intravenously, the most common side effects include skin reactions at the site of the injection, such as pain, swelling, and soreness. Some immunotherapy drugs may cause severe or even fatal allergic reactions, though this is rare.

Not all patients receiving immunotherapy drugs develop immune-related complications. And among patients who do develop these side effects, there is substantial variation in which organs are affected, noted Sang T. Kim, M.D., and Maria E. Suarez-Almazor, M.D., Ph.D., of MD Anderson in a recent commentary on managing side effects associated with checkpoint inhibitors.

Among patients receiving checkpoint inhibitors, the most commonly affected parts of the body are the skin, colon, endocrine system, liver, lungs, heart, musculoskeletal system, and central nervous system, Drs. Kim and Suarez-Almazor added.

Many patients who receive CAR T-cell therapy develop a condition known as cytokine release syndrome, which can cause a fever, fast heart rate, low blood pressure, and rash, among other symptoms. The syndrome is caused by the large and rapid release of proteins called cytokines into the blood from immune cells affected by immunotherapy.

Cytokine release syndrome generally develops within hours to days after an infusion; most patients have a mild reaction to the infusion, but some have more severe responses. Patients also may experience neurologic symptoms such as confusion, tremors, or difficulty communicating.

Unusual and Unexpected Side Effects

The timing of immunotherapy-related side effects is less predictable than with other types of cancer treatments. Patients receiving immunotherapy may develop side effects soon after receiving the first dose of a drug or long after a course of treatment has ended.

Physicians at MD Anderson reported recently, for example, that a patient being treated for sarcoma developed a serious complication of diabetes about 3 weeks after receiving a single dose of the immunotherapy drug pembrolizumab (Keytruda).

The 47-year-old woman, who had no known history of diabetes and had not received immunotherapy previously, was diagnosed with diabetic ketoacidosis during a trip to the emergency room.

“This case of abrupt adult-onset type 1 diabetes mellitus is an example of the undesirable side effects that can emerge after only a brief exposure to an immune checkpoint inhibitor,” Patrick Chaftari, M.D., and his colleagues wrote in a case report about the patient.

Patients receiving checkpoint inhibitors should “be closely monitored” so that potentially life-threatening complications can be diagnosed early and treated, the authors added.

It was after a routine scan a few years ago that doctors identified a suspicious mass in the lungs of an 83-year-old man participating in a clinical trial. The man had been receiving pembrolizumab for about 5 months to treat a type of skin cancer called Merkel cell carcinoma.

Further testing revealed something completely unexpected: While receiving a drug that strengthens the immune response against cancer, the patient developed tuberculosis.

“I was, of course, floored,” said Elad Sharon, M.D., M.P.H., of NCI’s Cancer Therapy Evaluation Program, who monitored side effects on the clinical trial for NCI. Nothing in the patient’s health history indicated that he’d been infected with the bacterium that causes tuberculosis, Mycobacterium tuberculosis (Mtb).

The patient was treated for both tuberculosis and cancer by infectious disease specialists and oncologists who worked in close consultation, and he is still alive, Dr. Sharon noted.

To understand what had happened, Dr. Sharon and his colleagues conducted an analysis of the patient’s disease with Daniel Barber, Ph.D., of the National Institute of Allergy and Infectious Diseases (NIAID), who has studied Mtb and immune responses in mice.

Their results were consistent with findings in mice showing that the use of an immunotherapy drug to boost the immune response can increase the risk or severity of tuberculosis, Dr. Barber and his colleagues reported last year, along with a second case of tuberculosis following immunotherapy.

“We’ve known for a long time that when we boost the responses of immune cells, it can be a good thing or a bad thing,” said Dr. Barber. Among individuals infected with Mtb, boosting the immune response “may be detrimental,” he added.

Managing Treatment-Related Side Effects in Patients

Because cancer immunotherapy drugs are relatively new, there is limited evidence from clinical trials about how to manage treatment-related side effects. “These drugs are so new that many emergency physicians and even some oncologists might not be aware of the potential side effects,” said Dr. Dubbs.

Recognizing this gap in knowledge, the American Society of Clinical Oncology and the National Comprehensive Cancer Network in 2018 issued guidelines for clinicians on managing complications of checkpoint inhibitors. The guidelines include recommendations on when to use steroids and when to discontinue immunotherapy, for example.

A panel of experts developed the guidelines based on a review of the scientific literature. These guidelines provide “best practices” for the management of immune-related side effects within the constraints of limited scientific evidence, noted Drs. Kim and Suarez-Almazor in their editorial. Other organizations also have developed guidance on how to best manage immunotherapy side effects.

Even though many questions about managing immune-related side effects remain unanswered, experts agree on the importance of diagnosing immune-related side effects before they progress to more serious complications.

“Our responsibility is to treat any kind of side effect related to immunotherapy early and effectively,” said Monjur Ahmed, M.D., a gastroenterologist at Thomas Jefferson University, who has written about the side effects of checkpoint inhibitors.

Dr. Ahmed noted that for some patients, this will involve stopping an immunotherapy drug, at least temporarily, and employing drugs such as steroids to treat the immune-related side effects.

“Some patients go back on the same treatment, and some do not,” he said. Identifying the optimal approaches for managing certain side effects will require more research, he added.

“Am I Eligible for Immunotherapy?”

In 2018, the most common question that Emil Lou, M.D., Ph.D., heard from patients with cancer in his clinic at the University of Minnesota was: “Am I eligible for immunotherapy?”

“Most of these patients had seen advertisements for immunotherapy on television or heard a story about a patient’s tumor melting away, and they wanted to know if they could get immunotherapy,” said Dr. Lou, who treats patients with gastrointestinal cancers.

His patients had heard of dramatic and lasting responses to immunotherapy drugs among some patients with advanced cancers.

Although few of his patients have been candidates for immunotherapy based on the genetic features in their tumors, Dr. Lou has discussed the treatment—and possible side effects—when it has been an option.

In these conversations, he would introduce the idea that immunotherapy drugs have side effects. “In that respect, immunotherapy drugs are like all treatments for cancer,” he tells his patients. “They can cause rashes and joint pain and diarrhea. And in a small percentage of patients, immunotherapy can cause shortness of breath and other more serious complications.”

Dr. Lou added, “Immunotherapy drugs are not perfect.”

More Research Needed on Immunotherapy-Related Side Effects

Knowledge gained from decades of treating autoimmune disorders has informed the ways that doctors identify and manage immune-related side effects, noted Dr. Sharon.

But he pointed out that immunotherapy-related side effects may develop through different biological mechanisms than autoimmune disorders, which suggests that the treatment of these side effects may also differ.

To more effectively explore such questions, doctors and researchers need to establish definitions of immunotherapy-related side effects and develop standards for reporting these side effects as they are observed in patients, Dr. Sharon noted.

Doctors could use definitions of immune-related side effects to identify patients who may need to be referred to specialists for treatment, he added.

“In addition to definitions, new biomarkers and tests for diagnosing immune-related side effects are needed, and that will require collaboration from experts across disciplines,” he said.

Dr. Sharon was one of the organizers of a scientific workshop on cancer, autoimmunity, and immunology held last year that brought together experts from different fields to discuss a range of topics, including immune-related side effects.

During a keynote presentation at the meeting, Jeffrey Bluestone, Ph.D., of the University of California, San Francisco, said: “We still have a lot to learn.”

Among other questions, it’s not clear why immune-related side effects occur in some patients but not in others or why different drugs induce different diseases in different patients, he added.

Whether treatment-related side effects could be an indication that a patient might be responding to immunotherapy is an area of ongoing research that was discussed at the workshop.

“We’d like to know whether having immune-related side effects could be a good sign for a patient’s treatment,” Dr. Sharon said, noting that there “isn’t any definitive evidence yet on this question one way or the other.”

Answering such questions could take years, but efforts are under way to advance the research.

For example, NCI has established a network of laboratories and a data center that could help identify biomarkers associated with the response to immunotherapy or treatment-related side effects. And researchers are working on developing mouse models for immunotherapy research as well as a biorepository for patients in immunotherapy clinical trials.

Some of these efforts and related ongoing work were discussed at the second workshop on cancer, autoimmunity, and immunology, which was sponsored by the National Institutes of Health and the American Association for Cancer Research, on April 15–16, 2019. [Recordings of both days of the workshop are available on the NIH Videocast website: day one and day two.]

“As we did last year, we brought together experts from different fields to help us to better understand these important new immunotherapy drugs, which are a real advance for patients,” said Dr. Sharon.

Cytokine release syndrome is a condition that may occur after treatment with some types of immunotherapy, such as monoclonal antibodies and CAR-T cells. Cytokine release syndrome is caused by a large, rapid release of cytokines into the blood from immune cells affected by the immunotherapy. Cytokines are immune substances that have many different actions in the body.

Signs and symptoms of cytokine release syndrome include fever, nausea, headache, rash, rapid heartbeat, low blood pressure, and trouble breathing. Most patients have a mild reaction, but sometimes, the reaction may be severe or life threatening.

Immunotherapy is a type of cancer treatment that strengthens your immune system’s response to cancer. One type of immunotherapy, called immune checkpoint inhibitor therapy, can trigger an immune response that causes inflammation to organs in your body. You’ll notice the suffix “-itis” (which means inflammation) in the names of many of these conditions.

Doctors and researchers are working to learn more about the best ways to prevent or manage inflammation-related side effects. Sometimes these side effects are managed with medicines, such as steroids, that work to slow down an overactive immune response. These side effects may be serious and even life-threatening. It’s important to talk with your health care team to know what signs and symptoms to expect, as well as when they may happen and what to do if they occur.

For people with an autoimmune disease it’s especially important to discuss this disease with your health care provider before starting treatment.

Side Effects in People Receiving Immunotherapy

This list of side effects can be a helpful reference as you learn more from your health care team about what to expect, based on the treatment you will be receiving.

Side effects are more common in these organs and systems:

• Digestive system: Inflammation to organs in your digestive system, called colitis, may cause stomach or abdominal pain, diarrhea, and black or bloody stools. Some people have mild hepatitis, which is diagnosed during a blood test.
• Endocrine system: When hormone-producing glands are inflamed you may have some of the problems listed below. Your doctor will check your hormone levels regularly to detect and diagnose these problems.
  • Pituitary gland inflammation is the most common endocrine system-related inflammatory problem; it may cause headaches and fatigue.
  • Adrenal gland inflammation may cause fatigue, muscle weakness, loss of appetite, weight loss, and abdominal pain.
  • Thyroid gland inflammation can cause problems such as hypothyroidism (which may cause weakness, constipation, dry skin, weight gain, and sensitivity to cold) and hyperthyroidism (which may cause diarrhea, weight loss, sweating, sensitivity to heat, and, in rare cases, atrial fibrillation).
  • Pancreatic inflammation, called pancreatitis, may cause severe abdominal pain, nausea, and vomiting.
• Musculoskeletalsystem: Inflamed joints and muscles may cause you to feel pain and weakness. Inflammation of the muscles is referred to as myositis. You may also have rheumatologic problems.
• Respiratory system (lung problems): Inflammation in the lungs, called pneumonitis, can cause you to feel short of breath and have a bad cough.
• Skin: Skin inflammatory problems may include rashes, itchy skin, blisters, and sores. Learn more about how to manage skin and nail changes.

Side effects are less common in these organs and systems:

• Blood (hematologic problems): You may bleed or bruise easier, a condition called thrombocytopenia. Other blood-related problems include anemia and neutropenia.
• Eyes: You may have vision changes and/or eye pain caused by inflammatory problems such as uveitis or episcleritis.
• Heart inflammation, called myocarditis, may lower your blood pressure. In rare cases, it may lower your heart’s ability to pump blood, disrupt your heartbeat, and cause a heart attack.
• Kidney inflammation, called nephritis, may decrease the amount of urine you produce. You may see blood in your urine.
• Liver inflammation, called hepatitis, may cause your skin and eyes to be yellowish. You may also have nausea or vomiting, stomach pain, fatigue, darker urine, and bleeding or bruising.
• Nervous system inflammation may cause your hands, feet, and sometimes your face to tingle and feel numb or weak. Inflammation to the brain, called encephalitis, may cause mild flu-like symptoms or more serious side effects, such as a sudden and high fever, confusion, hallucinations, seizures, and vomiting.

Be Alert for Changes and Problems

It’s important to have any possible inflammatory problems assessed by your oncologist. Your oncologist may advise you to call him or her first about inflammatory symptoms, or you may be advised to seek emergency medical care.

Write down key information about your treatment and keep it handy, in case you need to share it with doctors in the emergency room. It’s important for other medical professionals to know you are receiving immunotherapy, so you’ll want to write down:

• the drug name(s)
• your doctor’s contact information
• your hospital’s contact information

After Talking with Your Health Care Team, Make Sure You Have Answers to These Questions

• What organ-related inflammatory side effects might I have, based on the type of immunotherapy I am receiving?
• Should I try to manage any of these side effects at home?
• What side effects should I call you about? Which side effects need urgent medical care? Where should I go to get urgent medical care?
• When might these side effects start? How long might they last?
• What type of medicine or therapy is used to treat side effects that I may have?
• How long will it take to resolve any side effects?
• How long after treatment might these side effects occur?

Cancer treatments may cause skin and nail changes. Talk with your health care team to learn what side effects your treatment may cause. While skin problems caused by radiation therapy and chemotherapy are often mild, they may be more severe if you are receiving a stem cell transplant, targeted therapy, or immunotherapy. Let your health care team know if you notice any skin changes so they can be treated promptly.

• Sometimes radiation therapy can cause the skin on the part of your body receiving radiation to become dry and peel, itch (called pruritus), and turn red or darker. Your skin may look sunburned or become swollen or puffy. You may develop sores that become painful, wet, and infected. This is called a moist reaction.
• Some types of chemotherapy can cause your skin to become dry, itchy, red or darker, or peel. You may develop a minor rash or sunburn easily; this is called photosensitivity. Some people also have skin pigmentation changes. Your nails may be dark and cracked, and your cuticles may hurt. If you received radiation therapy in the past, the area of skin where you received radiation may become red, blister, peel, or hurt. This is called radiation recall. Signs of an allergic response to chemotherapy may include a sudden or severe rash or hives or a burning sensation.
• Stem cell transplants can cause graft-versus-host disease (GVHD), which may cause skin problems such as a rash, blisters, or thickening of the skin.
• Some types of immunotherapy can cause a severe and sometimes extensive rash. Your skin may be dry or blister.
• Some types of targeted therapy may cause dry skin, a rash, and nail problems. If you develop a rash, it is important to talk with your doctor before stopping targeted therapy.

Ask Your Health Care Team about Skin and Nail Changes

• What skin and nail changes might I have, based on the cancer treatment I am receiving?
• Which symptoms can be managed at home? Which symptoms need urgent medical care?

If you have a severe, extensive, blistering, or painful rash and are receiving immunotherapy, call your doctor to get their advice. It’s especially important to call about rashes that involve the eyes or a mucous membrane, such as your mouth, caused by immunotherapy.

Make note of all problems you should call your health care team about.

Skin changes:

• Acne (Acneiform eruptions)
• Bed sores (pressure ulcers)
• Blisters
• Burning or skin pain
• Dry skin
• Hand-foot syndrome (palmar-plantar erythrodysesthesia)
• Hyperpigmentation (darker areas of skin, tongue, and joints)
• Hypopigmentation (patches of skin that are lighter)
• Itchy skin (pruritus)
• Keratoacanthoma (dome-shaped skin growth)
• Peeling, flakey, or crusty skin
• Photosensitivity (sunburn easily)
• Rash
• Red or darkened skin
• Sores that are painful
• Swollen skin

Nail changes:

• Cracked nails
• Cuticles that are swollen and/or painful
• Nail infections (acute paronychia)
• Yellow nails

Ways to Prevent or Manage Mild Skin and Nail Changes during Cancer Treatment

Talk with your health care team to learn if you should manage these problems at home. Depending upon the treatment you are receiving, your health care team may advise you to take these steps:

• Use only recommended skin products. Use mild soaps that are gentle on your skin. Ask your nurse to recommend specific skin products. If you are receiving radiation therapy, ask about skin products, such as powder or antiperspirant, that you should avoid using before treatment.
• Prevent infection: Radiation therapy can cause skin in the treatment area to peel, become painful, and wet. Most often this happens in areas where the skin folds, such as around your ears, breast, or bottom. Try to keep the area clean and dry so it does not become infected. Your nurse will talk with you about how to clean the area and may prescribe special dressings that you can apply to the area and/or antibiotics.
• Moisturize your skin. Use recommended creams or lotions to prevent your skin from becoming dry and itchy. Irritated skin can become infected. Ask about special creams or ointments for severely dry, itchy, or painful skin.
• Protect your skin: Use sunscreen and sun-protective lip balm. Wear a loose-fitting long-sleeved shirt, pants, and a hat with a wide brim when outdoors to prevent sunburn. If you are receiving radiation therapy, don’t use heating pads, ice packs, or bandages on the treatment area. You may want to shave less often and use an electric razor or stop shaving if your skin is tender and sore.
• Prevent or treat dry, itchy skin. Avoid products that list alcohol or fragrance as an ingredient, since they can dry or irritate your skin. Your nurse may suggest you add colloidal oatmeal to your baths, as it can reduce itching. Take short showers or baths in lukewarm, not hot, water. Put on skin cream or ointment that is recommended by your nurse after drying off from a shower but while your skin is still a little damp. Apply a cool washcloth or ice to dry, itchy skin.
• Prevent or treat minor nail problems. Keep your nails clean and cut short to avoid accidentally tearing them. Protect your hands and nails by wearing gloves when you wash the dishes, or clean the house, for example. Avoid getting manicures and pedicures. Don’t wear tight-fitting shoes. Ask your nurse to recommend products that can be used to treat nail problems.
• Learn about treatments for irritating or painful skin rashes: Sometimes skin problems need medical treatment. Your rash may be treated with a medicated cream (topical corticosteroids) or with medicine that you take as a pill (oral corticosteroids or antibiotics).

Talking With Your Health Care Team about Skin and Nail Changes

Prepare for your visit by making a list of questions to ask. Consider adding these questions to your list:

• What skin-and nail related side effects are common for the type of treatment I’m receiving?
• Are there steps I can take to prevent any of these problems?
• What problems should I call you about? Are there any problems that need urgent medical care?
• When might these problems start? How long might they last?
• What brands of soap and lotion would you advise me to use on my skin? On my nails?
• Are there skin and nail products I should avoid?
• Should I see a dermatologist so I can learn more about how to prevent or manage skin problems?

Immunotherapy drugs known as immune checkpoint inhibitors (ICIs) are used to treat a growing number of cancers. These drugs can work very well, shrinking tumors and keeping them at bay for long periods. But for some patients, they can also have serious side effects.

A rare, but often fatal, side effect of these drugs is myocarditis, a raging inflammation in the heart. Researchers have now identified what they believe is one of the chief causes of this serious problem: immune cells called T cells attacking a protein in heart cells called α-myosin.

The study was done largely in mice, using mouse models that experience myocarditis after treatment with ICIs in much the same way as humans.

Limited experiments using blood and tissue samples from several people who had died of ICI-induced myocarditis were consistent with the mouse findings, the researchers reported November 16 in Nature.

“We’re starting to better understand the mechanisms of the [side effects] caused by immune checkpoint inhibitors. And now we have a better understanding of myocarditis” caused by ICIs, said study co-leader Justin Balko, Pharm.D., Ph.D., who develops new cancer treatments at the Vanderbilt University Medical Center. 

The findings could help researchers find a way to identify people who may be at increased risk of this side effect or even ways to prevent it, Dr. Balko continued.

“But we need a lot more data from a lot more patients before we can do that,” he said.

As more people take ICIs, myocarditis becomes a greater concern

Immune checkpoint inhibitors help the immune system detect and attack tumors, and in so doing they can recruit an army of T cells. But those T cells can sometimes go where they aren’t wanted, attacking healthy cells in different parts of the body, most commonly the colon and lungs.

These organs become inflamed, causing pain, difficulty breathing, and other symptoms. These side effects are typically treated with steroids, which can have their own side effects.

Dr. Balko and two other researchers on the study, Doug Johnson, M.D., and Javid Moslehi, M.D., started looking into ICI-induced myocarditis more than 6 years ago. Drs. Johnson and Moslehi, both clinical researchers at Vanderbilt at the time, had come to Dr. Balko to discuss an alarming problem: Two melanoma patients treated with a combination of ICIs developed severe myocarditis and died.

In collaboration with researchers at several other institutions, they published a short paper on these two deaths. Based on the response to their paper from other clinicians, they learned that these were not isolated incidents.

“It was definitely an issue and something that we felt we needed to solve,” Dr. Balko said.

The most recent data now suggest that less than 1% of people treated with ICIs get severe myocarditis, explained Elad Sharon, M.D., of NCI’s Cancer Therapy Evaluation Program. The condition, Dr. Sharon explained, occurs more often in people treated with the combination of two different checkpoint inhibitors. 

Despite its rarity, ICI-induced myocarditis is a serious concern, explained Syed Saad Mahmood, M.D., M.P.H., of Weill Cornell Medicine and a cardiologist who specializes in “cardio-oncology.” 

Experimental Drug Protects Heart from Doxorubicin

In mice, the drug did not interfere with doxorubicin’s ability to kill cancer cells.

This year “up to 1 million people [in the United States] with cancer may be candidates for an immune checkpoint inhibitor” at some point in their treatment course, Dr. Mahmood said. As many as half of the people who develop ICI-induced myocarditis will have a serious heart-related event, he continued, and many of those will die as a result. 

“That’s a lot of patients who may be considered at risk were they to be treated, especially [because we’ve] had a limited understanding of who is predisposed to myocarditis,” he said.

Immune checkpoint inhibitors are also increasingly being used in people who have earlier-stage cancer, both before and after surgery, Dr. Sharon said. To date, using immunotherapy in this way has generally been shown to improve a patient’s cancer-related outcomes, Dr. Sharon said. 

But it also means that “we’re giving checkpoint inhibitors to a healthier population of people,” he continued, and serious inflammatory side effects like myocarditis become a bigger concern.

Provoking an immune attack on the heart

In 2021, many of the same researchers involved in this new study published a paper describing a mouse model of ICI-induced myocarditis they had developed. With this model in hand, Dr. Balko said, the team could start to more thoroughly investigate why this inflammation occurs and, possibly, how to prevent it.

Some of the team’s findings were expected, Dr. Balko said. An overabundance of T cells is a hallmark of inflammation, so it wasn’t surprising that they found so many T cells in and around the hearts of the mice with myocarditis. 

But two other key findings were more of a surprise. One was that most of the T cells were CD8+ T cells, the kind of T cells that are primarily responsible for killing infected or diseased cells. The other was that a heavy presence of CD8+ T cells was a prerequisite for this type of myocarditis. Large populations of other types of T cells, they showed, did not cause serious inflammation in the heart. 

They also speculated from the beginning that α-myosin may be involved in myocarditis, Dr. Balko noted. As a protein that’s critical to the heart’s contracting functions, it’s one of the most common proteins in the heart. And earlier studies had linked the protein with myocarditis.

Focusing on α-myosin proved to be fruitful. For example, not only did α-myosin induce the production of more T cells (known as expansion), but many of the T cells in and around the hearts of the mice with myocarditis only recognized—and grabbed on to—α-myosin.

Taken together, Dr. Balko and his colleagues believe their findings indicate that α-myosin may be an “autoantigen” in mice—that is, it unleashes an autoimmune response, redirecting immune cells to attack the heart.

The question then became: Is α-myosin doing the same thing in humans? 

The researchers’ analysis of blood and tissue samples from three people who had ICI-induced myocarditis seemed to suggest that it may be. For example, as was seen in the mouse studies, many of the T cells in those samples recognized α-myosin specifically.

Prospects for myocarditis biomarkers and treatment

Dr. Balko cautioned that more research is needed to confirm that, in humans, myocarditis is caused by an accumulation of CD8+ T cells that specifically recognize α-myosin. If so, he’s hopeful that their work can lead to ways to better address ICI-induced myocarditis. 

Investigating the Cardiac Side Effects of Cancer Treatments

Cardiologists, oncologists working to better address cardiotoxicity.

Their findings “give us opportunities to develop biomarkers and diagnostics to identify patients at risk” of myocarditis, he said. “We’re working on that now.”

Dr. Mahmood said the findings might also point to potential options for treating ICI-induced myocarditis, he continued, such as potentially developing drugs that only block CD8+ T cells or that only recognize α-myosin.

In the meantime, at least one study has identified a way to potentially spot ICI-induced myocarditis before it becomes severe. And a large clinical trial is currently testing the drug abatacept (Orencia) as a treatment for ICI-induced myocarditis. Abatacept, which is approved to treat several autoimmune diseases, including rheumatoid and other forms of arthritis, works by blocking T cells.

When it comes to the side effects of immunotherapy drugs, it’s important to strike a balance, Dr. Sharon cautioned. 

“These are potentially life-saving therapies,” he said. Although the potential for any side effects ICIs may cause has to be considered, “we don’t want people to avoid taking them because of the fear of rare side effects.” 

The data on ICIs strongly favors their use for patients with potentially lethal cancers, he continued. 

“What this study shows most of all is that we have a path forward for finding ways to prevent, mitigate, and treat severe side effects of ICIs like myocarditis.”

Different forms of immunotherapy may be given in different ways. These include:

• Intravenous (IV)
  The immunotherapy goes directly into a vein.
• Oral
  The immunotherapy comes in pills or capsules that you swallow.
• Topical
  The immunotherapy comes in a cream that you rub onto your skin. This type of immunotherapy can be used for very early skin cancer.
• Intravesical
  The immunotherapy goes directly into the bladder.

You may receive immunotherapy in a doctor’s office, clinic, or outpatient unit in a hospital. Outpatient means you do not spend the night in the hospital.

How often and how long you receive immunotherapy depends on:

• Your type of cancer and how advanced it is
• The type of immunotherapy you get
• How your body reacts to treatment

You may have treatment every day, week, or month. Some immunotherapies are given in cycles. A cycle is a period of treatment followed by a period of rest. The rest period gives your body a chance to recover, respond to the immunotherapy, and build new healthy cells.

You will see your doctor often. He or she will give you physical exams and ask you how you feel. You will have medical tests, such as blood tests and different types of scans. These tests will measure the size of your tumor and look for changes in your blood work.

Researchers are focusing on several major areas to improve immunotherapy, including:

• Finding solutions for resistance.
  Researchers are testing combinations of immune checkpoint inhibitors and other types of immunotherapy, targeted therapy, and radiation therapy to overcome resistance to immunotherapy.
• Finding ways to predict responses to immunotherapy.
  Only a small portion of people who receive immunotherapy will respond to the treatment. Finding ways to predict which people will respond to treatment is a major area of research.
• Learning more about how cancer cells evade or suppress immune responses against them.
  A better understanding of how cancer cells get around the immune system could lead to the development of new drugs that block those processes.
• How to reduce the side effects of treatment with immunotherapy.