CAR-T cell therapy

CAR-T cell therapy is a cancer treatment that takes cells from the body and genetically changes them so they can fight cancer. It’s most often used to treat cancers that affect blood cells, such as certain types of leukemia, lymphoma and multiple myeloma.

CAR-T cell therapy stands for chimeric antigen receptor (CAR)-T cell therapy. This treatment falls under the category of immunotherapy. Immunotherapy for cancer harnesses the body’s immune system to attack cancer cells.

Making CAR-T cells starts with collecting a person’s own T cells. T cells, also known as T lymphocytes, are a type of white blood cell. T cells are key players in the body’s immune system because of their ability to identify and attack cells that don’t belong in the body, such as germs and cancer cells.

For CAR-T cell therapy, T cells are collected from the blood using a process called leukapheresis. In the lab, these T cells are modified to produce synthetic proteins called chimeric antigen receptors (CARs).

The modified cells are called CAR-T cells. The cells are grown to much higher numbers in the lab and then infused back into the person’s bloodstream.

The synthetic CARs allow the T cells to bind to specific proteins called antigens on cancer cells. This binding activates the T cells to kill the cancer cells. Dying cancer cells trigger further immune responses against the cancer. In addition, CAR-T cells can keep multiplying in the body, producing lasting anticancer results.

Types of CAR-T cell therapies

Different CARs can be made to target different antigens on the surface of cancer cells. The U.S. Food and Drug Administration (FDA) has approved many CAR-T cell therapy treatments for use. Some examples of these treatments include:

• Tisagenlecleucel (Kymriah). Tisagenlecleucel targets the CD19 antigen in pediatric and adult B-cell acute lymphoblastic leukemia, large B-cell lymphoma, and follicular lymphoma. Tisagenlecleucel also is known as tisa-cel.
• Axicabtagene ciloleucel (Yescarta). Axicabtagene ciloleucel targets the CD19 antigen in large B-cell lymphoma and follicular lymphoma. Axicabtagene ciloleucel also is known as axi-cel.
• Brexucabtagene autoleucel (Tecartus). Brexucabtagene autoleucel targets the CD19 antigen in mantle cell lymphoma and adult B-cell acute lymphoblastic leukemia. Brexucabtagene autoleucel also is known as brexu-cel.
• Lisocabtagene maraleucel (Breyanzi). Lisocabtagene maraleucel targets CD19 in large B-cell lymphoma, chronic lymphocytic leukemia, follicular lymphoma and mantle cell lymphoma. Lisocabtagene maraleucel also is known as liso-cel.
• Idecabtagene vicleucel (Abecma). Idecabtagene vicleucel targets the B-cell maturation antigen (BCMA) in multiple myeloma. Idecabtagene vicleucel also is known as ide-cel.
• Ciltacabtagene autoleucel (Carvykti). Ciltacabtagene autoleucel targets BCMA in multiple myeloma. Ciltacabtagene autoleucel also is known as cilta-cel.
• Obecabtagene autoleucel (Aucatzyl). Obecabtagene autoleucel targets CD19 in adult B-cell acute lymphoblastic leukemia. Obecabtagene autoleucel also is known as obe-cel.

This ability to be specific to a particular antigen makes CAR-T cell therapy different from other T-cell therapies, such as tumor-infiltrating lymphocyte and T-cell receptor therapies.

Tumor-infiltrating lymphocyte (TIL) therapy uses your own white blood cells to fight cancer cells — usually in the context of solid tumors. In this case, some white blood cells in the body have recognized and attached to cancer cells; there just may not be enough of them to overcome the cancer. These white blood cells are called tumor-infiltrating lymphocytes. TIL therapy extracts these white blood cells from a section of the cancer that has been surgically removed. The cells are grown in a lab and returned to the body to fight the cancer.

T-cell receptor (TCR) therapy extracts T cells from a person’s blood, similar to CAR-T cell therapy. Unlike T cells in CAR-T cell therapy, T cells in TCR therapy are engineered to express a natural T-cell receptor that recognizes proteins inside the cancer cells, rather than just on the surface. TCR therapy has been used to treat solid tumors. TCR therapy can target antigens that CAR-T cell therapy cannot reach.

CAR-T cell therapy also is different from stem cell transplant (SCT). Another term for stem cell transplant is bone marrow transplant. People who receive stem cell transplant receive healthy bone marrow stem cells. When the stem cells are donated from someone else, this is called an allogeneic SCT. When the stem cells used are a person’s own cells, it is called an autologous SCT.

CAR-T cell therapy is used to treat cancers that affect blood cells. This includes some types of leukemia, lymphoma and multiple myeloma.

CAR-T cell therapy may be recommended when a cancer:

• Doesn’t respond to other treatments, also called refractory cancer.
• Comes back within 12 months after the first treatment, or after several prior treatments, also called recurrent or relapsing cancer.

CAR-T cell therapy is approved to treat recurrences of the following cancers:

• B-cell acute lymphoblastic leukemia. This type of blood cancer is the most common cancer found in children.
• Chronic lymphocytic leukemia. This leukemia progresses more slowly than other leukemias. It occurs most often in older adults.
• Certain B-cell non-Hodgkin lymphomas. Lymphomas are cancers that affect white blood cells in the lymphatic system — a network of organs, glands, vessels and clusters of cells called lymph nodes. B-cell lymphomas for which CAR-T cell therapy may be an option include diffuse large B-cell lymphoma and primary mediastinal large B-cell lymphoma. They also include high-grade B-cell lymphoma, aggressive B-cell lymphoma not otherwise specified, follicular lymphoma and mantle cell lymphoma.
• Multiple myeloma. This uncommon form of blood cancer affects bone marrow. The cancer forms in a type of white blood cell called a plasma cell.

CAR-T cell therapy may not be for every person diagnosed with one of these cancers. Discuss the treatment risks and benefits with your cancer team. Also keep in mind that CAR-T cell therapy is evolving for many different types of cancers, sometimes in clinical trials. Ask your team if a clinical trial may be right for you.

Like other cancer treatments, CAR-T cell therapy has risks including long wait times and serious side effects that may require hospitalization. Some side effects can be life-threatening, so the healthcare team carefully watches for these side effects during and after treatment.

Long wait

It’s possible that you may need to wait up to two months for your T cells to be modified in the lab. Waiting this long may increase the chances that your cancer will progress.

Inflammatory side effects

The large quantity of CAR-T cells in the body after a treatment infusion helps stimulate the immune response. This in turn elevates inflammation levels.

Increased inflammation can sometimes cause a group of symptoms called cytokine release syndrome (CRS). Symptoms may include:

• High fever.
• Fast heart rate.
• Low blood pressure.
• Low blood oxygen.
• Rash.
• Headache.
• Body aches.

If severe, cytokine release syndrome can be fatal, although this is rare.

Another rare complication is a second potentially fatal inflammatory reaction. This may happen in people who’ve already recovered or been treated for cytokine release syndrome. Symptoms include high iron levels in the blood, low blood cell counts, blood-clotting problems, high liver enzyme levels and organ failure. This group of symptoms is referred to by the very long name of immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS).

Treatment is available for inflammatory side effects.

Nervous system side effects

CAR-T cells are small enough that they can cross the blood-brain barrier. This barrier is a protective membrane that separates the brain’s blood supply from the rest of brain tissue.

Within the brain and central nervous system, activated T cells can cause a group of symptoms known as immune effector cell-associated neurotoxicity syndrome (ICANS).

Symptoms typically include:

• Confusion.
• Difficulty remembering things.
• Excessive drowsiness.
• Trouble speaking.
• Fainting.
• Numbness in the hands and feet.
• Seizures.
• Brain swelling.

More-severe forms of ICANS can cause trouble with movement, seizures and brain swelling.

Treatment is available for these side effects too.

Low blood cell count and infections

After having CAR-T cell therapy, you have a higher chance of getting infections. This is because the treatment can lower your blood cell count, including white blood cells, which weakens your immune system.

Right after treatment, people are more likely to get bacterial infections. These usually happen in the first month. An increased risk of viral infections, such as colds or other breathing illnesses, may persist for even a year after treatment. Serious infections, including from COVID-19, also are possible. People may get serious fungal infections, but this isn’t common.

Taking extra measures to minimize the spread of germs can help. Preventive steps might include frequent hand-washing, limiting exposure to people who are sick, and avoiding uncooked or raw foods.

Cancer recurrence

One of the challenges facing CAR-T cell therapy is that cancer cells can change over time, adapting to new environments and treatments. For example, cancer cells can produce different antigens than the one the treatment is targeting. Having these other antigens may allow the cancer cells to escape the immune system and keep multiplying. Scientists are hoping to come up with treatments that target more than one antigen at once or target them in succession.

Secondary cancers

A few people have developed other kinds of blood or bone marrow cancers within five years of receiving CAR-T cell therapy. But it’s not clear whether this was due to CAR-T cell therapy or other treatments they received, such as chemotherapy. Because these developments have been rare, the benefit of CAR-T cell therapy is likely to outweigh the risk of a secondary cancer.

CAR-T cell therapy usually is offered at specialized medical centers. If you have a blood cancer that is not responding to treatment or has come back, your cancer doctor may refer you to a hospital that specializes in CAR-T cell therapy.

Evaluation and planning

At the hospital, you meet with a specialist or a team of specialists to determine whether CAR-T cell therapy is a good option for you. The team reviews various aspects of your health, including your medical history, diagnosis, stage of cancer and previous treatments you may have received. Most people need additional blood work, imaging scans and other tests after the initial discussion.

The CAR-T cell therapy specialist can help you assess the risks and benefits of CAR-T cell therapy for your circumstances. You also may be pointed toward a clinical trial or another treatment that may be more helpful for you.

This initial evaluation takes about a week. If you go ahead with the therapy, plan for a total treatment time of several months from referral to end of treatment. You need to be close to the hospital at different stages, especially during and after infusion of T cells. This may involve relocating for a time.

Most hospitals offering CAR-T cell therapy require you to have a caregiver with you during and after the infusion. This caregiver needs to stay with you 24 hours a day when you’re not in the hospital. A caregiver can:

• Get you to and from appointments and help you with daily routines.
• Watch you for side effects.
• Contact your healthcare team should you need help.
• Advocate for you.
• Provide practical and emotional support.

Often, these hospitals have a dedicated team to help you through different aspects of CAR-T cell therapy. This might include learning about the treatment, getting insurance approval, arranging transportation and finding housing.

Collection of T cells

If CAR-T cell therapy is an appropriate treatment for you, the next step is collection of your T cells. For this step, you go to the hospital where you’ll receive your treatment. This visit is usually as an outpatient, which means you don’t have to stay in the hospital unless it’s necessary for your safety and health.

Before this step, your healthcare team may have you stop any treatments that might have a negative impact on your T cells, such as chemotherapy, immunosuppressive medicines or steroids. Your care team also pauses any blood-thinning medicines that might increase your risk of bleeding.

The process for collecting your T cells is called leukapheresis. For some people, the cells are withdrawn using a thin, flexible tube called a catheter placed in a vein in the arm. For others, the best option is to collect cells through a catheter placed into a large vein in the chest or neck.

The catheter is connected to a machine that filters T cells from the blood being withdrawn and returns the rest of the blood to your body. This process can take several hours. Most people are able to have enough white blood cells collected during one session.

You’ll likely feel tired after the procedure, but you should be able to return home after this.

Lab modification of T cells

Once your T cells are collected, they are sent to a special laboratory. Lab professionals modify the cells to target the specific antigen that your cancer produces. Total manufacturing time usually takes around two weeks, although it can take up to a couple of months.

Bridging therapy

While you’re waiting, you may need to have what’s called bridging therapy. This is treatment such as chemotherapy, immunotherapy or radiation therapy to keep cancer growth to a minimum until your CAR-T cells are ready.

Rest and prep for infusion

Most people can go home while their T cells are being modified. Follow the instructions your healthcare team gives you about how to take care of yourself during this time. Tell your healthcare team about any new or worsening symptoms or about changes in your health.

You can use this time to finalize plans. The preparation for infusion, the infusion itself and care after the infusion happens without time in between. Plan to be near your treatment hospital for several weeks to months once the preparation for infusion begins.

When your CAR-T cells are ready, they’re sent back to your treatment facility for the infusion process. At this point, you and your caregiver need to be close to the treatment hospital. If you don’t live nearby, you may need to move closer to the hospital.

Before CAR-T cell infusion

About five days before the infusion, your healthcare team reassesses your health to make sure you’re ready for the treatment Your care team also wants to make sure you’re not fighting any active infections. This is so that treatment won’t overburden your immune system. If you’re still a good candidate for the therapy, you’ll be given chemotherapy daily over three days. You might hear this process referred to as lymphodepleting chemotherapy. This is to lower your level of existing T cells and make room for the new CAR-T cells. It also helps minimize anti-CAR reactions from your immune system.

Lymphodepleting chemotherapy is usually an outpatient procedure unless hospitalization is needed.

Make sure to tell your healthcare team if you experience side effects from the chemotherapy. There may be treatments that can ease the side effects and make you more comfortable.

After the chemotherapy, you typically have a couple of days to rest. Your CAR-T cell team gives you instructions about next steps and when to come for your infusion.

During CAR-T cell infusion

On the day of your infusion, your CAR-T cell team meets with you. Your care team runs a few tests to make sure that your health is stable and that you’re infection-free.

The CAR-T cells are given through a vein. The procedure may be done as an outpatient procedure, or you may be admitted to the hospital. The infusion is painless. You’re awake during the procedure. It usually takes about 30 to 90 minutes and sometimes as little as 15 minutes. However, plan for the infusion visit to take several hours to allow for care before and after the infusion.

After CAR-T cell infusion

Some people experience mild reactions, such as fever, itching and upset stomach, immediately after infusion.

Not everyone has a reaction. A reaction is not a sign that the treatment is or is not working.

Typically, your CAR-T cell team lets you know if you need to stay in the hospital right after the infusion.

Over the following weeks, CAR-T cells grow and multiply in your body. This can lead to the inflammatory side effects and the effects on your brain and nervous system. During this time, your healthcare team watches you closely and conducts daily tests. Doing this can help your care team identify and treat potentially life-threatening reactions to CAR-T cell therapy early. Depending on how your body reacts to the infusion, you may or may not need to be admitted to the hospital.

Monitoring may include:

• Physical exams. You may have one or more physical exams each day in the beginning.
• Blood tests. Your blood may be drawn daily to check your blood cell counts. Blood tests can show signs of an infection or other possible problems.
• Simple tasks. You may be asked to do simple tasks several times a day, such as write your name or create simple sentences. You may be asked for today’s date or other facts. Doing these steps can help your healthcare team know whether you are showing early signs of a neurotoxic reaction to the infused T cells.

When you’re not in the hospital, your caregiver should stay with you 24 hours a day. Your healthcare team tells you what activities you can and can’t do and provides any eating restrictions. For example, you can’t drive for an extended period after the infusion.

The results of CAR-T cell therapy can take time. Ask your healthcare team when you might know how well it’s working. During recovery, you have tests to check your cancer and you meet with your specialist to review results and plan future care.

Once your health is stable — usually about a month after the infusion — you can go home. After you go home, your local healthcare team takes over your care. Your local care team continues to monitor you for infections and any lingering side effects.

During the first year after CAR-T cell therapy, plan for frequent follow-up visits at the hospital where you had your therapy. Ongoing care may be needed for months to years after CAR-T cell therapy.

Along with your follow-up care, see your primary healthcare team for routine healthcare and health problems not related to your CAR-T cell therapy. If you have changes in your health or questions about CAR-T cell therapy, tell a member of your CAR-T cell care team.