Chimeric antigen receptor (CAR) T-cell therapy for children and teens

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CAR T-cell therapy is a blood cancer treatment that uses a person’s own immune system to identify and attack cancer cells. This fact sheet provides the latest information on this type of immunotherapy for patients, caregivers, and healthcare providers.

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Understanding the immune system

The immune system is the body’s defense against infection and cancer. It is made up of billions of cells that are divided into several different types.

Lymphocytes, a subtype of white blood cells, make up a major part of the immune system.

There are three types of lymphocytes:

B lymphocytes (B cells) make antibodies to fight infection
T lymphocytes (T cells) have several functions, including helping B lymphocytes to make antibodies to fight infection, and directly killing infected cells in the body
Natural killer cells also attack infected cells and eliminate viruses

Immunotherapy is a type of treatment that uses the body’s own immune system to fight cancer. It improves the body’s ability to detect and kill cancer cells and is based on the concept that immune cells or antibodies can recognize and kill cancer cells.

Immune cells or antibodies can be produced in the laboratory under tightly controlled conditions and then given to patients to treat cancer. Several types of immunotherapies are either approved for use or are under study in clinical trials to determine their effectiveness in treating various types of cancer.

How it works

T cells are collected from a patient via “apheresis,” a procedure during which blood is withdrawn from the body and one or more blood components (such as plasma, platelets, or white blood cells) are removed. The remaining blood is then returned to the body.
T cells are reengineered in a laboratory. The T cells are sent to a laboratory or a drug manufacturing facility where they are genetically engineered, by introducing DNA into them, to produce chimeric antigen receptors (CARs) on the surface of the cells.
After this reengineering, the T cells are known as “chimeric antigen receptor (CAR) T cells.” CARs are proteins that allow the T cells to recognize an antigen on targeted tumor cells.
The reengineered CAR T cells are then multiplied by growing cells in the laboratory. This takes about three to four weeks. When there are enough of them, these CAR T cells are frozen and sent to the hospital or center where the patient is being treated.
At the hospital or treatment center, the CAR T cells are thawed and infused into the patient. Many patients are given a brief course of one or more chemotherapy drugs to reduce the number of normal T cells in the body before they receive the infusion of CAR T cells. This is called “lymphodepletion,” and it makes space for the new CAR T cells. The new CAR T cells are infused into the patient’s bloodstream by IV or through an existing central line. This process takes less than 30 minutes. The CAR T cells that have been returned to the patient’s bloodstream multiply in number. These are the “attacker” cells that will recognize, attack, and kill cells that have the target antigen on their surface.

CAR T cells may help guard against recurrence. CAR T cells may not only eradicate all cancer cells in the body, but they may remain in the body months after the infusion. The therapy has resulted in long-term remissions for some patients with certain types of blood cancer.

FDA-approved treatments

The following FDA-approved treatments may be used in CAR T-cell therapy:

CAR T-cell therapy continues to be available to patients participating in a clinical trial for cancers other than the FDA-approved indications. Trial protocols vary. Depending on the clinical trial, care may be provided in either a hospital setting or an intensive outpatient treatment center with experience administering cellular immunotherapy. Patients may have to stay at the treatment facility and may need to plan to stay close by before, during, or following treatment. Some trial protocols require patients to confirm the availability of a caregiver before they can enroll in the trial.

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Watch this video to learn about CAR T-cell therapy, a type of immunotherapy treatment that uses gene editing and the body’s own immune system to fight cancer.

Possible side effects

While many people have reported only mild to moderate side effects with CAR T-cell therapy, this treatment is sometimes associated with serious side effects. It is important to speak with the healthcare team about potential side effects before your child starts treatment. Most side effects resulting from CAR T-cell therapy will either resolve on their own or can be managed with appropriate treatment. Open each section below to learn more.

This potentially serious side effect is frequently associated with CAR T-cell therapy. Cytokines (chemical messengers that help the T cells carry out their functions) are produced when the CAR T cells multiple in the body and kill the cancer cells. When the CAR T cells encounter their antigen targets, they are rapidly activated. At this point, numerous inflammatory cytokines, including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNFα) and interferon gamma (IFNγ), are released. The large amounts of cytokines produced and then released by the activated immune system cause a collection of mild to potentially life-threatening signs and symptoms.

Common symptoms of CRS include:

Fever
Fatigue
Headache
Hypotension (low blood pressure)
Hypoxia (lack of oxygen reaching the tissue)
Tachycardia (abnormally rapid heart rate)
Chills

The symptoms of CRS can also be more serious such as:

Capillary leakage (fluid and proteins leaking out of tiny blood vessels and flowing into surrounding tissues, resulting in dangerously low blood pressure and difficulty breathing)
Cardiac arrest (the heart stopping)
Cardiac arrhythmias (abnormal heartbeat)
Cardiac failure
Hemophagocytic lymphohistiocytosis (HLH) (life-threatening immune system condition when T and NK cells become overactive, causing too much inflammation)/macrophage activation syndrome (MAS) (an uncontrolled immune system working overtime, leading to inflammation)
Renal insufficiency (poor kidney function)
Poor lung oxygenation
Multiple organ failure

Severe CRS requires intensive care treatment. Although most symptoms are reversible, the potential life-threatening risk of CAR T-cell therapy should not be underestimated. Deaths have been reported in CART-cell therapy trials.

Depending on the patient and the CAR T cells, CRS may occur within one to 21 days of CAR T-cell infusion. The duration of CRS is variable and it depends on the type of intervention used to manage it.

Common signs and symptoms of ICANS include:

Language impairment (aphasia)
Confusion
Delirium
Involuntary muscle twitching
Hallucinations
Unresponsiveness
Seizures

The connection between CRS and neurologic adverse events is not completely understood. The frequency, severity, and nature of neurological toxicity is different among CAR T-cell products. The underlying cause of ICANS is unclear. The cause of neurotoxicity is the subject of intense investigation by researchers.

Neurotoxicity is reversible in most cases, and signs and/or symptoms usually resolve over several days without intervention or apparent long-term effects. However, neurologic complications of CAR T-cell therapy can be life-threatening. Harmful neurological events have been reported. Cerebral edema (swelling in the brain) is the most common. Neurotoxicity can also be fatal. Some symptoms of neurologic toxicity can be treated with anti-epileptic medication and/or corticosteroids. Some patients may receive prophylactic (preventative) anti-epileptic medications before undergoing CAR T-cell therapy. Sometimes lumbar puncture (a procedure typically used to remove a sample of spinal fluid for testing) can be used to relieve pressure from brain swelling caused by severe ICANS.

Signs and symptoms of ICANS can sometimes go undetected by the patient. As a result, patients are frequently asked to complete a series of assessments during their treatment to ensure that they do not have neurologic toxicities. This assessment may include asking patients to write a sentence, report the date, or perform other simple tasks to show that they do not have any neurologic symptoms.

Another known side effect of CAR T-cell therapy is tumor lysis syndrome (TLS), a group of metabolic complications that can occur due to the breakdown of dying cells—usually at the onset of toxic cancer treatments. However, TLS can be delayed and may occur one month or more after CAR T-cell therapy. TLS can cause organ damage and can be a life-threatening complication of any treatment that causes breakdown of cancer cells, including CAR T cells. The complication has been managed by standard supportive therapy.

Learn more about TLS.

There is potential for a patient receiving CAR T-cell therapy to have an overwhelming immune response against the CAR itself, called “anaphylaxis.” Symptoms associated with anaphylaxis include hives, facial swelling, low blood pressure, and respiratory distress. There have been a few reports of acute anaphylaxis. Thorough monitoring and immediate treatment of this life-threatening side effect are critical for patients receiving CAR T-cell therapy.

CAR T-cell therapy targeting antigens found on the surface of B cells destroys not only cancerous B cells but also normal B cells. Therefore, B-cell aplasia (low numbers of B cells or absent B cells) is an expected result of successful CD19-specific CAR T-cell treatment and has served as a useful indicator of ongoing CAR T-cell activity. This effect results in less ability to make the antibodies that protect against infection. Intravenous or subcutaneous immunoglobulin replacement therapy may be given to prevent infection. Long-term follow-up study is needed to assess the late effects of B-cell aplasia.

A number of patients (20 percent to 40 percent) who receive CAR T-cell therapy may have prolonged low blood cell counts. Low white blood cell count can result in serious bacterial, viral, or fungal infections. Additionally, opportunistic infections (infections that occur due to a unique opportunity, such as a weakened immune system) can occur. The most common types of infections occur within the first three months following the CAR T-cell infusion are upper and lower respiratory tract infections.

As a precautionary measure, following CAR T-cell therapy, depending on the patient’s blood cell count recovery, most patients will be maintained on prophylactic antimicrobial therapy (treatment designed to prevent an infection from occurring).

Learn more about infections, iron overload, and low blood counts.

Results, limitations, and the future of CAR T-cell therapy

CAR T-cell clinical trials have generated impressive results in the early outcomes of CAR T-cell therapy patients with blood cancers.

CAR T-cell clinical trials have generated impressive results in the early outcomes of patients with blood cancers. In some studies, up to 90 percent of children and adults with B-ALL whose disease had either relapsed multiple times or failed to respond to standard therapies achieved remission after receiving CAR T-cell therapy. Even though some of these therapies have only been recently approved by the FDA, they have been studied for many years in clinical trials prior to their approval.

Data from long-term outcome studies following CAR T-cell therapy indicates that CD19-targeted CAR T cells can induce prolonged remissions in patients with B-cell malignancies, while remissions induced by BCMA-targeted CAR T cells are typically more short-lived. Additionally, certain patient and disease factors are associated with achieving durable remissions after CAR T-cell therapy.

While CAR T-cell therapy has achieved great clinical results, there are some disadvantages to this type of therapy. The products are generated from a patient’s autologous T cells, which requires extensive and costly collection and manufacturing efforts. The time between apheresis (when the patient’s T cells are collected) to the infusion of the engineered CAR T cells back to the patient is called the “vein-to-vein” time.

Currently, all FDA-approved products require three to five weeks of manufacturing and quality assessment before the product is available to the patients. This delay can be problematic in some patients with certain diseases, such as acute leukemia, whose disease may progress before an autologous CAR T-cell treatment is ready for use.

Researchers have started to rethink the source of immune cells to produce CAR T-cell therapies to address some of the current limitations of this type of therapy. Using T cells collected from healthy donors or using umbilical cord blood are approaches used to produce “off-the-shelf” allogeneic CAR T cells.

The use of allogeneic CAR T cells has many potential advantages, including reduced costs, due to the implementation of industrialized processes, which produce a large number of CAR T cells that can be produced from a single donor and become immediately available for treatment in cancer patients.

This approach is being pursued by several manufacturing companies and is under study in clinical trials for hematological malignancies, including B-cell ALL, AML, NHL, and myeloma.

Dr. Renier Brentjens on CAR T-Cell Therapy

Renier Brenjtens, MD, PhD, Deputy Director at Roswell Park, provides an overview of CAR T-Cell clinical trials anticipated in the next year at Roswell Park--including trials for osteosarcoma, small-cell lung cancer and ovarian cancer.

Enrolling in a clinical trial

Many CAR-T cell therapies are being studied in clinical trials for indications or cancers other than the FDA-approved indications. Talk with your doctor about whether participation in a CAR T-cell therapy clinical trial is an option for you. Obtaining another opinion from a hematologist-oncologist (a blood cancer specialist), may be helpful in finding additional clinical trial information as well.

Learn more about making blood cancer treatment decisions. 

When you and your doctor discuss CAR T-cell therapy as a potential treatment option for you, it may be helpful to have:

A list of questions to ask concerning risks versus benefits of such a trial. Learn more about communicating with your blood cancer specialist or find a list of suggested questions to ask your healthcare providers. 
A family member, friend, or another advocate with you for support and to take notes.
Learn more about clinical trials.

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