Chimeric Antigen Receptor (CAR) T-Cell Therapy

Dr. Brentjens Talks about CAR T-Cell Therapy:

Possible Side Effects of CAR T-Cell Therapy

While many patients 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 starting any treatment. Most side effects resulting from CAR T-cell therapy will either resolve on their own or can be managed with appropriate treatment. 

Cytokine-Release Syndrome (CRS). 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 CAR-T cell therapy trials.

Depending on the patient and the CAR T cells, CRS may occur within 1 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. 

Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS). 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. Additionally, there have been fatalities. Some symptoms of neurologic toxicity can be treated with anti-epileptic medication and/or corticosteroids. Some patients may receive prophylactic (preventative, before CAR T-cell therapy) anti-epileptic medications. Sometimes a lumbar puncture (a procedure typically used to remove a sample of spinal fluid for testing) may be used to relieve pressure from brain swelling caused by severe ICANS. 

Signs and symptoms of ICANS can sometimes be subtle. 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, to report the date, or perform other simple tasks to demonstrate that they do not have any neurologic symptoms.

Tumor Lysis Syndrome (TLS). 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.

Anaphylaxis (Life-threatening Allergic Reaction). 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.

B-Cell Aplasia. CAR T-cell therapy targeting antigens found on the surface of B cells not only destroys 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.

Infection. A number of patients (20% to 40%) 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). 
 

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. 

Chimeric antigen receptor T-cell clinical trials have generated impressive results in the early outcomes of patients with blood cancers. With the FDA approvals multiple drugs, CAR T-cell therapy represents a potential to treat certain leukemias, lymphomas and myeloma in patients whose disease has relapsed or is refractory to treatment.  

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, who may show disease progression 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. These include decreased costs. The reduction in costs is 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. 

Video about CAR T-Cell Therapy

Enrolling in a 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. 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 (click here for lists of suggested questions).
• A family member, friend, or another advocate with you for support and to take notes.

Clinical Trial Support Center
Work one-on-one with an LLS Clinical Trial Nurse Navigator who will help you find clinical trials and personally assist you throughout the entire clinical-trial process.

For more information or to contact us, click here.

Additional Resources

For Patients

• Contact an LLS Information Specialist for more information
• Download or order these free materials:
  • The CAR T-Cell Therapy Process Graphic 
  • Chimeric Antigen Receptor (CAR) T-Cell Therapy Fact Sheet
  • CAR T-Cell Therapy Resources Card 
• Webcasts
• Education Videos
• Podcast Episodes

For Healthcare Professionals

• Fact sheet (Available to order or download)
• Podcast episodes
• CAR T-cell and Bispecific Therapies Webinar

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