What is CART Cell Therapy Toxicity?

Chimeric antigen receptor-T (CAR-T) cell therapy is a type of treatment that modifies a patient’s own immune cells to fight cancer. To do this, doctors take T-cells, a type of immune cell, from the patient’s blood and genetically alter them in a lab to recognize and attack cancer cells. This has dramatically changed how we treat blood cancers like B-cell lymphomas and multiple myeloma, and is showing promise for other types of cancer, including solid tumors.

One promising approach uses CAR-T cells that target CD-19, a protein found on the surface of B cells. This has shown positive results in treating a variety of cancers, including pediatric and B-cell acute lymphocytic leukemia (ALL), non-Hodgkin lymphoma (NHL), and chronic lymphocytic leukemia (CLL). The first CAR-T therapy that targets CD-19, known as tisagenlecleucel (ELIANA), was approved by the Food and Drug Administration (FDA) in 2017 for patients with ALL and later for other types of lymphoma. Around the same time, another therapy called axicabtagene ciloleucel (ZUMA-1) was approved for certain types of lymphoma.

Since then, more CAR-T therapies have come on to the market, including better-tolerated ones like lisocabtagene maraleucel (liso-cel). More recently, therapies targeting the B-cell Maturation Antigen (BCMA), like idecabtagene vicleucel (KarMMa) and ciltacabtagene autoleucel (CARTITUDE-1), have been approved for multiple myeloma.

While CAR-T therapy has shown success in treating cancers that didn’t respond to other treatments, it can also cause serious side effects. The most common issues are cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), which can cause high fever, severe fatigue, difficulty speaking or thinking, and other symptoms. Other side effects may include low blood cell counts (cytopenia), infections, tumor lysis syndrome (TLS, a rapid breakdown of cancer cells which can lead to kidney failure), and severe allergic reactions (acute anaphylaxis). As doctors use CAR-T therapy earlier in the course of treatment, managing these side effects has become even more important.

What Causes CART Cell Therapy Toxicity?

The exact way that CRS (Cytokine Release Syndrome) works isn’t fully understood. CRS is the body’s inflammatory response when CAR-T (Chimeric Antigen Receptor T-cells), a type of therapy that boosts the body’s immune response to cancer, is activated and starts to grow within the body. It’s believed to be connected with certain proteins called cytokines, that are released when tumor cells and immune cells interact. These cytokines can stimulate other immune cells to release more cytokines.

ICANS (Immune Effector Cell-Associated Neurotoxicity Syndrome), another side effect of CAR-T therapy, might be related to the activation of certain immune cells, and their subsequent release of cytokines.

There’s a part of CAR-T cell therapy called the “costimulatory domain” that’s necessary to kickstart the activation and growth of CAR-T cells in the body. Some types of CAR-T therapies that use a different costimulatory domain have been shown to expand more slowly, leading to longer-lasting CAR-T cells in the system and a delayed onset of CRS.

While this has made managing these therapies outside of the hospital easier, there are still significant challenges in handling logistics, payments, and managing side effects of CAR-T therapies.

Risk Factors and Frequency for CART Cell Therapy Toxicity

Adverse effects related to CAR-T treatment can happen at different rates and depend on various factors. The most common side effect associated with this treatment is Cytokine Release Syndrome (CRS), with Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) coming up second.

CRS is a side effect that can commonly be reversed in those undergoing CAR-T therapy, appearing in around 42-100% patients. The severity varies, and it may turn severe in 0-46% of patients. It may even turn fatal in the most severe cases (0-9.1%).

CRS occurs in about 42 to 100% of patients
The severity varies with 0 to 46% presenting severe symptoms
Fatal outcomes can occur in 0 to 9.1% of cases

Just like CRS, ICANS can be reversed and tends to show up in patients after their CAR-T treatment. However, ICANS happens less often and may take longer to appear compared to CRS. The occurrence of ICANS varies from 3-64% of the patients. Of these, 0 to 54% might display signs of high severity illness.

ICANS occurs in about 3 to 64% of patients
It is often delayed compared to CRS
Severe illness can occur in 0 to 54% of cases

Signs and Symptoms of CART Cell Therapy Toxicity

Healthcare professionals and nurses who treat patients using commercial CAR-T products are required to complete specific training. This training focuses on recognizing CAR-T related side-effects, particularly Cytokine Release Syndrome (CRS) and Immune Cell-associated Neurotoxicity Syndrome (ICANS).

Each center using CAR-T therapy has its own guidelines to monitor patients for side-effects. The guidelines differ depending on whether treatment is provided in an outpatient or inpatient setting. Generally, if the treatment is given outside the hospital, patients are checked daily for signs of CRS and ICANS for 14 to 30 days after their treatment. If patients receive therapy in the hospital, their vital signs, overall health, and blood count are checked regularly, often every four hours.

For patients admitted with side effects like CRS, checks become more frequent with vital signs monitored every 2-4 hours. Blood tests are performed at least once to twice a day. A test called an ICE score, which helps assess brain function, is evaluated daily or up to every eight hours.

Most centers will have a neurological assessment of the patient done before the CAR-T treatment is started. If a patient shows symptoms of neurotoxicity, this examination schedule is increased to at least every 4-6 hours or more often if the patient’s condition worsens. Further neurological tests such as imaging and EEG are carried out if concerns for ICANS symptoms arise.

Testing for CART Cell Therapy Toxicity

The side effects of CAR-T cell therapy, a type of treatment that uses a patient’s own immune cells to fight cancer, can vary widely and are not yet fully understood. Determining the severity of these side effects is done by looking at patient symptoms, as well as results from lab tests and/ or radiology scans.

One side effect is known as CRS, which can cause symptoms like fever, rapid heart rate, low blood pressure, shortness of breath, and nausea or vomiting. The frequency of symptom checks varies based on how severe the CRS is and the policy of the medical institution. Often, symptoms are evaluated every 4 hours for mild to moderate cases or every 1 to 2 hours for severe cases.

Lab tests for CRS can include a complete blood count (CBC), tests for kidney and liver function, a coagulation profile (which checks how well your blood clots), LDH, serum ferritin, IL-6, and CRP. These tests, referred to as biomarkers, are performed regularly to see how severe the CRS is and how well the treatment is working. There have been suggestions to also test for IL-5, IL-13, TNF-a, and IFN-γ levels.

Another side effect is ICANS, which can cause symptoms such as headaches, trouble paying attention, drowsiness, restlessness, hallucinations, shaking, difficulty speaking, a condition called encephalopathy, and seizures. The severity of ICANS is monitored based on the ICE criteria; this includes more objective ways to grade the severity of neurotoxic symptoms.

Lab tests for ICANS include many of the same biomarkers as CRS. Other tests that may be performed include a lumbar puncture to examine cerebrospinal fluid (the fluid around the brain and spinal cord), neuroimaging (which creates images of the nervous system), and an EEG (which measures brain electrical activity), to determine the extent of damage from ICANS and rule out other causes such as infections.

Treatment Options for CART Cell Therapy Toxicity

CAR-T cell therapy, a type of cancer treatment, can sometimes cause unwanted side effects. The most severe of these are the Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS). Doctors are constantly working to standardize ways to treat CRS and ICANS and ensure the safety of patients receiving CAR-T cell therapy.

CRS and ICANS are regularly monitored and graded, and treatments can change based on these grades. Supportive care such as monitoring vital signs, controlling blood pressure, and fighting any infections is crucial. The drug tocilizumab is often used to treat CRS, and corticosteroids are used when CRS doesn’t respond to tocilizumab or for neurologic toxicities.

CRS is divided into four categories, depending on the severity of symptoms and response to treatments. The mildest form of CRS (grade 1) usually presents with symptoms like fever, nausea, fatigue, and headache, among others, but doesn’t involve low blood pressure or low oxygen levels. More severe cases of CRS can cause low blood pressure or low oxygen levels and may require more aggressive treatments.

ICANS is also divided into four categories based on the severity of symptoms. The mildest form can cause slight confusion but the patient is easily aroused. More severe cases can cause unresponsiveness, or seizures and could need very aggressive treatment.

In rare cases, if CRS and ICANS don’t improve despite these treatments, other medications like siltuximab and Anakinra might be used.

CAR-T cell therapy can also cause low blood cell counts (called cytopenias), tumor lysis syndrome (a rapid release of cell contents into the blood), low antibody levels (hypogammaglobulinemia) due to low B-cells, and infections. These conditions are typically managed with supportive care and, in some cases, specific medications.

In any case, always remember to contact your healthcare provider if you experience any symptoms, as early intervention is key in managing the side effects of CAR-T cell therapy.

When looking for causes of CRS, a.k.a. Cytokine Release Syndrome, doctors mainly take into account its symptoms and test results, such as high fever, low oxygen levels, low blood pressure, and increased levels of certain substances in the blood like CRP, ferritin, and IL-6. Conditions to consider might include:

Infection or sepsis
Severe allergic reactions or shock
Heart failure
Blood clot
Recurring or stubborn cancer
TLS, a disorder due to breakdown of cancer cells
HLH, a severe systemic inflammatory syndrome

Patients with these symptoms usually need thorough examinations and tests to check for these other conditions. Oftentimes, doctors begin treatments before they even know the exact cause.

As for ICANS, or Immune Effector Cell-Associated Neurotoxicity Syndrome, it may be mistaken for less common viral infections, strokes, side effects of chemotherapy, or cancer that has spread to the central nervous system.

What to expect with CART Cell Therapy Toxicity

CRS, which stands for Cytokine Release Syndrome, is a complication that typically reverses on its own, with symptoms mostly clearing up within 2 to 6 weeks. It can be serious, causing death in about 0 to 9.1% of cases as shown in various studies. However, most studies have reported less than 1% fatal outcomes.

ICANS, standing for Immune effector Cell-Associated Neurotoxicity Syndrome, refers to the harmful effects on the nervous system that can occur with some types of immunotherapy. In the majority of cases, symptoms usually clear up within 3 to 8 weeks. By recognizing these symptoms early and treating them aggressively, it’s possible to reverse even severe cases of CRS.

Possible Complications When Diagnosed with CART Cell Therapy Toxicity

While complications from CAR-T (a type of immunotherapy treatment) are usually reversible, sometimes they can cause irreversible damage to organs or even lead to death. Common side effects of CAR-T treatment may also include mental health issues such as anxiety, depression, or memory problems. In one study, these issues were reported in up to 37.5% of people who survived in the long-term after undergoing CAR-T treatment.

Common Side Effects of CAR-T Treatment:

Irreversible damage to organs
Potentially fatal complications
Anxiety
Depression
Cognitive difficulty or memory problems

Preventing CART Cell Therapy Toxicity

It is important to regularly check on the patients, provide clear instructions to both patients and caregivers, and establish a strong system that can be contacted any time after the CAR-T treatment. Both patients and their caregivers need to be given information about checking symptoms and vital signs, who to contact outside of office hours, and when it’s necessary to go to the hospital.

Patients should also be provided with a wallet card that identifies them as a recipient of a CAR-T cell product and includes information about their cancer specialist. It would be crucial for patients to show this wallet card whenever they go for a check-up concerning their symptoms, especially, if they go to a hospital or emergency department that is not affiliated with the CAR-T therapy programs.

Support from caregivers is a crucial factor throughout the CAR-T treatment process and afterward. The necessity for a caregiver to be present 24/7 for at least the first four weeks and staying close to the treatment center should be emphasized. Caregivers should be involved from the very beginning, from providing consent for treatment to accompanying the patient to clinic visits and helping them after being discharged from the hospital.

Frequently asked questions

CAR-T cell therapy toxicity refers to the potential side effects and adverse reactions that can occur as a result of CAR-T cell therapy. The most common toxicities associated with CAR-T cell therapy include cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), which can cause symptoms such as high fever, severe fatigue, difficulty speaking or thinking, and other complications. Other potential toxicities include low blood cell counts, infections, tumor lysis syndrome (TLS), and severe allergic reactions. Managing these toxicities is crucial for the successful use of CAR-T cell therapy.

CART cell therapy toxicity is common, with Cytokine Release Syndrome (CRS) occurring in about 42 to 100% of patients and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) occurring in about 3 to 64% of patients.

The signs and symptoms of CAR-T Cell Therapy toxicity include: - Cytokine Release Syndrome (CRS): This is characterized by flu-like symptoms such as fever, chills, headache, nausea, and muscle pain. It can also cause low blood pressure, rapid heartbeat, and difficulty breathing. In severe cases, CRS can lead to organ dysfunction and even death. - Immune Cell-associated Neurotoxicity Syndrome (ICANS): This syndrome affects the central nervous system and can cause confusion, delirium, seizures, and difficulty speaking or understanding speech. Patients may also experience tremors, weakness, and loss of coordination. - Neurological symptoms: Patients may exhibit symptoms such as altered mental status, agitation, and irritability. They may also have difficulty with memory, attention, and concentration. - Changes in vital signs: Monitoring of vital signs such as blood pressure, heart rate, and respiratory rate is important to detect any abnormalities that may indicate toxicity. - Abnormal blood counts: Regular blood tests are performed to monitor for any changes in blood cell counts, such as low platelet or white blood cell counts, which may be indicative of toxicity. - ICE score evaluation: The ICE score is a test that helps assess brain function. It is evaluated daily or up to every eight hours to monitor for any neurotoxicity symptoms. - Neurological assessments: Centers typically conduct neurological assessments before starting CAR-T treatment to establish a baseline. If neurotoxicity symptoms arise, these assessments are done more frequently, usually every 4-6 hours or more often if the patient's condition worsens. - Additional tests: If there are concerns for ICANS symptoms, further neurological tests such as imaging and EEG may be performed to evaluate brain function and detect any abnormalities. It is important for healthcare professionals and nurses to be trained in recognizing these signs and symptoms of CAR-T Cell Therapy toxicity to ensure prompt detection and management of any adverse effects.

The exact way that CAR-T cell therapy toxicity occurs is not fully understood, but it is believed to be connected with the activation and growth of CAR-T cells in the body, as well as the release of certain proteins called cytokines when tumor cells and immune cells interact. This can lead to Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), which are the most common side effects of CAR-T therapy.

The conditions that a doctor needs to rule out when diagnosing CART Cell Therapy Toxicity include: - Infection or sepsis - Severe allergic reactions or shock - Heart failure - Blood clot - Recurring or stubborn cancer - TLS, a disorder due to breakdown of cancer cells - HLH, a severe systemic inflammatory syndrome

The types of tests that are needed for CAR-T cell therapy toxicity include: - Complete blood count (CBC) - Tests for kidney and liver function - Coagulation profile - LDH - Serum ferritin - IL-6 - CRP - IL-5 (suggested) - IL-13 (suggested) - TNF-a (suggested) - IFN-γ levels (suggested) Additional tests that may be performed for CAR-T cell therapy toxicity include: - Lumbar puncture to examine cerebrospinal fluid - Neuroimaging to create images of the nervous system - EEG to measure brain electrical activity

CAR-T cell therapy toxicity is treated through a combination of supportive care and specific medications. The severity of the toxicity is regularly monitored and graded, and treatments can be adjusted accordingly. For Cytokine Release Syndrome (CRS), the drug tocilizumab is commonly used, and corticosteroids may be used if CRS does not respond to tocilizumab or for neurologic toxicities. CRS is divided into four categories, and more severe cases may require more aggressive treatments. Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) is also divided into four categories, and treatment can range from slight interventions for mild cases to very aggressive treatment for severe cases. In rare cases where CRS and ICANS do not improve with standard treatments, other medications like siltuximab and Anakinra may be used. Supportive care, such as monitoring vital signs, controlling blood pressure, and managing infections, is crucial in managing the side effects of CAR-T cell therapy.

The side effects when treating CAR-T cell therapy toxicity include: - Cytokine Release Syndrome (CRS) - Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) - Low blood cell counts (cytopenias) - Tumor lysis syndrome - Low antibody levels (hypogammaglobulinemia) - Infections - Irreversible damage to organs - Potentially fatal complications - Anxiety - Depression - Cognitive difficulty or memory problems

The prognosis for CAR-T cell therapy toxicity depends on the specific side effects experienced by the patient. The most common side effects are cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). While these side effects can be serious and even fatal in some cases, they are often reversible with appropriate management and treatment. The severity and outcome of CRS and ICANS can vary, with fatal outcomes occurring in less than 1% of cases for both.

An oncologist or a hematologist should be consulted for CAR-T cell therapy toxicity.

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