Immune Effector Cell-Associated Neurotoxicity Syndrome

Immune effector cell-associated neurotoxicity syndrome (ICANS) happens when your immune system harms your central nervous system. It’s a complication of a cancer treatment called immunotherapy. ICANS most often happens after specific types of immunotherapy called CAR T-cell therapy and bispecific antibody therapy.

This treatment changes your immune cells (T cells), so they’re better at fighting blood cancers. But problems happen if the T cells use that fighting power against your own body. The supercharged T cells can cause inflammation that damages your organs. This is called cytokine release syndrome (CRS). With ICANS, inflammation harms your nerves and brain, specifically. In severe cases, it may cause swelling in your brain that can be fatal.

This is why your care team will watch you closely for signs of CRS and ICANS after immunotherapy. At the first signs of an issue, they’ll provide treatment to keep you safe.

Symptoms of ICANS

Symptoms typically start within four to 10 days of treatment. For most people, ICANS symptoms happen alongside CRS symptoms. Or symptoms start soon after those of CRS have gone away. Both the onset time and symptoms vary depending on the specific drug you get.

Symptoms include:

• Confusion
• Feeling sluggish or sleepy
• Headache
• Seizures or tremors
• Slower movements
• Slurred speech or trouble speaking
• Trouble concentrating or understanding others
• Trouble writing simple words or sentences
• Vision changes

In rare cases, people may slip into a coma. The condition may result in irreversible brain damage or lead to death at this point.

Your care team will monitor you closely so they can intervene before ICANS progresses to a life-or-death situation.

ICANS causes

Experts are still researching possible causes. But a common theory is that ICANS involves an increase of proteins called cytokines in your bloodstream. Typically, the increase is a good thing. Cytokines help your immune cells fight cancer.

But in some cases, they cause inflammation that damages healthy tissue, too. With ICANS, the cytokines may flood across the blood-brain barrier (BBB). The BBB is a wall of cells that prevents harmful substances in your blood from reaching your brain. When cytokines cross that barrier, they can damage your brain. 

Risk factors

Factors that may increase your risk include:

• Fever or other signs of CRS
• Advanced cancer
• Having preexisting conditions that affect your central nervous system
• Specific immunotherapy drugs (your healthcare provider will let you know the kind they recommend)

What drugs can cause ICANS?

Any of the medicines currently approved by the Food and Drug Administration (FDA) for CAR T-cell therapy can lead to ICANS. The risk varies based on how the drugs work to destroy cancer cells. Severe ICANS — the type that’s serious enough to be fatal — is uncommon across all of them. Types include:

• Axicabtagene ciloleucel (Yescarta^®)
• Brexucabtagene autoleucel (Tecartus^®)
• Ciltacabtagene autoleucel (Carvykti^®)
• Idecabtagene vicleucel (Abcema^®)
• Lisocabtagene maraleucel (Breyanzi^®)
• Obecabtagene autoleucel (Aucatzyl^®)
• Tisagenlecleucel (Kymriah^®)

Other drugs that may lead to ICANS help your T cells fight cancer but aren’t a part of CAR T-cell therapy. This is less common. Drugs include blinatumomab (Blincyto^®) and teclistamab (Tecvayli^®).

How doctors diagnose this condition

Your care team will monitor you for signs of ICANS while you recover from treatment in the hospital. They’ll check you regularly for signs of CRS or ICANS.

You’ll need blood work to check your levels of cytokines or other inflammatory markers. If you have symptoms, you may need an EEG to check for signs of atypical brain activity or seizures. 

Grading ICANS

Healthcare providers grade ICANS from one to four, with four being the most severe. They use a tool called the Immune Effector Cell Encephalopathy (ICE) Score to monitor everyone who’s had CAR T-cell therapy for symptoms. This tool checks for nervous system issues. You’ll complete simple tasks like:

• Counting
• Drawing simple figures
• Following basic commands
• Identifying common objects
• Saying where you are and what day it is
• Writing simple sentences

Your providers will also note how alert and in tune with your surroundings you are.

These things help providers assess how your brain is working. That way, they can start treatment right away if there are signs of a decline.

How is it treated?

Treatments work to reverse your symptoms. So, if you’re having seizures, you may need antiseizure medicine. (Your healthcare provider may also give you this medicine before treatment to prevent ICANS.)

Healthcare providers use corticosteroids to calm inflammation. One of the most common medicines to treat ICANS is dexamethasone (Decadron^®). A newer medicine known as anakinra (Kineret^®) may be an option. They may give you chemotherapy in your spinal fluid to kill the T cells responsible for this syndrome. You may also need tocilizumab (Actemra®) if you have CRS.

Your provider will work to give you a dose that eases your symptoms without weakening the cancer-fighting power of your immune cells. Often, they start with a steroid at a high dose. They taper the dosage as your symptoms improve.

Recovery time

Most people with ICANS get better within two weeks. The most severe symptoms usually resolve sooner, within a week. But a lot depends on the drug and ICANS grade. Some people have mild side effects for a year or longer.

Ask your healthcare provider what to expect based on the drug you received.

When should I see my healthcare provider?

Care teams go to great lengths to monitor people recovering from immunotherapy for side effects. But if you’re caring for someone after an immunotherapy linked to ICANS and you notice concerning changes, don’t hesitate to contact a provider.

Let a healthcare provider know if something seems “off” about your loved one’s speech or personality. Sometimes, minor changes are just a sign of exhaustion. This is normal after major treatment. But other times, the observation or gut feeling that something’s not quite right is a warning sign.

Don’t second-guess yourself. Reach out to a provider.

What can I expect if I have this condition?

Your outlook depends on how severe your condition is and how effectively treatment works. Time is of the essence when it comes to managing ICANS. Even with careful management, ICANS can lead to death in rare instances.

But for the most part, ICANS is something people recover from. It’s often reversible when it’s managed right away. And care teams know to stand at the ready so they can intervene ASAP if you’re showing signs of this syndrome.