CAR T-cell Therapy and Its Side Effects

Your immune system works by keeping track of all the substances normally found in your body. Any new substance the immune system doesn't recognize raises an alarm, causing the immune system to attack it.

Chimeric antigen receptor (CAR) T-cell therapy is a way to get immune cells called T cells(a type of white blood cell)to fight cancer by changing them in the lab so they can find and destroy cancer cells. CAR T-cell therapy is also sometimes talked about as a type of cell-based gene therapy, because it involves altering the genes inside T cells to help them attack the cancer.

This type of treatment can be very helpful in treating some types of cancer, even when other treatments are no longer working.

How CAR T-cell therapy works

Immune receptors and foreign antigens

The immune system recognizes foreign substances in the body by finding proteins called antigens on the surface of those cells. Immune cells called T cells have their own proteins called receptors that attach to foreign antigens and help trigger other parts of the immune system to destroy the foreign substance.

The relationship between antigens and immune receptors is like a lock and key. Just as a lock can only be opened with the right key, each foreign antigen has a unique immune receptor that can bind to it.

Cancer cells also have antigens, but if your immune cells don't have the right receptors, they can't attach to the antigens and help destroy the cancer cells.

Chimeric antigen receptors (CARs)

In CAR T-cell therapies, T cells are taken from the patient's blood and are changed in the lab by adding a gene for a receptor (called a chimeric antigen receptor or CAR), which helps the T cells attach to a specific cancer cell antigen. The CAR T cells are then given back to the patient.

Since different cancers have different antigens, each CAR is made for a specific cancer's antigen. For example, in certain kinds of leukemia or lymphoma, the cancer cells have an antigen called CD19. Many of the CAR T-cell therapies to treat these cancers are made to attach to the CD19 antigen and will not work for a cancer that does not have the CD19 antigen.

Getting CAR T-cell therapy

The process for CAR T-cell therapy can take several weeks.

Collecting the T cells

First, white blood cells (which include T cells) are removed from the patient’s blood using a procedure called leukapheresis. During this procedure, patients usually lie in bed or sit in a reclining chair. Two IV lines are needed because blood is removed through one line, the white blood cells are separated out, and then the blood is put back into the body through the other line. Sometimes a special type of IV line called a central venous catheter is used, which has both IV lines built in.

The patient will need to stay seated or lying down for 2 to 3 hours during the procedure. Sometimes blood calcium levels can drop during leukapheresis, which can cause numbness and tingling or muscle spasms. This can be treated by replacing the calcium, which may be given by mouth or through an IV.

Making the CAR T cells

After the white cells are removed, the T cells are separated, sent to the lab, and altered by adding the gene for the specific chimeric antigen receptor (CAR). This makes them CAR T cells. These cells are then grown and multiplied in the lab. It can take several weeks to make the large number of CAR T cells needed for this therapy.

Receiving the CAR T-cell infusion

Once enough CAR T cells have been made, they will be given back to the patient. A few days before the CAR T-cell infusion, the patient might be given chemotherapy to help lower the number of other immune cells. This gives the CAR T cells a better chance to get activated to fight the cancer. This chemotherapy is usually not very strong because CAR T cells work best when there are still some cancer cells to attack. Once the CAR T cells start binding with cancer cells, they start to increase in number and can help destroy even more cancer cells.

Approved CAR T-cell therapies

CAR T-cell therapies are approved by the US Food and Drug Administration (FDA) to treat some kinds of lymphomas and leukemias, as well as multiple myeloma. CAR T-cell therapy is typically used after other types of treatment have been tried.

Examples of CAR T-cell therapies currently approved include:

• Tisagenlecleucel, also known as tisa-cel (Kymriah)
• Axicabtagene ciloleucel, also known as axi-cel (Yescarta)
• Brexucabtagene autoleucel, also known as brexu-cel (Tecartus)
• Lisocabtagene maraleucel, also known as liso-cel (Breyanzi)
• Idecabtagene vicleucel, also known as ide-cel (Abecma)
• Ciltacabtagene autoleucel, also known as cilta-cel (Carvykti)
• Obecabtagene autoleucel, also known as obe-cel (Aucatzyl)

Many other CAR T-cell therapies (and similar types of treatment) are now being studied in clinical trials, in the hope of treating other types of cancer as well.

Possible CAR T-cell therapy side effects

CAR T-cell therapy can be very effective against some types of hard-to-treat cancers, but it can also sometimes cause serious or even life-threatening side effects. Because of this, it needs to be given in a medical center that is specially trained in its use, and patients need to be watched closely for several weeks after getting the CAR T cells.

Cytokine release syndrome (CRS): As CAR T cells multiply, they can release large amounts of chemicals called cytokines into the blood, which can ramp up the immune system. Serious side effects from this release can include:

• High fever and chills
• Trouble breathing
• Severe nausea, vomiting, and/or diarrhea
• Feeling dizzy or lightheaded
• Headaches
• Fast heartbeat
• Feeling very tired
• Muscle and/or joint pain

As doctors are gaining more experience with CAR T-cell therapy, they are learning how to recognize CRS early, as well as how to treat it.

Nervous system problems: This treatment can sometimes have serious effects on the nervous system, leading to a condition known as immune effector cell-associated neurotoxicity syndrome (ICANS). This can result in symptoms such as:

• Headaches
• Changes in consciousness
• Confusion or agitation
• Seizures
• Shaking or twitching (tremors)
• Trouble speaking and understanding
• Loss of balance

Because of the risk of these side effects, adult patients are typically advised not to drive, operate heavy machinery, or do any other potentially dangerous activities for at least several weeks after getting treatment.

Other serious side effects: Other possible serious side effects of CAR T-cell therapy can include:

• Allergic reactions during the infusion
• Abnormal levels of minerals in the blood, such as low potassium, sodium, or phosphorous levels
• A weakened immune system, with an increased risk of serious infections
• Low blood cell counts, which can increase the risk of infections, fatigue, and bruising or bleeding
• An increased risk of getting another type of blood cancer

If you are getting CAR T-cell therapy, it’s very important to report any side effects to your health care team right away, as there are often medicines that can help treat them.