What is CAR T-cell therapy?

CAR T-cell therapy

CAR (Chimeric Antigen Receptor) T-cell Therapy is a type of cancer treatment. CAR T-cells are made in the laboratory and they have an artificially created receptor on the surface of T-Cells (white blood cells). These engineered receptors allow for the body's own immune system to target specific cancers. CAR T-cells consist of two classes: CARs that target surface antigens on tumor cells, CAR-Ts, and CARs that target cytokine receptors expressed on T-cells. CAR-Ts are the most common CARs used in CAR T-cell therapy.

Anti-CD19 CAR T-cell therapy has gained major success throughout the years and it led to the approval of the therapy in 2017 against B-cell malignancies by the FDA (Food and Drug Administration). There are both advantages and disadvantages to CAR T-cell therapy. At present, many approaches use CAR T-cell therapy in combination with anticancer therapies.

What is the difference between the CAR T-cells and our own T-cells?

Once these CAR T-cells are reengineered they are much stronger than natural T-cells since they have been enhanced with CAR receptors that allow them to bind onto specific antigens on cancerous tumors. However, before being transfused back into a patient where they will hopefully kill cancerous cells, CAR T-cell therapy requires patients to undergo chemotherapy or radiation in order to remove their existing immune system which would otherwise attack the CAR receptor bound onto their own body's healthy tissues. Once healthy immune systems are disabled, patients are administered CAR T-cells via intravenous infusion. The CAR T-cells are now free to roam through the blood system, find the cancerous cells and destroy them.

How do CAR receptors distinguish between healthy tissue and tumors?  

CAR receptors were created by splicing together a human antibody protein with a mouse receptor protein that allows it to bind specifically onto tumor associated antigens since these antigens tend to be absent on healthy tissues.

It is possible to target CAR T-cells to tumor sites to prevent any toxicity against TAA (tumor-associated antigens)-expressing normal tissues. For example CAR T-cells can be targeted to the tumor site through the expression of homing molecules along with CAR like CCR2 which migrates towards neuroblastoma, CCR4 which migrates towards Hodgkin lymphoma and CXCR2 which is known for migrating in the direction of melanoma. This allows for the migration of modified T-cells to the location of the cancer.

As well as this, it is beneficial to limit CAR T-cell persistence to avoid toxicity against TAA-expressing normal tissues. This can be done with the use of sucicde genes, CAR expression by mRNA modification and having inducible CAR expression. Researchers are still trying to find the best approach to overcome this issue of toxicity.

How are CAR T-cells made?

CAR T-cells are developed by harvesting mononuclear cells, activating, modifying and expanding the T-cells to express a transgene encoding a cancer specific CAR and then infusing the CAR T-cells into the patient. Retroviral or lentiviral vectors are used for gene transfer, although non-viral delivery systems are being investigated. As aforementioned, the patient must undergo chemotherapy before the infusion of the CAR T-cells can commence.

18th Jan 2022 Fiona Redmond, PhD

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