We have many lymph glands at different parts of our bodies that help defend us against pathogens. The spleen is like a big lymph gland beneath our ribs on the left side, that screens our blood for infections. Inside these lymph glands, the cells of an important part of our adaptive immune system reside. Two of these cells are the B-cells and the T-cells.

These cells interact frequently to exchange information. Every minute billions of interactions occur between the B and T cells inside our lymph glands. During each interaction, they are trying to determine if a cell from each arm of the immune system has spotted the same pathogen.

If a B-cell and a T-cell interact and they have come across the same pathogen, a huge alert is triggered. The T-cells and particularly the B-cells multiply in large numbers very quickly.

Our B-cells, unlike any other cell in our body, have a unique property. They can selectively modify their own DNA, so that inside each lymph node, each B-cell is able to recognize a particular pathogen in a slightly different way than its neighbour.

B-cells that are best able to recognize that pathogen grow in number and those that are less able to recognize the pathogen dwindle in number. This is called affinity maturation.

Our immune system also helps to protect us against cells within our own bodies. Our T-cells help defend against cancer cells that have mutations. They screen for cells displaying signs of these mutations. When they find these cancer cells, they destroy them.

Sometimes a cell acquires a particular set of mutations that allow it not only to grow but also help it evade the T-cells. These cancer cells develop into a tumor. If the tumor is detected early, it can be removed with surgery or eradicated completely with radiotherapy.

In less fortunate cases, some cells within a tumor might develop an additional ability to invade into other tissues or to metastasize i.e. spread to different parts of the body. In these cases, other treatments such as chemotherapy or immunotherapy are required.

Immunotherapies are increasingly used to treat various types of cancers and there are several ways that immunotherapy is used today.  CAR (chimeric antigen receptor) T-cell therapy is a form of immunotherapy developed as an individual treatment against cancer. The patient’s T-cells are reprogrammed and the CAR is artificially expressed to fight cancer cells.

T-cells are an important pillar of the immune system. They can mount a strong response against viral infections. They can also recognize and eliminate cancer cells. However, cancer cells often acquire mechanisms to escape the immune system.

This is a big problem. In order to tackle this issue, we need to find out which specific antigens are expressed only on the cell surface of cancer cells.  CAR T-cells are modified to detect these antigens. Like regular T-cells they possess normal T-cell receptors. In addition, specific chimeric antigen receptors (CARs) are expressed artificially on these CAR T-cells. CAR T-cells perfectly match the tumor antigen. The T-cells’ cytotoxic mechanisms eliminate these cancer cells.

The only characteristic that makes CAR T-cells different from natural T-cells is the chimeric antigen receptor.

How are CAR T-cells made?

Blood is removed from the patient and the T-cells are collected through apheresis and cultured. CAR T-cells are created from these cultured T-cells. These T-cells are genetically modified to add the chimeric antigen receptor (CAR) to them and activated. A viral vector such as the lentivirus is used for this purpose. This virus carries the genetic information that encodes for the chimeric antigen receptor (CAR). In a process known as viral transduction the T-cells are infected with the lentivirus which inserts the CAR gene.

Following transcription and translation the protein receptor is produced and the patient’s T-cells are now equipped with tumor-specific chimeric antigen receptors (CARs). The cultured CAR T-cell population is expanded in the lab and then finally infused back into the patient.

 How does CAR T-cell therapy work?

Inside the patient, the CAR T-cells patrol the whole body looking for cancer cells. Once they encounter tumor cells with the distinct antigen, they recognize the cancer cell and the CAR T-cells get activated. The activated CAR T-cells multiply and release cytokines. Cytokines are signaling proteins which signal to other parts of the immune system to come to the site of the cancer cell.

These cytokines and activated T-cells cause inflammation focused at the site of the cancer cell and kill it.

Common Side-Effects of CAR T-cell Therapy 

1. Cytokine Release Syndrome (CRS) – Occurs as a result of over activation of the immune system. Can be very dangerous and needs to be treated immediately.

2. Immune effector Cell-associated Neurotoxicity Syndrome (ICANS) – Occurs due to the cytokines affecting the brain. It is almost always associated with CRS and usually occurs after CRS. Symptoms can vary from mild to severe confusion or rarely seizures. It can also cause memory loss.

Cancers Currently Treated Using CAR T-cell Therapy

1. Diffuse Large B-cell Lymphoma (DLBCL)

2. Follicular Lymphoma

3. Mantle-cell Lymphoma

4. Multiple Myeloma

5. B-cell Acute Lymphoblastic Leukemia (ALL)

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