Chimeric antigen receptor (CAR) T-cell therapy is a type of immunotherapy. To understand how CAR-T cell therapy works, one must know a thing or two about the human immune system. The immune system recognizes foreign substances in the body by finding proteins (antigens) on the surface of these substances. These antigens are recognized by proteins on the cell surface of T-lymphocytes who bind to antigens and trigger other parts of the immune system to destroy the foreign substance. The interplay between antigens and immune receptors on T-cells 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. While cancer cells carry antigens on their cell surface, immune cells not always have the corresponding ‘key’ (receptor) for these antigens. As a result, cancer cells are not recognized by T-cells and escape elimination by the immune system.
In CAR T-cell therapies, T cells are taken from the patient's blood and manipulated in the lab to add a receptor which enables T-cells to attach to a specific antigen on cancer cells. The receptor that is added is called a chimeric antigen receptor, or CAR. These CAR-T cells are now able to recognize and kill the cancer cells carrying the target antigen. Every CAR is made to recognize a specific cancer antigen. For example, certain leukemia or lymphoma cells have an antigen called CD19. The CAR T-cell therapies to treat these cancers are made to attach to the CD19 antigen. However, these CAR-T cells will not work for cancers that do not express CD19.
CAR-T cell therapy is a complex process that starts with a procedure called leukapheresis to remove white blood cells from the patient. Subsequently, T-cells are separated from the other white blood cells, the CAR Is added, and cells are multiplied in the lab. A few days before the CAR-T cells are given back to the patient, a mild course of chemotherapy is administered to lower the number of other immune cells. This gives the CAR-T cells the best chance to survive in the bloodstream of the patient, multiply and attack cancer cells.
For the moment, CAR-T cell therapies are available for some children with acute lymphocytic leukemia (ALL) and for adult patients with certain types of non-hodgkin lymphoma (NHL). In addition to this, CAR-T cell therapies are under evaluation in other hematological malignancies, including multiple myeloma.
CAR-T cell therapy proved to be very effective in the treatment of several blood cancers, but also comes with the risk for certain side effects. First of all, patients can have an allergic reaction to the CAR-T cells, leading to fever, chills and breathing difficulties. A second important side effect of CAR-T cell therapy consists of cytokine release syndrome (CRS). CAR-T cell therapy stimulates the immune system to produce large amounts of cytokines, leading to an excessive activation of the immune system. This immune overreaction can induce fever, dizziness and breathing difficulties. In addition to this, CAR-T cell therapy is associated with certain neurological side effects, which can lead to headaches, an altered consciousness, disorientation, speech difficulties and seizures. Finally, CAR-T cell therapy increases the risk for infections and increases the level of uric acid in the blood due to a rapid breakdown of a large number of cancer cells (tumor lysis syndrome).
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