Chimeric Antigen Receptor (CAR) T-cell therapy represents a significant advancement in cancer treatment, harnessing the body’s own immune system to fight disease. This innovative approach involves genetically modifying a patient’s T-cells, a type of white blood cell, to specifically recognize and eliminate cancer cells. This therapy has emerged as a promising option, particularly when other treatments have not been effective or the cancer has returned.
Understanding Chimeric Antigen Receptors
A chimeric antigen receptor (CAR) is a synthetic protein engineered to empower T-cells with the ability to detect and destroy cancer cells. This lab-made receptor combines elements of both an antibody and a T-cell receptor. The CAR is designed with an extracellular domain, which acts like an antenna to specifically bind to a unique protein, or antigen, found on the surface of cancer cells.
This extracellular binding domain is connected to a transmembrane domain, which anchors the CAR within the T-cell’s membrane. Inside the T-cell, the CAR has intracellular signaling domains, including the CD3ΞΆ chain and often co-stimulatory domains like 4-1BB or CD28. These internal domains are responsible for activating the T-cell once the CAR binds to its target antigen, triggering a powerful anti-tumor response. The addition of co-stimulatory domains in newer generations of CARs, such as the second and third generations, enhances the T-cell’s ability to persist and effectively kill cancer cells.
How CAR T-Cell Therapy Works
The process of CAR T-cell therapy begins with the collection of a patient’s T-cells, typically through a procedure called leukapheresis. During this process, blood is drawn from the patient, and a specialized machine separates out the T-cells, returning the remaining blood components to the patient. This collection usually takes several hours in an outpatient setting.
Once collected, these T-cells are sent to a specialized laboratory for genetic engineering. Here, a new gene encoding the chimeric antigen receptor (CAR) is introduced into the T-cells, often using a viral vector. This genetic modification programs the T-cells to express the CAR on their surface, enabling them to specifically recognize a particular antigen present on cancer cells.
After genetic modification, the newly engineered CAR T-cells are expanded in the laboratory, a process that involves growing them until there are millions of cells. This expansion typically takes several weeks.
Before the infusion, patients often receive a short course of chemotherapy, known as lymphodepletion. This preparatory chemotherapy helps to reduce the number of existing immune cells, creating more space and a favorable environment for the newly infused CAR T-cells to expand and function.
Finally, the modified CAR T-cells are infused back into the patient, much like a blood transfusion. Once infused, these re-engineered T-cells circulate in the bloodstream, actively seeking out and binding to cancer cells that express the target antigen. Upon binding, the CAR T-cells become activated, proliferate, and release cytotoxic substances and inflammatory cytokines, which kill the cancer cells.
Diseases Treated with CAR T-Cell Therapy
CAR T-cell therapy has shown significant success primarily in the treatment of certain blood cancers. The therapy is approved for specific types of leukemia and lymphoma, and also for multiple myeloma. It is considered for patients whose cancer has relapsed or become refractory after other treatments.
CAR T-cell therapies are approved for pediatric and young adult patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).
In lymphomas, it is used for certain B-cell lymphoma subtypes, including diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and follicular lymphoma. A common target for these CAR T-cells in B-cell malignancies is the CD19 antigen. Another target, B-cell maturation antigen (BCMA), is used for CAR T-cell therapies approved for multiple myeloma.
Managing Potential Side Effects
CAR T-cell therapy can lead to serious side effects that require careful management in specialized medical centers. Two common complications are Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS). These side effects occur within the first few weeks after the CAR T-cell infusion.
Cytokine Release Syndrome (CRS) is a systemic inflammatory response triggered by the rapid activation and expansion of CAR T-cells, leading to the release of inflammatory proteins called cytokines. Symptoms can range from fever, chills, and fatigue to more severe manifestations like low blood pressure, difficulty breathing, and organ dysfunction. Management involves supportive care, and for more severe cases, medications such as tocilizumab or corticosteroids are administered to reduce the inflammatory response.
Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) affects the nervous system and can occur alongside or independently of CRS, appearing within one to three weeks post-infusion. Neurological symptoms can include confusion, language difficulties (aphasia), tremors, and in more severe instances, seizures or cerebral edema. The treatment of ICANS involves corticosteroids.