CAR T-cell therapy is an innovative cancer treatment, leveraging the body’s immune system. This immunotherapy modifies a patient’s T-cells, a type of white blood cell, to specifically target and destroy cancer cells. These engineered cells are often referred to as a “living drug” because they can multiply within the body and continue to fight the disease over time. The development of CAR T-cells has introduced a personalized treatment option for various blood cancers.
Designing CAR T-Cells
CAR T-cell creation begins with apheresis, where a patient’s T-cells are collected from their blood. This collected T-cell sample is then sent to a specialized laboratory for genetic modification.
In the laboratory, a new gene encoding a Chimeric Antigen Receptor (CAR) is introduced into the T-cells, typically using a viral vector. A CAR is a synthetic receptor designed to combine the antigen-binding domain of an antibody with the signaling domains of a T-cell receptor. This genetic engineering equips the T-cells with the ability to recognize specific proteins on cancer cells.
Following genetic modification, engineered CAR T-cells are expanded in large quantities to ensure enough cells for re-infusion. This entire manufacturing process can take several weeks, during which the cells are carefully monitored for quality and quantity.
How CAR T-Cells Target Cancer
Once infused, the engineered CAR T-cells identify and eliminate cancer cells. The chimeric antigen receptor (CAR) on the surface of these T-cells binds to a specific protein (antigen) expressed on cancer cells. For instance, many CAR T-cell therapies target the CD19 antigen found on certain leukemia and lymphoma cells.
Upon binding to their target antigen, CAR T-cells become activated. This triggers a cascade of intracellular signaling within the T-cell. The activated CAR T-cell then initiates its cytotoxic functions, releasing various substances, such as perforin and granzymes.
These cytotoxic substances create pores in the membrane of the cancer cell and induce programmed cell death, effectively destroying the malignant cell. The precision of this targeted recognition and destruction mechanism helps minimize damage to healthy cells that do not express the specific cancer antigen.
Approved Uses of CAR T-Cell Therapy
CAR T-cell therapy has received regulatory approval for treating specific types of blood cancers, generally after other treatments have proven unsuccessful. One of the first approved indications was for B-cell acute lymphoblastic leukemia (ALL) in children and young adults. This therapy has provided a significant option for patients whose ALL has relapsed or is refractory to conventional chemotherapy.
The therapy is also approved for certain aggressive non-Hodgkin lymphomas in adults, including diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (PMBCL), and follicular lymphoma. These approvals often apply to patients who have not responded to at least two prior lines of systemic therapy.
More recently, CAR T-cell therapy has gained approval for treating multiple myeloma, a cancer of plasma cells. This offers an advanced treatment option for adult patients with relapsed or refractory multiple myeloma after they have undergone several previous therapies.
Managing Treatment Side Effects
CAR T-cell therapy can induce significant side effects, necessitating careful monitoring in specialized medical centers. Cytokine Release Syndrome (CRS) is a common and potentially severe complication, resulting from a widespread inflammatory response. Symptoms of CRS can range from fever, fatigue, and muscle aches to more severe manifestations like low blood pressure, difficulty breathing, and organ dysfunction.
Management of CRS often involves supportive care, such as intravenous fluids and medications to manage fever and blood pressure. For more severe cases, an anti-inflammatory medication called tocilizumab, which blocks the interleukin-6 receptor, is used to counteract the inflammatory cascade.
Another serious side effect is Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), which affects the nervous system. ICANS symptoms can include confusion, language difficulties, headaches, tremors, and sometimes seizures. These neurological effects arise within the first few weeks after infusion. Management strategies for ICANS involve supportive care, close neurological monitoring, and sometimes corticosteroids to reduce inflammation in the brain.
The Patient Journey with CAR T-Cells
The patient journey begins with an initial comprehensive evaluation to determine eligibility. This assessment involves reviewing medical history, current health status, and the specific cancer diagnosis.
Following evaluation, the patient undergoes apheresis to collect their T-cells. After collection, T-cells are sent to a specialized manufacturing facility, where they are genetically modified and expanded. During this manufacturing period, which can last approximately three to six weeks, patients may receive bridging chemotherapy to control their cancer progression.
Before the CAR T-cell infusion, patients typically undergo lymphodepleting chemotherapy for a few days. This chemotherapy helps prepare the body by reducing existing immune cells, creating space for the newly infused CAR T-cells to engraft and expand. The CAR T-cells are then infused intravenously, similar to a standard blood transfusion. Following the infusion, patients are closely monitored in a specialized hospital unit for several weeks to manage and mitigate potential side effects like Cytokine Release Syndrome or neurotoxicity.