chimeric antigen receptor T-cell therapy

chimeric antigen receptor T-cell therapy (CAR T-cell therapy), type of immunotherapy in which a patient’s T cells are modified to recognize and attack cancer cells. A T cell is a type of white blood cell that determines the specificity of immune response to antigens (foreign substances) in the body. Chimeric antigen receptor (CAR) T-cell therapy effectively harnesses the body’s immune system to fight cancer.

CAR T-cell therapy is used primarily to treat blood cancers, such as leukemia, lymphoma, and multiple myeloma. The first such therapy to gain approval for use in humans was tisagenlecleucel (brand name: Kymriah), which was approved by the U.S. Food and Drug Administration in 2017. Tisagenlecleucel is used in the treatment of pediatric and young adult acute lymphoblastic leukemia (ALL).

The first CAR T-cell therapies

​In 1987 Japanese immunologist Yoshikazu Kurosawa and colleagues engineered T cells to express chimeric receptor molecules composed of antibody-derived variable regions and T-cell receptor-derived constant regions. Their preliminary studies were critical in showing that CARs are capable of activating T cells. Between 1989 and 1993, Israeli immunologists Gideon Gross and Zelig Eshhar, working at the Weizmann Institute of Science, demonstrated the potential of CARs for targeting tumor antigens. These first-generation CARs contained the T-cell CD3-zeta intracellular domain, which is responsible for T-cell activation. Although the cells demonstrated significant promise in vitro, they were relatively ineffective in human cancer patients.

In the late 1990s and early 2000s second-generation CARs were developed that included both the CD3-zeta intracellular domain and a co-stimulatory domain, which provided a necessary second signal for T cells to be fully activated. Co-stimulatory signaling, via domains such as CD28 and OX40, allowed CAR T cells to proliferate, survive longer, and kill tumor cells more effectively than first-generation agents.

Between 2006 and 2010 some of the first clinical trials using second-generation CAR T cells began. These early investigations centered on B-cell malignancies, specifically targeting CD19, a protein on the surface of B cells. In 2010, tisagenlecleucel, a second-generation CD19 CAR T-cell therapy, was administered to a patient with chronic lymphocytic leukemia (CLL), and significant tumor reduction was observed. This success was followed by a larger trial of tisagenlecleucel in patients with B-cell ALL in which the treatment eliminated cancer cells and induced complete remission in multiple patients. In 2018, one year after its approval for use in pediatric and young adult ALL, tisagenlecleucel received expanded approval for the treatment of adults with large B-cell lymphoma. By 2025 six CAR T-cell therapies had become available for the treatment of various blood cancers: in addition to tisagenlecleucel, these were axicabtagene ciloleucel (Yescarta), brexucabtagene autoleucel (Tecartus), lisocabtagene maraleucel (Breyanzi), idecabtagene vicleucel (Abecma), and ciltacabtagene autoleucel (Carvykti).

CAR T-cell production

CAR T-cell therapy begins with the extraction of T cells from the patient’s blood through a process known as leukapheresis, which separates out white blood cells; the remaining blood components are returned to the patient. In a laboratory, the T cells are modified via genetic engineering to express a CAR on their surface. This receptor is engineered by inserting a CAR gene into the T cells, using viral vectors, such as retrovirus or lentivirus vectors. The CAR protein enables the T cells to recognize a specific antigen on cancer cells (e.g., CD19 for B-cell cancers).

The modified CAR T cells are carefully cultivated and multiplied until a large quantity, often in the millions, is produced. Before receiving CAR T cells, the patient undergoes a procedure known as lymphodepletion, in which low-dose chemotherapy is used to reduce the level of normal T cells, which may compete with CAR T cells. The engineered CAR T cells are then infused into the patient’s bloodstream. Once in the body, they destroy cancer cells by binding to their specific antigen. This attack phase can continue for weeks or months—in some cases, leading to long-term disease remission. The production of CAR T-cell therapy takes about three to five weeks, from the time the T cells are collected to the time that the engineered cells are infused back into the patient.

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Side effects

After undergoing CAR T-cell therapy, patients are closely monitored for side effects and immune reactions. Among the most severe reactions are cytokine release syndrome (CRS) and neurotoxicity. In CRS, which typically occurs two to seven days after the infusion, large amounts of substances known as cytokines are released into the blood, triggering a severe immune reaction characterized by fever, low blood pressure, rapid heart rate, difficulty breathing, and nausea and vomiting. Neurotoxicity after CAR T-cell therapy often manifests as immune effector cell-associated neurotoxicity syndrome (ICANS), with symptoms such as confusion, seizures, or memory problems. ICANS appears to be linked to a massive release of cytokines, particularly in the cerebrospinal fluid.

Other side effects include hematologic toxicity, in which CAR T-cell therapy damages bone marrow, causing a decrease in blood cells. Some patients experience heightened vulnerability to infections. Patients with high tumor burden, preexisting kidney dysfunction, or certain other risk factors may experience tumor lysis syndrome, in which large numbers of cancer cells die quickly, flooding the blood with toxic substances and overwhelming the body’s metabolic and excretion capability.

Prognosis

Prognosis for CAR T-cell therapy varies depending on the type of cancer, the patient’s health, and response to treatment. In general, CAR T-cell therapy has shown remarkable success: more than half of patients have achieved remission within the first three months. It is particularly effective for relapsed or refractory blood cancers (cancers that have returned or that do not respond to standard treatments). For example, 80 to 90 percent of patients with relapsed or refractory B-cell ALL enter remission after treatment. About half of these patients, however, experience disease relapse within two years. Improving the long-term effectiveness and durability of CAR T-cell therapy is an area of ongoing research.