On August 30, 2017, the U.S. Food and Drug Administration (FDA) approved a novel immunotherapy for the treatment of acute lymphoblastic leukemia (ALL) in children or young patients – -tisagenlecleucel intravenous infusion suspension (trade name Kymriah™, manufactured by Novartis). This drug is administered intravenously for the treatment of B-cell acute lymphoblastic leukemia in those under 25 years of age who have relapsed or are refractory to treatment after receiving at least two prior systemic therapies.
What is CAR T therapy?
CAR T is a cellular immunotherapy approach in which T cells from patients are modified in vitro to express receptors that specifically recognize tumor cell surface targets – chimeric antigen receptors (CARs) – and then infused back into the patient to exert anti-tumor effects.
T cells in the body can express CD4 and CD8, respectively. CD4 T cells are helper T cells that primarily regulate the function of other immune cells. CD8 T cells, on the other hand, are called killer T cells, and they specifically recognize and kill abnormal cells.
CAR T is a treatment regimen that is customized for each patient using the patient’s own T cells. First, T cells are isolated from the patient’s blood and modified – a receptor that recognizes the CD19 molecule, which is expressed by all B cells, is added to a signaling region that causes T cell activation, creating a chimeric artificial receptor. This modified T cell is then able to attack and destroy all CD19-expressing cells. Afterwards, the modified T cells are expanded with T cell receptor activators and drugs such as growth factor-interleukin 2. Finally, the doctors infuse the expanded T cells back into the patient to exert their anti-cancer effects. This entire process takes about 22 days.
Why can tisagenlecleucel be used to treat childhood acute lymphoblastic leukemia?
Acute lymphoblastic leukemia is a rapidly progressive cancer that manifests as an accumulation of abnormal lymphocytes in the body that prevents the production of normal blood cells (red blood cells, white blood cells, and platelets). The abnormal lymphocytes may be B cells or T cells. About 1/4 of childhood tumors under 15 years of age are acute lymphoblastic leukemia. More than 80% of acute lymphoblastic leukemia in children is B-cell acute lymphoblastic leukemia.
The current standard of care for childhood acute lymphoblastic leukemia is combination chemotherapy. There are few previously effective treatment options for patients who do not go into remission after standard therapy or whose cancer has recurred. Given that almost all B cells express CD19, tisagenlecleucel is genetically modified to recognize and eliminate CD19-expressing cancer cells and is therefore efficacious.
Evidence of efficacy: 81% overall remission rate
The approval of Tisagenlecleucel was based primarily on a multicenter clinical study. Seventy-five pediatric and young B-cell acute lymphoblastic leukemia patients in the study received CAR T-cell therapy, and researchers followed the 75 patients who received Tisagenlecleucel infusions for at least 3 months, showing an overall remission rate of 81% (95% CI, 71-89) and a negative loss cytometric analysis of microscopic residual lesions in patients who responded to treatment. negative. event-free survival and overall survival at 6 and 12 months were 73% and 90%, and 50% and 76%, respectively. Median duration of remission was not reached.
Originally in 2010, the University of Pennsylvania tried this treatment in adult patients with advanced chronic lymphocytic leukemia (CLL). 2012 saw the first treatment of pediatric acute lymphoblastic leukemia with this therapy at the Children’s Hospital of Philadelphia (CHOP). Since then, the treatment has been administered at 13 medical centers in the United States and at several medical centers in other countries.
Black box warning: need to be wary of cytokine release syndrome
The main common adverse reactions to Tisagenlecleucel include cytokine release syndrome, hypogammaglobulinemia, sectoral causes of infection, fever, poor appetite, headache, encephalitis, hypotension, bleeding, tachycardia, nausea, diarrhea, vomiting, hypoxia, fatigue, acute kidney injury, and delirium.
It is important to note that the instructions for tisagenlecleucelk include a black box warning that the drug may cause a lethal inflammatory response, cytokine release syndrome (CRS), with manifestations including fever, flu The FDA recommends that tocilizumab (trade name: Actemra) be used to treat CRS.
How do I use tisagenlecleucel?
According to the approved product insert, the recommended use and dosage of tisagenlecleucel is as follows:
- Dosing in children and adolescents needs to be differentiated based on body weight: 0.2 x 10 to 5.0 x 10 CAR-positive live T cells per kg body weight for weights below 50 kg; 0.1 x 10 to 2.5 x 10 CAR-positive live T cells per kg body weight for weights above 50 kg.
- Lymphocyte clearance by fludarabine (30 mg/m, IV, QD, for 4 days) and cyclophosphamide (500 mg/m, IV, once daily for 2 days when fludarabine is started) is required before treatment, and tisagenlecleucel treatment is carried out within 2 to 14 days after completion of clearance.
- After receiving treatment, patients with ALL will need monthly outpatient immunoglobulin injections to prevent infection.
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In May 2018, tisagenlecleucel received FDA approval for an expanded indication – adult patients with large B-cell lymphoma whose cancer has returned or is refractory after two or more systemic treatments. In addition, in addition to tisagenlecleucel, another company – Yescarta (trade name: axicabtagene ciloleucel), a CAR T therapy developed by Kite Pharma – was also approved in late 2017 for the treatment of refractory large B-cell lymphoma.
Tisagenlecleucel is not yet available in China, but the series of CAR T therapies represented by it brings hope for a cure for patients with hematologic malignancies, while at the same time facing challenges such as how to regulate production, how to quality control, and how to deal with serious side effects. It is hoped that along with the continued maturation of the technology, CAR T-cell therapies will change the treatment paradigm of hematologic tumors and even the entire oncology field in the future.