The most common serious side effects are cytokine release syndrome (a potentially life-threatening condition that can cause fever, vomiting, shortness of breath, pain and low blood pressure) and decreases in platelets (components that help the blood to clot), hemoglobin (the protein found in red blood cells that carries oxygen around the body) or white blood cells including neutrophils and lymphocytes.[9]
T cells from a person with cancer are removed, genetically engineered to make a specific chimeric cell surface receptor with components from both a T-cell receptor and an antibody specific to a protein on the cancer cell, and transferred back to the person. The T cells are engineered to target a protein called CD19 that is common on B cells. A chimeric T cell receptor ("CAR-T") is expressed on the surface of the T cell.[medical citation needed]
The platform invented at the University of Pennsylvania was clinically developed by Novartis, including market authorization, and real world evidence.[11][12] In August 2017, it became the first FDA-approved treatment that included a gene therapy step in the United States.[10]
Medical uses
Tisagenlecleucel is indicated for the treatment of those under 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse; or adults with relapsed or refractory (r/r) large B-cell lymphoma after two or more lines of systemic therapy including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high grade B-cell lymphoma and DLBCL arising from follicular lymphoma.[7][9]
In May 2022, the indication in the US was updated to include the treatment of adults with relapsed or refractory follicular lymphoma (FL) after two or more lines of systemic therapy.[13]
Serious side effects occur in most patients.[9] The most common serious side effects are cytokine release syndrome (a potentially life-threatening condition that can cause fever, vomiting, shortness of breath, pain and low blood pressure) and decreases in platelets (components that help the blood to clot), hemoglobin (the protein found in red blood cells that carries oxygen around the body) or white blood cells including neutrophils and lymphocytes.[9] Serious infections occur in around three in ten diffuse large B-cell lymphoma (DLBCL) patients.[9]
In April 2024, the FDA label boxed warning was expanded to include T cell malignancies.[15]
History
The treatment was developed by a group headed by Carl H. June and co-invented by Michael C. Milone[16] at the University of Pennsylvania, and is licensed to Novartis.[17]
In July 2017, an FDA advisory committee unanimously recommended that the agency approve it to treat B cell acute lymphoblastic leukemia that did not respond adequately to other treatments or have relapsed.[14][19][20]
In August 2017, the FDA granted approval for the use of tisagenlecleucel in people with acute lymphoblastic leukemia.[21][22][23] According to Novartis, the treatment will be administered at specific medical centers where staff have been trained to manage possible reactions to this new type of treatment.[24]
In May 2018, the FDA further approved tisagenlecleucel to treat adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), based on results from the JULIET phase II trial.[21][25]
In England, the NHS will use the procedure to treat children with acute lymphoblastic leukemia (ALL) if earlier treatments including stem cell transplants have failed; it is expected to apply to between 15 and 20 children.[26] In March 2019, NICE issued guidance approving Kymriah for treatment of relapsed or refractory diffuse large B-cell lymphoma in adults after 2 or more systemic therapies.[27]
Manufacture
In a 22-day process, the treatment is customized for each person. T cells are purified from blood drawn from the person, and those cells are then modified by a virus that inserts a gene into the cells' genome. The gene encodes a chimaeric antigen receptor (CAR) that targets leukaemia cells.[19] It uses the 4-1BB co-stimulatory domain in its CAR to improve response.[28]
Modification of the cells to create the customized therapeutic has been a major bottleneck in expanding availability of the treatment, requiring T cells extracted in Europe to be transported to the United States where they are modified, then back to Europe.[29] Novartis has been expanding a facility in France, and constructed a new facility in Stein, Switzerland, to relieve this bottleneck beginning in 2020.[29] Novartis uses the company Cryoport Inc. for temperature-controlled transportation required for the manufacture and distribution of Kymriah.[30][31]
^"Kymriah (tisagenlecleucel)". U.S. Food and Drug Administration. 7 July 2022. Archived from the original on 19 November 2022. Retrieved 19 November 2022.
^ abcdef"Kymriah EPAR". European Medicines Agency (EMA). 17 September 2018. Archived from the original on 21 October 2020. Retrieved 15 August 2020. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
^"FDA approves tisagenlecleucel". U.S. Food and Drug Administration. 31 May 2022. Archived from the original on 5 December 2023. Retrieved 1 June 2022. This article incorporates text from this source, which is in the public domain.
^Harris E (27 November 2019). "Challenges Facing The Cell And Gene Sector's Regulation Landscape". Life Science Leader. Pennsylvania, United States: VertMarkets. Archived from the original on 14 December 2019. Retrieved 13 December 2019. After Kymriah (Novartis), Yescarta (Gilead), and Luxturna (Spark) were approved in the U.S. in 2017, they were subsequently approved in 2018 in the EU. Kymriah also has received approval in Australia and an additional indication in the U.S.{{cite magazine}}: CS1 maint: overridden setting (link)
^World Health Organization (2018). "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 79". WHO Drug Information. 32 (1). hdl:10665/330941.
