Tisagenlecleucel
Tisagenlecleucel, marketed as Kymriah, is a treatment for B-cell acute lymphoblastic leukemia (ALL) which uses the body's own T cells to fight cancer (adoptive cell transfer).
| Clinical data | |
|---|---|
| Trade names | Kymriah |
| Other names | CTL019 |
| AHFS/Drugs.com | kymriah |
| Routes of administration | Intravenous infusion |
| ATC code |
|
| Legal status | |
| Legal status |
|
| Pharmacokinetic data | |
| Elimination half-life | 16.8 days |
| Identifiers | |
| DrugBank | |
| KEGG | |
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.
It was invented and initially developed at the University of Pennsylvania; Novartis completed development, obtained FDA approval, and markets the treatment.[1] In August 2017, it became the first FDA-approved treatment that included a gene therapy step in the United States.[2]
It is administered in a single treatment, which will cost US$475,000. Novartis says this is cheaper than some bone marrow transplants, and that it will not charge people whose conditions do not respond to the treatment.[3]
Indications
Tisagenlecleucel is currently approved to treat acute lymphoblastic leukemia and relapsed or refractory diffuse large B-cell lymphoma.
Adverse effects
A frequent side effect seen is cytokine release syndrome (CRS).[1][4]
History
The treatment was developed by a group headed by Carl H. June at the University of Pennsylvania, and is licensed to Novartis.[5]
In April 2017, CTL019 received breakthrough therapy designation by the US FDA for the treatment of relapsed or refractory diffuse large B-cell lymphoma.[6]
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.[4][7][8]
In August 2017 the FDA granted approval for the use of tisagenlecleucel in people with acute lymphoblastic leukemia.[9][10] 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.[11]
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.[12]
In England, the NHS will use the procedure to treat children with ALL if earlier treatments including stem cell transplants have failed; it is expected to apply to between 15 and 20 children.[13] The drug has been licensed to treat adults with diffuse large B-cell lymphoma (DLBCL), but as of September 2018 it had not been decided whether the NHS would use it.
It has undergone a phase 2 clinical study for relapsing/remitting B cell acute lymphoblastic leukemia.[14]
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.[7] It uses the 4-1BB co-stimulatory domain in its CAR to improve response.[15]
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.[16] Novartis has been expanding a facility in France, and constructed a new facility in Stein, Switzerland, to relieve this bottleneck beginning in 2020.[16] Novartis uses the company Cryoport Inc. for temperature-controlled transportation required for the manufacture and distribution of Kymriah.[17][18]
References
- "BLA 125646 Tisagenlecleucel - Novartis Briefing document to FDA ODAC" (PDF).
- "FDA approval brings first gene therapy to the United States". FDA - U.S. Food & Drug Administration. U.S. Department of Health and Human Services. Retrieved 31 August 2017.
- F.D.A. Approves First Gene-Altering Leukemia Treatment, Costing $475,000, By DENISE GRADY, New York Times, AUG. 30, 2017
- "FDA Panel Backs Novartis' Pioneering New Cancer Gene Therapy". New York Times. 12 July 2017 – via NYTimes.com.
- F.D.A. Panel Recommends Approval for Gene-Altering Leukemia Treatment, By DENISE GRADY, New York Times, JULY 12, 2017
- "Novartis gets second CAR-T candidate FDA 'breakthrough' tag". www.fiercebiotech.com. Fierce Biotech.
- Ledford, Heidi (12 July 2017). "Engineered cell therapy for cancer gets thumbs up from FDA advisers". Nature. 547 (7663): 270. doi:10.1038/nature.2017.22304. PMID 28726836.
- Stein, Rob (2017-07-12). "'Living Drug' That Fights Cancer By Harnessing The Immune System Clears Key Hurdle". NPR. Retrieved 2017-07-13.
- "FDA approval brings first gene therapy to the United States". FDA - Food & Drug Administration. Retrieved 6 September 2017.
- Harris, Erin (27 November 2019). "Challenges Facing The Cell And Gene Sector's Regulation Landscape". Life Science Leader. Pennsylvania, United States: VertMarkets. Retrieved 13 Dec 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.
- Grady, Denise. "F.D.A. Approves First Gene-Altering Leukemia Treatment, Costing $475,000". The New York Times. Retrieved 6 September 2017.
- "FDA Expands Tisagenlecleucel Approval - The ASCO Post". www.ascopost.com.
- Sarah Boseley (5 September 2018). "NHS to treat young cancer patients with expensive 'game changer' drug". The Guardian. Retrieved 5 September 2018.
- "Determine Efficacy and Safety of CTL019 in Pediatric Patients With Relapsed and Refractory B-cell ALL". clinicaltrials.gov.
- "FDA Panel Unanimously Recommends Approval for Novartis' CAR T-Cell Therapy CTL019". GEN. GEN Genetic Engineering & Biotechnology News.
- Miller, John (28 November 2019). "Novartis's $90 million Swiss factory to help solve cell therapy bottleneck". Reuters. Retrieved 1 Dec 2019.
- biopharma-reporter.com. "Cryoport's CEO on cell therapies' market 'robust demand'". biopharma-reporter.com. Retrieved 2019-10-18.
- outsourcing-pharma.com. "Cryoport talks compliance, biopharma expansion, and Brexit". outsourcing-pharma.com. Retrieved 2019-10-18.