Tisagenlecleucel

Tisagenlecleucel, sold under the brand name Kymriah, is a medication for the treatment of B-cell acute lymphoblastic leukemia (ALL) which uses the body's own T cells to fight cancer (adoptive cell transfer).[1][2]

Tisagenlecleucel
Clinical data
Pronunciationtis" a jen" lek loo' se
/ˌtɪsədʒen'leklusel/
Trade namesKymriah
Other namesCTL019, CART-19
AHFS/Drugs.comProfessional Drug Facts
MedlinePlusa617053
License data
Routes of
administration		Intravenous infusion
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • US: ℞-only
  • EU: Rx-only
Pharmacokinetic data
Elimination half-life16.8 days
Identifiers
CAS Number
DrugBank
UNII
KEGG

Serious side effects occur in most patients.[3] 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.[3] Serious infections occur in around three in ten diffuse large B-cell lymphoma (DLBCL) patients.[3]

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.[4] In August 2017, it became the first FDA-approved treatment that included a gene therapy step in the United States.[1]

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.[2][3]

Adverse effects

A frequent side effect seen is cytokine release syndrome (CRS).[4][5]

Serious side effects occur in most patients.[3] 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.[3] Serious infections occur in around three in ten diffuse large B-cell lymphoma (DLBCL) patients.[3]

History

The treatment was developed by Dario Campana at St. Jude's Children's Research Hospital and transferred to a group headed by Carl H. June at the University of Pennsylvania, which violated the terms of an MTA with St. Jude's and has been subsequently licensed to Novartis after a multimillion dollar lawsuit (https://www.biopharma-reporter.com/Article/2015/04/07/Novartis-settles-CAR-T-patent-dispute-with-Juno-for-12m-future-payments) .[6]

In April 2017, tisagenlecleucel received breakthrough therapy designation by the U.S. Food and Drug Administration (FDA) for the treatment of relapsed or refractory diffuse large B-cell lymphoma.[7]

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.[5][8][9]

In August 2017, the FDA granted approval for the use of tisagenlecleucel in people with acute lymphoblastic leukemia.[10][11][12] 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.[13]

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.[10][14]

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.[15] 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 II clinical study for relapsing/remitting B cell acute lymphoblastic leukemia.[16]

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.[8] It uses the 4-1BB co-stimulatory domain in its CAR to improve response.[17]

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.[18] Novartis has been expanding a facility in France, and constructed a new facility in Stein, Switzerland, to relieve this bottleneck beginning in 2020.[18] Novartis uses the company Cryoport Inc. for temperature-controlled transportation required for the manufacture and distribution of Kymriah.[19][20]

References
  1. "FDA approval brings first gene therapy to the United States". U.S. Food & Drug Administration (FDA) (Press release). Retrieved 31 August 2017.
  2. "Kymriah- tisagenlecleucel injection, suspension". DailyMed. 14 June 2019. Retrieved 1 April 2020.
  3. "Kymriah EPAR". European Medicines Agency (EMA). Retrieved 15 August 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  4. "BLA 125646 Tisagenlecleucel - Novartis Briefing document to FDA ODAC" (PDF).
  5. "FDA Panel Backs Novartis' Pioneering New Cancer Gene Therapy". The New York Times. Reuters. 12 July 2017. Archived from the original on 14 July 2017.
  6. Grady D (12 July 2017). "F.D.A. Panel Recommends Approval for Gene-Altering Leukemia Treatment". The New York Times. Retrieved 1 April 2020.
  7. "Novartis gets second CAR-T candidate FDA 'breakthrough' tag". www.fiercebiotech.com. Fierce Biotech.
  8. Ledford H (July 2017). "Engineered cell therapy for cancer gets thumbs up from FDA advisers". Nature. 547 (7663): 270. Bibcode:2017Natur.547..270L. doi:10.1038/nature.2017.22304. PMID 28726836.
  9. Stein R (12 July 2017). "'Living Drug' That Fights Cancer By Harnessing The Immune System Clears Key Hurdle". NPR. Retrieved 13 July 2017.
  10. "Kymriah (tisagenlecleucel)". U.S. Food and Drug Administration (FDA). 1 April 2018. Retrieved 1 April 2020.
  11. "FDA approval brings first gene therapy to the United States". U.S. Food and Drug Administration (FDA) (Press release). Retrieved 6 September 2017.
  12. Harris E (27 November 2019). "Challenges Facing The Cell And Gene Sector's Regulation Landscape". Life Science Leader. Pennsylvania, United States: VertMarkets. 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.
  13. Grady D (30 August 2017). "F.D.A. Approves First Gene-Altering Leukemia Treatment, Costing $475,000". The New York Times. Retrieved 6 September 2017.
  14. "FDA Expands Tisagenlecleucel Approval - The ASCO Post". www.ascopost.com.
  15. Sarah Boseley (5 September 2018). "NHS to treat young cancer patients with expensive 'game changer' drug". The Guardian. Retrieved 5 September 2018.
  16. "Determine Efficacy and Safety of CTL019 in Pediatric Patients With Relapsed and Refractory B-cell ALL". clinicaltrials.gov.
  17. "FDA Panel Unanimously Recommends Approval for Novartis' CAR T-Cell Therapy CTL019". GEN. GEN Genetic Engineering & Biotechnology News.
  18. Miller J (28 November 2019). "Novartis's $90 million Swiss factory to help solve cell therapy bottleneck". Reuters. Retrieved 1 December 2019.
  19. "Cryoport's CEO on cell therapies' market 'robust demand'". biopharma-reporter.com. Retrieved 18 October 2019.
  20. "Cryoport talks compliance, biopharma expansion, and Brexit". outsourcing-pharma.com. Retrieved 18 October 2019.

Further reading
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