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Tisagenlecleucel

Tisagenlecleucel, sold under the brand name Kymriah, is a CAR T cells 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).[10][7]

Tisagenlecleucel
Clinical data
Pronunciationtis" a jen" lek loo' se
/ˌtɪsədʒen'leklusel/
Trade namesKymriah
Other namesCTL019, CART-19, tisa-cel
AHFS/Drugs.comProfessional Drug Facts
MedlinePlusa617053
License data
Pregnancy
category
Routes of
administration		Intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Elimination half-life16.8 days
Identifiers
CAS Number
DrugBank
UNII
KEGG

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

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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]

Adverse effects

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A frequent side effect seen is cytokine release syndrome (CRS).[12][14]

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

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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 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.[18]

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

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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]

Society and culture

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Names

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Tisagenlecleucel is the international nonproprietary name.[32]

References

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  1. ^ "Updates to the Prescribing Medicines in Pregnancy database". Therapeutic Goods Administration (TGA). 12 May 2022. Archived from the original on 3 April 2022. Retrieved 13 May 2022.
  2. ^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 October 2023.
  3. ^ "KYMRIAH (Novartis Pharmaceuticals Australia Pty LTD) | Therapeutic Goods Administration (TGA)". Archived from the original on 2 January 2024. Retrieved 2 January 2024.
  4. ^ "KYMRIAH (Novartis Pharmaceuticals Australia Pty LTD) | Therapeutic Goods Administration (TGA)". Archived from the original on 2 January 2024. Retrieved 2 January 2024.
  5. ^ "KYMRIAH (Novartis Pharmaceuticals Australia Pty LTD) | Therapeutic Goods Administration (TGA)". Archived from the original on 2 January 2024. Retrieved 2 January 2024.
  6. ^ "Summary Basis of Decision (SBD) for Kymriah". Health Canada. 23 October 2014. Archived from the original on 31 May 2022. Retrieved 29 May 2022.
  7. ^ a b c "Kymriah- tisagenlecleucel injection, suspension". DailyMed. 14 June 2019. Archived from the original on 22 October 2020. Retrieved 1 April 2020.
  8. ^ "Kymriah (tisagenlecleucel)". U.S. Food and Drug Administration. 7 July 2022. Archived from the original on 19 November 2022. Retrieved 19 November 2022.
  9. ^ a b c d e f "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.
  10. ^ a b "FDA approval brings first gene therapy to the United States". U.S. Food & Drug Administration (FDA) (Press release). Archived from the original on 24 April 2019. Retrieved 31 August 2017.
  11. ^ Awasthi R, Maier HJ, Zhang J, Lim S (2023). "Kymriah® (Tisagenlecleucel) – an overview of the clinical development journey of the first approved CAR-T therapy". Human Vaccines & Immunotherapeutics. 19 (1). doi:10.1080/21645515.2023.2210046. PMC 10294746. PMID 37185251.
  12. ^ a b "BLA 125646 Tisagenlecleucel - Novartis Briefing document to FDA ODAC" (PDF). Food and Drug Administration. Archived (PDF) from the original on 16 July 2017. Retrieved 16 July 2017.
  13. ^ "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.
  14. ^ a b "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.
  15. ^ "FDA Requires Boxed Warning for T cell Malignancies Following Treatment with BCMA-Directed or CD19-Directed Autologous Chimeric Antigen Receptor (CAR) T cell Immunotherapies". U.S. Food and Drug Administration (FDA). 18 April 2024. Archived from the original on 19 April 2024. Retrieved 19 April 2024.   This article incorporates text from this source, which is in the public domain.
  16. ^ Clark H (5 January 2024). "Dr. Carl H. June: Forging a Path for Cancer Cell Therapy". Leading Discoveries Magazine. Retrieved 5 June 2024.
  17. ^ Grady D (12 July 2017). "F.D.A. Panel Recommends Approval for Gene-Altering Leukemia Treatment". The New York Times. Archived from the original on 22 November 2017. Retrieved 1 April 2020.{{cite web}}: CS1 maint: overridden setting (link)
  18. ^ "Novartis gets second CAR-T candidate FDA 'breakthrough' tag". www.fiercebiotech.com. Fierce Biotech. 18 April 2017. Archived from the original on 20 April 2017. Retrieved 19 April 2017.
  19. ^ a b 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.
  20. ^ Stein R (12 July 2017). "'Living Drug' That Fights Cancer By Harnessing The Immune System Clears Key Hurdle". NPR. Archived from the original on 8 February 2018. Retrieved 13 July 2017.{{cite news}}: CS1 maint: overridden setting (link)
  21. ^ a b "Kymriah (tisagenlecleucel)". U.S. Food and Drug Administration (FDA). 1 April 2018. Archived from the original on 21 December 2019. Retrieved 1 April 2020.
  22. ^ "FDA approval brings first gene therapy to the United States". U.S. Food and Drug Administration (FDA) (Press release). Archived from the original on 24 April 2019. Retrieved 6 September 2017.
  23. ^ 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)
  24. ^ Grady D (30 August 2017). "F.D.A. Approves First Gene-Altering Leukemia Treatment, Costing $475,000". The New York Times. Archived from the original on 28 January 2018. Retrieved 6 September 2017.{{cite news}}: CS1 maint: overridden setting (link)
  25. ^ "FDA Expands Tisagenlecleucel Approval - The ASCO Post". www.ascopost.com. Archived from the original on 27 November 2018. Retrieved 11 June 2019.
  26. ^ Sarah Boseley (5 September 2018). "NHS to treat young cancer patients with expensive 'game changer' drug". The Guardian. Archived from the original on 4 September 2018. Retrieved 5 September 2018.
  27. ^ "Overview | Tisagenlecleucel for treating relapsed or refractory diffuse large B-cell lymphoma after 2 or more systemic therapies | Guidance | NICE". www.nice.org.uk. 13 March 2019. Archived from the original on 28 July 2021. Retrieved 3 August 2021.
  28. ^ "FDA Panel Unanimously Recommends Approval for Novartis' CAR T-Cell Therapy CTL019". GEN. GEN Genetic Engineering & Biotechnology News. 13 July 2017. Archived from the original on 16 July 2017. Retrieved 16 July 2017.
  29. ^ a b Miller J (28 November 2019). "Novartis's $90 million Swiss factory to help solve cell therapy bottleneck". Reuters. Archived from the original on 30 November 2019. Retrieved 1 December 2019.{{cite news}}: CS1 maint: overridden setting (link)
  30. ^ "Cryoport's CEO on cell therapies' market 'robust demand'". biopharma-reporter.com. 22 April 2019. Archived from the original on 24 October 2020. Retrieved 18 October 2019.
  31. ^ "Cryoport talks compliance, biopharma expansion, and Brexit". outsourcing-pharma.com. 13 November 2018. Archived from the original on 30 November 2020. Retrieved 18 October 2019.
  32. ^ World Health Organization (2018). "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 79". WHO Drug Information. 32 (1). hdl:10665/330941.

Further reading

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