Tisagenlecleucel Explained

Pronounce:tis" a jen" lek loo' se
/ˌtɪsədʒen'leklusel/
Tradename:Kymriah
Dailymedid:Tisagenlecleucel
Pregnancy Au:C
Pregnancy Au Comment:[1]
Routes Of Administration:Intravenous
Atc Prefix:L01
Atc Suffix:XL04
Legal Au Comment:C4 (class 4 biological)[2] [3] [4]
Legal Ca:Rx-only
Legal Ca Comment:/Schedule D[5]
Legal Us:Rx-only
Legal Us Comment:[6]
Legal Eu:Rx-only
Elimination Half-Life:16.8 days
Cas Number:1823078-37-0
Drugbank:DB13881
Unii:Q6C9WHR03O
Kegg:D11386
Synonyms:CTL019, CART-19

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).[7]

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

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.[8] In August 2017, it became the first FDA-approved treatment that included a gene therapy step in the United States.[9]

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.[10]

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.[11]

Adverse effects

A frequent side effect seen is cytokine release syndrome (CRS).[8]

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

In April 2024, the FDA label boxed warning was expanded to include T cell malignancies.[12]

History

The treatment was developed by a group headed by Carl H. June and co-invented by Michael C. Milone[13] at the University of Pennsylvania, and is licensed to Novartis.[14]

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.[15]

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.[16] [17] [18]

In August 2017, the FDA granted approval for the use of tisagenlecleucel in people with acute lymphoblastic leukemia.[19] [20] [21] 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.[22]

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.[23]

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.[24] 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.[25]

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. It uses the 4-1BB co-stimulatory domain in its CAR to improve response.[26]

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.[27] Novartis has been expanding a facility in France, and constructed a new facility in Stein, Switzerland, to relieve this bottleneck beginning in 2020. Novartis uses the company Cryoport Inc. for temperature-controlled transportation required for the manufacture and distribution of Kymriah.[28] [29]

Society and culture

Names

Tisagenlecleucel is the international nonproprietary name.[30]

Further reading

Notes and References

  1. Web site: Updates to the Prescribing Medicines in Pregnancy database . Therapeutic Goods Administration (TGA) . 12 May 2022 . 13 May 2022 . 3 April 2022 . https://web.archive.org/web/20220403064059/https://www.tga.gov.au/updates-prescribing-medicines-pregnancy-database . live .
  2. Web site: KYMRIAH (Novartis Pharmaceuticals Australia Pty LTD) | Therapeutic Goods Administration (TGA) . 2 January 2024 . 2 January 2024 . https://web.archive.org/web/20240102053117/https://www.tga.gov.au/resources/prescription-medicines-registrations/kymriah-novartis-pharmaceuticals-australia-pty-ltd-0 . live .
  3. Web site: KYMRIAH (Novartis Pharmaceuticals Australia Pty LTD) | Therapeutic Goods Administration (TGA) . 2 January 2024 . 2 January 2024 . https://web.archive.org/web/20240102053117/https://www.tga.gov.au/resources/prescription-medicines-registrations/kymriah-novartis-pharmaceuticals-australia-pty-ltd-1 . live .
  4. Web site: KYMRIAH (Novartis Pharmaceuticals Australia Pty LTD) | Therapeutic Goods Administration (TGA) . 2 January 2024 . 2 January 2024 . https://web.archive.org/web/20240102053116/https://www.tga.gov.au/resources/prescription-medicines-registrations/kymriah-novartis-pharmaceuticals-australia-pty-ltd . live .
  5. Web site: Summary Basis of Decision (SBD) for Kymriah . . 23 October 2014 . 29 May 2022 . 31 May 2022 . https://web.archive.org/web/20220531070211/https://hpr-rps.hres.ca/reg-content/summary-basis-decision-detailTwo.php?linkID=SBD00416&lang=en . live .
  6. Web site: Kymriah (tisagenlecleucel) . U.S. Food and Drug Administration . 7 July 2022 . 19 November 2022 . 19 November 2022 . https://web.archive.org/web/20221119053704/https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/kymriah-tisagenlecleucel . live .
  7. Web site: Kymriah- tisagenlecleucel injection, suspension . DailyMed . 14 June 2019 . 1 April 2020 . 22 October 2020 . https://web.archive.org/web/20201022130745/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=aad3ba54-dfd3-4cb3-9e2b-c5ef89559189 . live .
  8. Web site: BLA 125646 Tisagenlecleucel - Novartis Briefing document to FDA ODAC. Food and Drug Administration. 16 July 2017. 16 July 2017. https://web.archive.org/web/20170716062757/https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM566166.pdf. live.
  9. FDA approval brings first gene therapy to the United States. U.S. Food & Drug Administration (FDA). 31 August 2017. 24 April 2019. https://web.archive.org/web/20190424162456/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm574058.htm. live.
  10. Web site: Kymriah EPAR . European Medicines Agency (EMA) . 17 September 2018 . 15 August 2020 . 21 October 2020 . https://web.archive.org/web/20201021082500/https://www.ema.europa.eu/en/medicines/human/EPAR/kymriah . live . Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  11. Web site: FDA approves tisagenlecleucel . U.S. Food and Drug Administration . 31 May 2022 . 1 June 2022 . 5 December 2023 . https://web.archive.org/web/20231205045000/https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tisagenlecleucel-relapsed-or-refractory-follicular-lymphoma . live .
  12. Web site: 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 . 19 April 2024 . 19 April 2024 . https://web.archive.org/web/20240419003946/https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/fda-requires-boxed-warning-t-cell-malignancies-following-treatment-bcma-directed-or-cd19-directed . live .
  13. Web site: Clark . Heather . 5 January 2024 . Dr. Carl H. June: Forging a Path for Cancer Cell Therapy . 5 June 2024 . Leading Discoveries Magazine . en-US.
  14. Web site: Grady . Denise . vanc . F.D.A. Panel Recommends Approval for Gene-Altering Leukemia Treatment . The New York Times . 12 July 2017 . 1 April 2020 . 22 November 2017 . https://web.archive.org/web/20171122015255/https://www.nytimes.com/2017/07/12/health/fda-novartis-leukemia-gene-medicine.html . live .
  15. Web site: Novartis gets second CAR-T candidate FDA 'breakthrough' tag. Fierce Biotech. www.fiercebiotech.com. 18 April 2017. 19 April 2017. 20 April 2017. https://web.archive.org/web/20170420045912/http://www.fiercebiotech.com/biotech/novartis-gets-second-car-t-candidate-fda-breakthrough-tag. live.
  16. News: FDA Panel Backs Novartis' Pioneering New Cancer Gene Therapy. 12 July 2017. The New York Times. Reuters. https://web.archive.org/web/20170714180028/https://www.nytimes.com/reuters/2017/07/12/business/12reuters-novartis-cancer.html . 14 July 2017 . dead.
  17. Ledford H . Engineered cell therapy for cancer gets thumbs up from FDA advisers . Nature . 547 . 7663 . 270 . July 2017 . 28726836 . 10.1038/nature.2017.22304 . 2017Natur.547..270L . free .
  18. News: 'Living Drug' That Fights Cancer By Harnessing The Immune System Clears Key Hurdle. Stein. Rob. vanc. NPR. 12 July 2017. 13 July 2017. 8 February 2018. https://web.archive.org/web/20180208183952/https://www.npr.org/sections/health-shots/2017/07/12/536812206/living-drug-that-fights-cancer-by-harnessing-the-immune-system-clears-key-hurdle. live.
  19. Web site: Kymriah (tisagenlecleucel) . U.S. Food and Drug Administration (FDA) . 1 April 2018 . 1 April 2020 . 21 December 2019 . https://web.archive.org/web/20191221084858/https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/kymriah-tisagenlecleucel . live .
  20. FDA approval brings first gene therapy to the United States. U.S. Food and Drug Administration (FDA). 6 September 2017. 24 April 2019. https://web.archive.org/web/20190424162456/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm574058.htm. live.
  21. Harris. Erin. vanc. 27 November 2019. Challenges Facing The Cell And Gene Sector's Regulation Landscape. Life Science Leader. Pennsylvania, United States. VertMarkets. 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.. 14 December 2019. https://web.archive.org/web/20191214023402/https://www.lifescienceleader.com/doc/challenges-facing-the-cell-and-gene-sector-s-regulation-landscape-0001. live.
  22. News: Grady. Denise. vanc. F.D.A. Approves First Gene-Altering Leukemia Treatment, Costing $475,000. 30 August 2017. 6 September 2017. The New York Times. 28 January 2018. https://web.archive.org/web/20180128120235/https://www.nytimes.com/2017/08/30/health/gene-therapy-cancer.html. live.
  23. Web site: FDA Expands Tisagenlecleucel Approval - The ASCO Post. www.ascopost.com. 11 June 2019. 27 November 2018. https://web.archive.org/web/20181127022431/http://www.ascopost.com/issues/may-25-2018/fda-expands-tisagenlecleucel-approval/. live.
  24. News: NHS to treat young cancer patients with expensive 'game changer' drug . The Guardian . 5 September 2018 . Sarah Boseley . 5 September 2018 . 4 September 2018 . https://web.archive.org/web/20180904231911/https://www.theguardian.com/society/2018/sep/05/nhs-treat-young-cancer-patients-expensive-game-changer-drug-kymriah . live .
  25. Web site: Overview Tisagenlecleucel for treating relapsed or refractory diffuse large B-cell lymphoma after 2 or more systemic therapies Guidance NICE. 3 August 2021. www.nice.org.uk. 13 March 2019. 28 July 2021. https://web.archive.org/web/20210728062253/https://www.nice.org.uk/guidance/ta567. live.
  26. Web site: FDA Panel Unanimously Recommends Approval for Novartis' CAR T-Cell Therapy CTL019 . GEN Genetic Engineering & Biotechnology News . GEN . 13 July 2017 . 16 July 2017 . 16 July 2017 . https://web.archive.org/web/20170716054217/http://www.genengnews.com/gen-news-highlights/fda-panel-unanimously-recommends-approval-for-novartis-car-t-cell-therapy-ctl019/81254648? . live .
  27. News: Novartis's $90 million Swiss factory to help solve cell therapy bottleneck. Miller. John. vanc. 28 November 2019. 1 December 2019. Reuters. 30 November 2019. https://web.archive.org/web/20191130164045/https://www.reuters.com/article/us-novartis-swiss-factory/novartiss-90-million-swiss-factory-to-help-solve-cell-therapy-bottleneck-idUSKBN1Y214Y. live.
  28. Web site: Cryoport's CEO on cell therapies' market 'robust demand'. biopharma-reporter.com. 22 April 2019. 18 October 2019. 24 October 2020. https://web.archive.org/web/20201024180004/https://www.biopharma-reporter.com/Article/2019/04/22/Cryoport-on-cell-therapy-market-robust-demand. live.
  29. Web site: Cryoport talks compliance, biopharma expansion, and Brexit. outsourcing-pharma.com. 13 November 2018. 18 October 2019. 30 November 2020. https://web.archive.org/web/20201130052256/https://www.outsourcing-pharma.com/Article/2018/11/13/Cryoport-talks-compliance-biopharma-expansion-and-Brexit. live.
  30. ((World Health Organization)) . 2018 . International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 79 . WHO Drug Information . 32 . 1 . 10665/330941 . free . World Health Organization .

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