View source for Biology:Tisagenlecleucel

{{Infobox drug
| type              = 
| image             = 
| alt               = 
| caption           =

<!-- gene therapy -->
| gt_target_gene      =
| gt_vector            = 
| gt_nucleic_acid_type = 
| gt_editing_method    = 
| gt_delivery_method   =

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| pronounce         = tis" a jen" lek loo' se<br>/ˌtɪsədʒen'leklusel/
| tradename         = Kymriah
| Drugs.com         = {{Drugs.com|ppa|tisagenlecleucel}}
| MedlinePlus       = a617053
| licence_CA        = <!-- Health Canada may use generic or brand name (generic name preferred) -->
| licence_EU        = yes
| DailyMedID        = Tisagenlecleucel
| pregnancy_AU      = C
| pregnancy_AU_comment = <ref>{{cite web | title=Updates to the Prescribing Medicines in Pregnancy database | website=Therapeutic Goods Administration (TGA) | date=12 May 2022 | url=https://www.tga.gov.au/resources/resource/guidance/updates-prescribing-medicines-pregnancy-database | access-date=13 May 2022}}</ref>
| pregnancy_category= 
| routes_of_administration = Intravenous
| class             = 
| ATCvet            = 
| ATC_prefix        = L01
| ATC_suffix        = XL04
| ATC_supplemental  = 

<!-- Legal status -->
| legal_AU          = S4
| legal_AU_comment  = 
| legal_BR          = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F -->
| legal_BR_comment  = 
| legal_CA = Rx-only
| legal_CA_comment = <ref>{{cite web | title=Summary Basis of Decision (SBD) for Kymriah | website=[[Organization:Health Canada|Health Canada]] | date=23 October 2014 | url=https://hpr-rps.hres.ca/reg-content/summary-basis-decision-detailTwo.php?linkID=SBD00416&lang=en | access-date=29 May 2022}}</ref>
| legal_DE          = <!-- Anlage I, II, III or Unscheduled -->
| legal_DE_comment  = 
| legal_NZ          = <!-- Class A, B, C -->
| legal_NZ_comment  = 
| legal_UK          = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM / Class A, B, C -->
| legal_UK_comment  = 
| legal_US          = Rx-only
| legal_US_comment  = <ref name="Kymriah FDA label" /><ref>{{cite web | title=Kymriah (tisagenlecleucel) | website=U.S. Food and Drug Administration | date=7 July 2022 | url=https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/kymriah-tisagenlecleucel | access-date=19 November 2022}}</ref>
| legal_EU          = Rx-only
| legal_EU_comment  = 
| legal_UN          = <!-- N I, II, III, IV / P I, II, III, IV -->
| legal_UN_comment  = 
| legal_status      = <!-- For countries not listed above -->

<!-- Pharmacokinetic data -->
| bioavailability   = 
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| onset             = 
| elimination_half-life = 16.8 days
| duration_of_action =
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<!-- Identifiers -->
| CAS_number_Ref    = 
| CAS_number        = 1823078-37-0
| CAS_supplemental  = 
| PubChem           = 
| IUPHAR_ligand     = 
| DrugBank_Ref      = 
| DrugBank          = DB13881
| ChemSpiderID_Ref  = 
| ChemSpiderID      = 
| UNII_Ref          = 
| UNII              = Q6C9WHR03O 
| KEGG_Ref          = 
| KEGG              = D11386
| ChEBI_Ref         = 
| ChEBI             = 
| ChEMBL_Ref        = 
| ChEMBL            = 
| NIAID_ChemDB      = 
| PDB_ligand        = 
| synonyms          = CTL019, CART-19
}}

'''Tisagenlecleucel''', sold under the brand name '''Kymriah''', is a CAR T cells medication for the treatment of B-cell [[Medicine:Acute lymphoblastic leukemia|acute lymphoblastic leukemia]] (ALL) which uses the body's own T cells to fight [[Medicine:Cancer|cancer]] ([[Biology:Adoptive cell transfer|adoptive cell transfer]]).<ref name="FDA PR" /><ref name="Kymriah FDA label">{{cite web | title=Kymriah- tisagenlecleucel injection, suspension | website=DailyMed | date=14 June 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=aad3ba54-dfd3-4cb3-9e2b-c5ef89559189 | access-date=1 April 2020}}</ref>

Serious side effects occur in most patients.<ref name="Kymriah EPAR" /> 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.<ref name="Kymriah EPAR" /> Serious infections occur in around three in ten diffuse large B-cell lymphoma (DLBCL) patients.<ref name="Kymriah EPAR" />

T cells from a person with cancer are removed, genetically engineered to make a specific chimeric cell surface receptor with components from both a [[Biology:T-cell receptor|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 [[Biology:CD19|CD19]] that is common on B cells. A chimeric T cell receptor ("CAR-T") is expressed on the surface of the T cell.{{medcn|date=August 2020}}

It was invented and initially developed at the [[Organization:University of Pennsylvania|University of Pennsylvania]]; [[Company:Novartis|Novartis]] completed development, obtained FDA approval, and markets the treatment.<ref name=Nov-BD>{{cite web|url=https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM566166.pdf|title=BLA 125646 Tisagenlecleucel - Novartis Briefing document to FDA ODAC|website=[[Organization:Food and Drug Administration|Food and Drug Administration]]|publisher=}}</ref> In August 2017, it became the first FDA-approved treatment that included a [[Biology:Gene therapy|gene therapy]] step in the United States.<ref name="FDA PR">{{cite press release |title=FDA approval brings first gene therapy to the United States|url=https://www.fda.gov/news-events/press-announcements/fda-approval-brings-first-gene-therapy-united-states |website=U.S. Food & Drug Administration (FDA) |access-date=31 August 2017}}</ref>

== 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.<ref name="Kymriah FDA label" /><ref name="Kymriah EPAR">{{cite web | title=Kymriah EPAR | website=[[Organization:European Medicines Agency|European Medicines Agency]] (EMA) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/kymriah | access-date=15 August 2020}} Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.</ref>

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.<ref>{{cite web | title=FDA approves tisagenlecleucel | website=U.S. Food and Drug Administration | date=31 May 2022 | url=https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tisagenlecleucel-relapsed-or-refractory-follicular-lymphoma | access-date=1 June 2022}} {{PD-notice}}</ref>

== Adverse effects ==
A frequent side effect seen is [[Medicine:Cytokine release syndrome|cytokine release syndrome]] (CRS).<ref name=Nov-BD/><ref name=nyt0712/>

Serious side effects occur in most patients.<ref name="Kymriah EPAR" /> 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.<ref name="Kymriah EPAR" /> Serious infections occur in around three in ten diffuse large B-cell lymphoma (DLBCL) patients.<ref name="Kymriah EPAR" />

== History ==
The treatment was developed by a group headed by Carl H. June at the University of Pennsylvania, and is licensed to Novartis.<ref>{{cite web | last=Grady | first=Denise | name-list-style = vanc | title=F.D.A. Panel Recommends Approval for Gene-Altering Leukemia Treatment | website=The New York Times | date=12 July 2017 | url=https://www.nytimes.com/2017/07/12/health/fda-novartis-leukemia-gene-medicine.html | access-date=1 April 2020}}</ref>

In April 2017, tisagenlecleucel received [[Medicine:Breakthrough therapy|breakthrough therapy]] designation by the U.S. [[Organization:Food and Drug Administration|Food and Drug Administration]] (FDA)  for the treatment of relapsed or refractory diffuse large B-cell lymphoma.<ref>{{cite web|url=http://www.fiercebiotech.com/biotech/novartis-gets-second-car-t-candidate-fda-breakthrough-tag|title=Novartis gets second CAR-T candidate FDA 'breakthrough' tag |publisher=Fierce Biotech|website=www.fiercebiotech.com|date=18 April 2017 }}</ref>

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.<ref name=nyt0712>{{cite news|url=https://www.nytimes.com/reuters/2017/07/12/business/12reuters-novartis-cancer.html|title=FDA Panel Backs Novartis' Pioneering New Cancer Gene Therapy|date=12 July 2017|newspaper=The New York Times|agency=Reuters| archive-url=https://web.archive.org/web/20170714180028/https://www.nytimes.com/reuters/2017/07/12/business/12reuters-novartis-cancer.html | archive-date=14 July 2017 | url-status=dead}}</ref><ref name=":0">{{cite journal | vauthors = Ledford H | title = Engineered cell therapy for cancer gets thumbs up from FDA advisers | journal = Nature | volume = 547 | issue = 7663 | pages = 270 | date = July 2017 | pmid = 28726836 | doi = 10.1038/nature.2017.22304 | bibcode = 2017Natur.547..270L | doi-access = free }}</ref><ref name=N206>{{cite news|url=https://www.npr.org/sections/health-shots/2017/07/12/536812206/living-drug-that-fights-cancer-by-harnessing-the-immune-system-clears-key-hurdle|title='Living Drug' That Fights Cancer By Harnessing The Immune System Clears Key Hurdle |last=Stein |first=Rob | name-list-style = vanc |publisher=NPR|date=2017-07-12|access-date=2017-07-13}}</ref>

In August 2017, the FDA granted approval for the use of tisagenlecleucel in people with acute lymphoblastic leukemia.<ref name="FDA Kymriah">{{cite web | title=Kymriah (tisagenlecleucel) | website=U.S. [[Organization:Food and Drug Administration|Food and Drug Administration]] (FDA) | date=1 April 2018 | url=http://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/kymriah-tisagenlecleucel | access-date=1 April 2020}}</ref><ref>{{cite press release |title=FDA approval brings first gene therapy to the United States|url=https://www.fda.gov/news-events/press-announcements/fda-approval-brings-first-gene-therapy-united-states |website=U.S. [[Organization:Food and Drug Administration|Food and Drug Administration]] (FDA) |access-date=6 September 2017}}</ref><ref>{{Cite magazine|last=Harris|first=Erin | name-list-style = vanc |date=27 November 2019|title=Challenges Facing The Cell And Gene Sector's Regulation Landscape|url=https://www.lifescienceleader.com/doc/challenges-facing-the-cell-and-gene-sector-s-regulation-landscape-0001|magazine=Life Science Leader|location=Pennsylvania, United States|publisher=VertMarkets|access-date=13 Dec 2019|quote=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.}}</ref>  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.<ref name="NYT0830">{{cite news |last1=Grady |first1=Denise | name-list-style = vanc |title=F.D.A. Approves First Gene-Altering Leukemia Treatment, Costing $475,000|url=https://www.nytimes.com/2017/08/30/health/gene-therapy-cancer.html| date=30 August 2017|access-date=6 September 2017|newspaper={{wipe|The New York Times}}}}</ref>

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.<ref name="FDA Kymriah" /><ref>{{cite web|url=https://www.ascopost.com/issues/may-25-2018/fda-expands-tisagenlecleucel-approval/|title=FDA Expands Tisagenlecleucel Approval - The ASCO Post|website=www.ascopost.com}}</ref>

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.<ref>{{cite news|url=https://www.theguardian.com/society/2018/sep/05/nhs-treat-young-cancer-patients-expensive-game-changer-drug-kymriah |title=NHS to treat young cancer patients with expensive 'game changer' drug |newspaper=The Guardian |date=5 September 2018  |author= Sarah Boseley  |access-date= 5 September 2018}}</ref> 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.<ref>{{Cite web|title=Overview {{!}} Tisagenlecleucel for treating relapsed or refractory diffuse large B-cell lymphoma after 2 or more systemic therapies {{!}} Guidance {{!}} NICE|url=https://www.nice.org.uk/guidance/ta567|access-date=2021-08-03|website=www.nice.org.uk}}</ref>

== 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' [[Biology:Genome|genome]].  The gene encodes a [[Biology:Chimeric antigen receptor|chimaeric antigen receptor]] (CAR) that targets leukaemia cells.<ref name=":0" />  It uses the 4-1BB co-stimulatory domain in its CAR to improve response.<ref>{{cite web|url=http://www.genengnews.com/gen-news-highlights/fda-panel-unanimously-recommends-approval-for-novartis-car-t-cell-therapy-ctl019/81254648|title=FDA Panel Unanimously Recommends Approval for Novartis' CAR T-Cell Therapy CTL019 |publisher=GEN Genetic Engineering & Biotechnology News |website=GEN|date=13 July 2017 }}</ref>

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.<ref name=":1">{{Cite news|url=https://www.reuters.com/article/us-novartis-swiss-factory/novartiss-90-million-swiss-factory-to-help-solve-cell-therapy-bottleneck-idUSKBN1Y214Y|title=Novartis's $90 million Swiss factory to help solve cell therapy bottleneck |last=Miller |first=John | name-list-style = vanc |date=28 November 2019|access-date=1 Dec 2019|work=Reuters}}</ref>  Novartis has been expanding a facility in France, and constructed a new facility in Stein, Switzerland, to relieve this bottleneck beginning in 2020.<ref name=":1" />  Novartis uses the company Cryoport Inc. for temperature-controlled transportation required for the manufacture and distribution of Kymriah.<ref>{{Cite web|url=https://www.biopharma-reporter.com/Article/2019/04/22/Cryoport-on-cell-therapy-market-robust-demand|title=Cryoport's CEO on cell therapies' market 'robust demand' |website=biopharma-reporter.com|access-date=2019-10-18}}</ref><ref>{{Cite web|url=https://www.outsourcing-pharma.com/Article/2018/11/13/Cryoport-talks-compliance-biopharma-expansion-and-Brexit|title=Cryoport talks compliance, biopharma expansion, and Brexit |website=outsourcing-pharma.com|access-date=2019-10-18}}</ref>

== References ==
{{reflist}}

== Further reading ==
* [https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM566166.pdf BLA 125646 Tisagenlecleucel - Novartis Briefing document to FDA ODAC]

== External links ==
* {{cite web | url = https://druginfo.nlm.nih.gov/drugportal/name/tisagenlecleucel-t | publisher = U.S. National Library of Medicine | work = Drug Information Portal | title = Tisagenlecleucel-T }}

{{Chemotherapeutic agents}}

[[Category:Breakthrough therapy]]
[[Category:Gene therapy]]
[[Category:Orphan drugs]]

{{Sourceattribution|Tisagenlecleucel|1}}