Jirkaagu wuxuu leeyahay noocyo kala duwan oo ah unugyada dhiigga cad. Hal nooc, lymphocyte , waxay ka timaadaa laba nooc oo waaweyn: B-unug iyo T-unug. Halkan, marka la eego qaabka daaweynta kansarku, waxaan inta badan ka welwelsanahay nooca labaad, T-cell.
Sidaa darteed, waa maxay daaweynta T-daaweeye (chemic antigen) (daaweynta T-cell)? Mudo gaaban, waa daaweyn goosad ah oo lagu garto unugyada T-yada si ay ugu fiicnaadaan aqoonsiga iyo weerarka kansarka gudaha.
Waa mid ka mid ah noocyada kala duwan ee immunoteraabiya la baadho. Haddii aad xiiseyneyso bayotechnoolajiga ka dambeeya nooca daaweynta, sharraxaad faahfaahsan oo ku saabsan sida ay u shaqeeyso Tixraaca daaweynta CAR T-cell-ka ee muuqaalkan.
Halkan, fiiro gaar ah ayey ku leedahay "daaweynta noolasha" iyo daaweyn kale oo isku mid ah oo ka shaqeeya T-unugyada - "habka difaaca jidhka" ee jidhkaaga - la dagaallanka kansarka adiga oo ogaanaya kuna weeraraya unugyada tumingka. Qaar ka mid ah daaweynta kansarka ee isticmaala T-yada unugyada jirka ayaa mar horeba la ansixiyay, qaar kalena waxaa la filayaa inay si dhakhso ah u raacaan.
Dib u Dhigista Daaweynta Daawooyinka Ku Saleysan Dabiiciga ah
Naasnuujinta habdhiska difaaca jirka si aad isugu daydo inaad ula dagaallanto kansarka maahan mid gebi ahaanba cusub. Xaqiiqdii, waxaa jira tusaalooyin daaweyn noocaas ah (kuwaas oo diirada saaraya jawaabta T-cell) kuwaas oo horey u helay oggolaanshaha FDA: tusaale ahaan sipuleucel-T, ipilimumab, iyo blinatumomab.
Daaweynta | Nooca Kansarka | Nidaamka Nidaamka Nidaamka Nidaamka |
Sipuleucel-T (Bixiye) | Kiisaska qaarkood ee kansarka qanjidhka casriga ah |
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Ipilimumab (Yervoy) | Kiisaska qaarkood ee kansarka maqaarka ee melanoma |
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Blinatomomab (Blincyto) | Qanjiraha 'Lymphoblastic Lymphoblastic Leukemia (ALL') ee qaangaareyaal |
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Mid ka mid ah iyaga, sipuleucel-T, waxay u egtahay sida daaweynta T-cell-CAR-yada in ay isticmaasho unugyadaada unugyada kuwaas oo marka hore laga soo qaado dhiigga si gaar ah kadibna lagu baari karo shaybaarka; waxay u hawlgalaan oo ay sameeyaan inay noqdaan kuwa ka jawaab celiya unugyada burooyinka, ka dibna dib loogu celiyo dhiigga sida daaweynta.
Sipuleucel-T ayaa loo tixgeliyaa "tallaalka autologous," ama "immunotherapy cell otunotherapy", si kastaba ha ahaatee, iyo ma aha daaweynta T-cell-ka ah tan iyo unugyada difaaca jirka oo loo tababbaray in ay wax ka qabtaan, halkii ay ka dhalan lahaayeen hiddo-siinta si looga jawaabo unugyada tumo .
Kontoroolka koontaroolayaasha ee iminka ku jira sida ipilimumab (kor) waxay ka shaqeeyaan hababka difaaca jirka ee hababka kala duwan ee "isticmaalka bareegyada," ama "garaaca gaaska gaas" habka difaaca jidhka, si loo isku dayo inuu difaaco difaaca difaaca jirka ee lagaga hortago kansarka. Ipilimumab waa hal tusaale oo daawo ah oo sidan u shaqeeya. Tusaale kale oo ka mid ah koontaroolka difaaca difaaca jirka waa isudolizumab (Keytruda), kaas oo bartilmaameed u ah "isdul-marinta" for T-unugyada, loo yaqaan PD-1.
Daaweynta Gawaarida Gawaarida ee "CAR-T"
Si kastaba ha ahaatee, daaweynta unugyada CAR-T, si kastaba ha ahaatee, waxay si cad u yihiin cidda iska leh. Unugyada T-yada waxaa laga qaadaa jirkaaga, jimicsigaaga si habboon loo aqoonsado oo loo dilo unugyada burooyinka, kadibna dib loo soo dhigo sida daaweynta noolaha. Unugyada ayaa la abuuri karaa oo kori karaa ugu yaraan 21 maalmood kadibna waxay dib ugu noqdaan dhiigga.
Tijaabada daaweynta T-cell ma aha nooca daaweynta ee la isticmaali lahaa ka hor inta aanad isku dayin daweyno kale-ugu yaraan, hadda ma ahan. Daawooyinkan cusubi guud ahaan waxay ka soo baxaan xaqiiqda nasiib-darrada ah, in bukaanka qaba xanuunka dambe, daaweynta kansarka dhaqameed, oo ay ka mid yihiin qalliinka, daaweynta kiimikada, daaweynta kiimikada iyo daaweynta shucaaca, marar badan ayaa bixiya waxtarka xadidan.
Sidaasi darteed, illaa iyo hadda, daaweynta unugyada CAR-T waxay helayaan oo kaliya bukaannada ka diiwaangashan tijaabada bukaan-socodka, maadaama daaweynaha loo tixgelinayo baaritaan Maraykanka, laakiin taasi waxay dhici karta in dhawaan la beddelo. Daaweynta unugyada CAR-T waxay noqon kartaa FDA ansaxin waxaana la heli karaa tijaabooyin ka baxsan tijaabada caafimaadka sida ugu dhakhsaha badan 2017-2018.
Liiska kooban ee qaar ka mid ah musharrixiinta waaweyn ee lagu kobciyo kiliinikada ayaa soo socota.
CTL019 (tisagenlecleucel) by Novartis
CTL019 waa daaweeynta T-daaweynta T-cell oo ah CD19-ga gaar ah ee antigen-ka (CAR).
Aynu bilowno anagoo soo saarnay jumlada hore: CD19 waa unugyo unugyada difaaca ah ee loo yaqaan "B-cells", oo unugyadaasi waxay noqon karaan ilaha noocyada qaar ee leukemia iyo lymfoma .
Hal qiyaas oo ah CTL019 ayaa keentay daaweyn dheer iyo suurtogal ahaan daaweyn (ma aynaan weli garaneynin) buundada bukaanka ee daraasadaha ka soo baxayay kala doorashooyinka daaweynta.
Waa kuwan hoos-u-dhaca cudurada ee CTL019 loo tixgelinayo hadda:
- CTL019 waxay heshay FDA Breakthrough Therapy si loogu daaweeyo bukaanno qaangaar ah oo leh dib-u-soo-ceshad / dib-u-dhac balaadhan oo ballaaran B-unug B-cell (DLBCL). (Lymphomas guud ahaan waxaa loo kala saaraa laba kooxood oo aasaasi ah: Hodgkin iyo non-Hodgkin, nooca ugu badan ee lymphoma aan ahayn Hodgkin Lymphoma waa DLBCL).
- CTL019 sidoo kale waxay u taagan tahay oggolaansho daaweynta cudurrada carruurta ee dib u soo noqda ama dib-u-ceshadeysan ama bukaanno qaangaar ah oo leh bukaan-socodka 'B-cell lymphoblastic leukemia (ALL').
CTL019 waxay heshay codad dhan 10-0 oo codsi ah oo ka soo baxay Guddiga La-talinta Mukhaadarada Isticmaalka Daroogada ee FDA, taas oo macnaheedu yahay in waxyaaluhu u ekaanayaan balanqaadkii ugu dambeyntii oggolaanshaha. Novartis waxaa loogu talagalay in CTL019 loo oggolaado daaweynta B-unugyada dib-u-noqoshada ama dib-u-ceshadeysan ee bukaanka carruurta iyo dhalinyarada qaangaarka ah. Leukemia waa lambarka kowaad ee kansarka caruurta, iyo DHAMMAAN waa qaabka ugu caansan, oo mas'uul ka ah qiyaastii 25 boqolkiiba kansarka carruurnimada. Waxaa jira noocyo kala duwan oo DHAMAAN ah, oo ay ku jiraan B-cell ALL iyo T-cell ALL, iyo subtypes-ka gudahooda ayaa laga yaabaa inay qaadaan garashadooda.
CTL019 ayaa hadda ku jirta dib-u-fiirin mudnaansiin ah oo ansixinta waqtigeeda ayaa ka dhigeysa daaweynta CAR-T ee ugu horeysa ee la heli karo. Daaweynta CAR-T-cell waxaa lagu heli karaa kaliya tirada yar ee carruurta iyo dhalinyarada qaan-caleenka ah ee aan ka soo jawaabin daryeelka caadiga ah. Bukaannadani waxay caadi ahaan qabaan qiyaaso liidata, laakiin tijaabada ugu muhiimsan ee tijaabinta daaweynta ku dhowaad wadamo daraasiin ah, 83 boqolkiiba bukaannada ayaa dib u soo noqdey. Sannad ka dib, saddex-meelood laba meel ayaa sidaas ah.
Sababtoo ah daaweyntu ma baabi'i doonto oo kaliya maaha bakteeriyada B-buclaha laakiin sidoo kale kuwa caafimaadka qaba, noocyada kala duwan ee jeermisyada, bukaanku waxay u baahan yihiin daaweyn si looga ilaaliyo caabuqa. Waxay helayaan infusions of globulins immun dhawr bilood kasta sida qiyaasta ilaalinta.
Mid ka mid ah waxyeelada ugu caansan waxaa lagu magacaabaa 'cytokine' release syndrome, taas oo keenta calaamado qandho sare leh iyo calaamado hargab oo mararka qaar noqon kara halis ah in bukaanku uu ku dhammaado daryeelka degdegga ah. Welwelka kale ee weyni waa neurotoxis, taas oo keeni karta jahwareer ku meel gaar ah ama barar maskaxeed oo dhici karta.
Si loo hubiyo in la hubiyo amniga bukaanka, Novartis ma qorshaynayso wax soo saarka alaabta caadiga ah, iyada oo daroogada la riixo sida ugu ballaaran iyo si taxadar leh. Shirkaddu waxay u beddeli doontaa 30 ilaa 35 xarumo caafimaad si ay u maamulaan daaweynta. Qaar badan oo ka mid ah ayaa ka qayb qaatay tijaabada bukaan-eegtada, dhammaantoodna waxay heleen tababarka ballaaran.
Axicabtagene Ciloleucel by Kite Pharma
Iyadoo ku saleysan Santa Monica, Kaliforniya, Kite Pharma waa shirkad diiradda saareysa daaweeynta CAR iyo T-cell oo lagu naqshadeeyey daaweynta unugyada. Kite wuxuu horumarinayaa daaweynta T-cell-CAR-loo yaqaan 'axicabtagene ciloleucel', taas oo hadda ku jirta dib-u-eegista mudnaanta ee Maraykanka si loogu daaweeyo bukaanada qaba lafdhabarka aan sal-lahayn ee Hodgkin Lymphoma (NHL). Bukaannada qaba niyadjab salaysan NHL waxay la kulmayaan qiyaas ahaan 50% boqolkiiba lix bilood. Tani waxay muujineysaa baahida caafimaad ee deg-deg ah ee loogu talagalay bukaannada.
Sida CTL019, axalabtagene ciloleucel ayaa sidoo kale bartilmaameedsanaya CD19 antigen, oo ah borotiin lagu soo bandhigay dusha unugyada B-cell lymphomas iyo leukemias. Unugyada T ee bukaanka ayaa loo naqshadeeyey inay muujiyaan soo celiyaha antigen-ka (CAR) si loo beegsado CD19 antigen.
Qalabka horumarinta daroogada iyo oggolaanshaha, axicabtagene ciloleucel wuxuu leeyahay cilaaqaad la mid ah tan CTL019, taas oo diiradda saareysa kansarka leh asal ahaan B-unug, laakiin unug B-ga TUSAAN uma muuqato inuu qeyb ka yahay horumarinta kiliinikada xiligaan.
Halkan waxaa ah xakamaynta cudurada kuwaas oo loo yaqaan 'cicoleucel axicus' ee hadda loo yaqaan '
- Axicabtagene ciloleucel ayaa la siiyay xaalad loo yaqaan 'Breakthrough Therapy status status' oo loogu talagalay xannibaadda ballaaran ee B-unug B-cell (DLBCL), Lymphoma oo loo beddelay (TFL), iyo asaasiga caadiga ah ee B-unugyada B-cell (PMBCL) by FDA iyo Daawooyinka Aasaasiga ah (PRIME) DLBCL ee Midowga Yurub.
Aqbalaaddu waa Daaweyn Dheeraad ah oo FDA ay taageerto xogta laga helay tijaabada ZUMA-1 Wajiga 2 oo la kulmay heerka ugu sarreeya ee jawaab celinta ujeedada (ORR) ka dib markii hal kaneeco faleebo ah loo yaqaan 'axicabtagene ciloleucel' oo leh boqolkiiba 82 (p <0.0001). Marka la eego dhexdhexaadinta 8.7 bilood, 44 boqolkiiba bukaannada ayaa qaatay jawaab celin joogto ah, oo ay ku jiraan 39 boqolkiiba bukaanada jawaab celin dhammaystiran (CR).
Dhacdooyinka is-galka ah ee caadiga ah waxaa ka mid ah unugyada caafimaadka qaba ee la dagaallanka caabuqa waxayna caawiyaan dhiigga xinjirowga. Sida CTL019, mid ka mid ah dhibaatooyinka ugu caansan waxaa loo yaqaan 'cytokine release' syndrome, taas oo keenta calaamado qandho sare leh iyo calaamado hargab oo mararka qaar noqon kara halis ah in bukaanku uu ku dhammaado daryeelka degdegga ah. Encephalopathy wuxuu dhalin karaa jahwareer ku meel gaar ah ama bararka maskaxda ee dilaaca. Waxaa jiray saddex dhimasho intii lagu gudajiray tijaabada diiwaan-gelinta oo aan sabab u ahayn horumarka cudurka, kuwaas oo laba dhacdooyin, loo maleynayay inay la xiriiraan axilaabucel. Mar labaad, horumarinta kiliinikada ee daroogooyinka ayaa la filayaa inay sii wado taxadar.
GoCAR-T, Musharaxa loogu talagalay Tumors Solid by Pharmaceuticals
Houston, Texas-based Pharmaceuticals, Inc., ayaa leh musharaxyo daroogo oo ay ka mid yihiin BPX-601 (Guud GoCAR-T, oo ah burooyin culus, oo loogu talagalay wacyigelinta iMC ee macaamiisha si loo hagaajiyo waxtarka, heerka I), iyo BPX-701 -waxaa loo aqoonsan yahay TCR, oo ah burooyin culus , oo loogu talagalay beddelka Badalka CaspaCIDe, wajiga I).
Haddaba, maxay tahay macnaheedu? Dhab ahaantii, kooxdani waxay ka shaqaynaysaa sidii loo farsameyn lahaa tiknoolajiyada T-cell-ka si ay u awooddo in ay kantaroolatada si xakameysan uga jawaabto jawaabta T-cell. Unugyada GoCAR-T waxaa loogu talagalay oo kaliya in si buuxda loo hirgeliyo marka laga eego unugyada kansarka iyo wakiil loo yaqaanno 'rimiducid'. Sidaas daraadeed, dhakhtarka ayaa awoodi doona inuu xakameynayo heerka uu ku shaqeynayo unugyada CAR-T-da iyada oo la habaynayo jadwalka maamulka rimiducid, laakiin dilka unugyada ayaa wali ku dhacaya habdhiska caanaha.
Musharixiinta kale
Juno waa shirkad hadda diiradda saareysa JCAR017, oo ah unug ka tirsan CAR-T ee bartilmaameedsanaya CD19. Juno waxa uu raadin doonaa inuu helo JCAR017 suuqyada sida ugu dhaqsaha badan 2018 ee NHL. Shirkadda waxay la shaqeyneysaa Celgene dadaalkaas.
ZIOPHARM Oncology wuxuu leeyahay badeeco gaar ah oo CD19 waxana uu ka shaqeynayaa daaweynta TD-ga ee CD33-ga ee loogu talagalay daaweynta 'myeloid leukemia' (AML) ee soo noqnoqoshada / celceliska. Nantuuwest waa shirkad difaac ah oo diiradda saareysa isticmaalka unugyada dabiiciga ah (NK) si loo daaweeyo kansarka, cudurrada faafa, iyo cudurrada caabuqa.
NK-ga NK-ga ee shirkadda ayaa loogu talagalay in lagu soo bandhigo dhimashada unugyada kansarka ama unugyada infekshinka leh saddex nooc oo ah noocyo kala duwan oo ah dil iyo tallaabo toos ah oo la isticmaalayo unugyada firfircoon ee NK (aNK); dilka antibody-dhexdhexaad ah oo loo adeegsado isticmaalka nadaafadda, iyo bartilmaameed dil ah oo loo adeegsado isticmaalka nadaafadda.
Ereyga
Qaar ka mid ah natiijooyinka hore ee daaweynta Qaad-ka-daaweynta CAR-T ayaa aad u xiiso leh, oo bixiya daaweyn cusub oo loogu talagalay kooxo bukaan ah oo aan waligood helin doorashooyinkan ka hor. Si kastaba ha ahaatee, waxaa jira fashilaadaa, si kastaba ha ahaatee, iyo waxoogaa dhibaato ah oo dhibaatooyin ah si ay u sameeyaan daaweyntan sida ugu waxtarka leh ee suurtogalka ah ee qadarka ugu yar ee sunta.
Maadaama cilmi-baadhayaashu ay wax badan ka baranayaan jawaab-celinta difaaca ee ka soo baxa daweyntaan, iyo saameynta ku-oolnimada ee la beegsanayo, sawir cad oo khataraha iyo faa'iidooyinka waa in ay soo baxaan.
> Ilo:
> Wang M, Yin B, Wang HY, Wang RF. Horumarka hadda jira ee ka hortagga difaaca jirka ee T-cell-ku salaysan. Immunotherapy . 2014; 6 (12): 1265-1278.
> Bhoj VG, Arhontoulis D, Wertheim G, et al. Ku adkaysiga unugyada birta ee dheeraadka ah iyo difaacida nafsadda ee shakhsiyaadka ka jawaabaya daaweynta TT-cell-ka ee CD19. Dhiiga. 2016; 128 (3): 360-370.
> Kite wuxuu soo qaataa Dib u Eegista Mudnaanta Maamulka Cuntada iyo Dawooyinka ee Axicabtagene Ciloleucel. http://ir.kitepharma.com/releasedetail.cfm?releaseid1028075 Gaaray July 2017.
> Morris EC, Stauss HJ. Qalabka daaweynta hidda-wata ee T-cell-ka ee daaweynta kansarka hematologi. Dhiiga . 2016; 127 (26): 3305-3311.
> Park JH, Geyer MB, Brentjens RJ. Daaweynta CD-tiknoolajiyadda T-cell ee loogu talagalay daaweynta jeermiska cudurada wadnaha: tarjuma natiijooyinka daaweynta ilaa taariikhda. Dhiiga . 2016; 127 (26): 3312-3320.