I-Las Amaseli e-CAR-T izimila eziqinile Baphinde baba sesikhungweni sempikiswano yesayensi kulandela uchungechunge lwezifundo zangaphambi kokuhlolwa eziholwa yiColumbia University ezikhomba ushintsho lwendlela yokuphila. Iqoqo lezifundo ezishicilelwe ku Isayensi chaza inguqulo ezwela kakhulu yalezi zindlela zokwelapha zamaseli ikwazi ukuthola nokubhubhisa izimila zezinso, i-pancreatic kanye ne-ovarian kumamodeli okuhlola, into okwakucatshangwa ukuthi ayinakutholakala kuze kube manje.
Ngesikhathi lapho ukwelashwa kwe-CAR-T sekuyingxenye yomkhuba wezokwelapha eminingana umdlavuza we-hematological ESpain nakwamanye amazwe aseYurophu, le miphumela ivula kabusha ingxoxo ku- indlela yokusebenzisa leli qhinga kumdlavuza wezitho eziqinileokuyimbangela enkulu yokutholakala komdlavuza. Ochwepheshe bayayamukela intuthuko, kodwa baxwayisa ngokuthi lezi yizifundo zangaphambi kokwelashwa futhi banxusa ukuqapha: imibuzo isalokhu ingaphendulwa mayelana ubuthi, umthethonqubo, izindleko, kanye nokukhethwa kweziguli.
Kungani ukwelashwa kwe-CAR-T kwehlulekile ezinhlamvini eziqinile
Ukwelashwa kwamaseli e-CAR-T kwaqala njengokwelashwa okusebenzayo. "umuthi ophilayo"Ama-T lymphocyte akhishwa emzimbeni wesiguli, aguqulwe elabhorethri ukuze aqaphele iphrotheni ethile yomdlavuza, bese ephinde afakwe ukuze kutholakale futhi kubhujiswe isimila. Leli cebo lishintshe inkambo yezinhlobo ezahlukene ze-leukemia nama-lymphoma, lafinyelela ukuphulukiswa okude ngisho nakubantu ababesebenzise ezinye izindlela zokwelapha.
Nokho, ukugxuma kusuka egazini kuya ezithweni eziqinile Kube yinkinga iminyaka engaphezu kweyishumi. Ngokungafani nomdlavuza we-hematological, lapho cishe wonke amangqamuzana omdlavuza eveza khona indawo efanayo (njenge-CD19), izimila eziqinile zibonisa i- ukungafani okukhuluAmanye amangqamuzana aveza i-antigen eningi eqondiwe, amanye amancane kakhulu, kanti amanye abonakala engabonisi nhlobo. Lolu hlobo "lwe-mosaic" lwenza kube lula ukuthi ingxenye yesimila ihlale ingaphandle kokufinyelela kokwelashwa futhi ekugcineni ibuye.
Ngaphezu kwalokho, imvelo yesimila ngokwayo isebenza njenge- "Inqaba" kunzima ukuyihlaselaIzithiyo zomzimba zivimbela ukungena kwamaseli e-T, izimpawu zokucindezela amasosha omzimba ziyawaqeda amandla, futhi umongo wokuvuvukala ukhawulela ukusinda kwawo. Kulesi simo, izivivinyo zokuqala ngamaseli e-CAR-T ahlose izimila eziqinile ziveze imiphumela emincane, futhi ezimweni eziningi, edumazayo.
Enye yamaprotheni ayephakanyiswe njengenhloso engaba khona kwaba I-CD70, okutholakale ukuthi kukhona kuma-carcinoma amaningi, ikakhulukazi ku- izinso, ama-ovary, amathumba obuchopho kanye ne-pancreasInkinga ukuthi izifundo zendabuko ziphakamise ukuthi iphesenti elilodwa kuphela lamaseli ngaphakathi kwesimila ngasinye liveza i-CD70, okunciphisa ukusebenza kwalo njengenhloso eyodwa yokwelapha. Ukuhlolwa kwemitholampilo ngamaseli e-anti-CD70 CAR-T ku-metastatic renal cell carcinoma, isibonelo, kuholele emazingeni aphansi okusabela okuqondile, phakathi kuka-6% no-21%.
I-CD70, kusukela ekuhlosweni "okungajwayelekile" kuya ekuhlosweni kwe-pan-tumoral
Ithimba eliholwa yisazi sezifo zomzimba UMichel SadelainUmuntu odumile ekuthuthukisweni kwezindlela zokwelapha ze-CAR-T, wanquma ukubuyekeza ngokugcwele indima ye-CD70. Umcwaningi unqume ukuthi angayihlola kanjani indlela i-CD70 esetshenziswa ngayo. USophie Hanina Kwaqala ngombono olula kodwa ophazamisayo: mhlawumbe amaseli amaningi abhekwa njenge-"CD70-negative" ayenalo iphrotheni, kodwa emazingeni aphansi kangangokuthi aphunyuka ezindleleni ezivamile zokuthola kanye nokuqashelwa kwamaseli avamile e-CAR-T.
Ngo i-microscopy ethuthukisiwe kanye nokuhlaziywa kwe-fluorescence kumamodeli asuselwa esigulini (ama-xenograft), iqembu lithole ukuthi isimo sasingafani njengoba kwakucatshangwa ngaphambili. Ukuvezwa kwe-CD70 kwakhiwe i-spectrum eqhubekayoKusukela emazingeni aphezulu kakhulu kuya enanini elingabonakali, kodwa elikhona. Ngisho namaseli abonakala engemihle abonise i-CD70 eningi kunalawo lapho i-gene yayisuswe khona ngokuphelele elabhorethri.
Ucwaningo luphinde luhlolisise indlela esebenza ngayo le ndlela yokukhuluma ephansi kakhulu. Ababhali baxhumanisa lesi simo ne- Ukuthulisa i-epigenetic okubangelwa yi-EZH2 kanye ne-histone marker H3K27me3, ehlotshaniswa nokucindezelwa kwezakhi zofuzo. Emaseli ane-CD70 encishisiwe kakhulu, ukunongwa kwalezi zimpawu zokucindezela kwabonwa kumgqugquzeli wezakhi zofuzo. Lapho i-EZH2 ivinjelwa, ukuvezwa kwe-CD70 kwanda, okuqinisa umqondo wokuthi isimila "sicisha" ingxenye yethagethi ukuze sigweme amasosha omzimba.
Ngokusekelwe kulolu lwazi, ucwaningo luphakamisa ukuchazwa kabusha kwe-"heterogeneity" yesimila sakudala: esikhundleni sezimila ezinamaseli amahle noma angemuhle ngokuphelele e-CD70, kuzoba khona ukuhlukaniswa okulawulwa yi-epigeneticallyLokhu kusenza sikwazi ukubuyisa umqondo we-CD70 njengoba umgomo womdlavuza we-pan uma nje ama-receptor akwazi ukubona ngisho nalawo mazinga asele etholakala.
I-HIT: isizukulwane esisha sabamukeli abanembile kakhulu
Isihluthulelo sokuthuthuka sikulolu hlobo olusha lomamukeli. Iqembu laseColumbia lithuthukise lokho okubizwa ngokuthi Amaseli e-HIT (i-HLA-Independent T cell receptor), ukuvela kwamaseli e-CAR-T ajwayelekile okulingisa kangcono indlela yemvelo amaseli e-T aqaphela ngayo ama-antigen.
Ngokungafani nama-CAR endabuko, adinga ukuminyana okuphezulu kwe-antigen eqondiwe Ukuze kusebenze, ama-receptor e-HIT aklanyelwe ukusabela kumanani "I-Ultra-low" ye-CD70Abalobi bachaza la maseli njengohlobo "lwenzwa enembile kakhulu" ekwazi ukubona "ukuhleba" lapho ngaphambili kwakuzwakala "ukumemeza" kuphela.
Ukuze bathuthukise ukusebenza kwabo, abacwaningi bahlanganise ama-HIT receptors kanye ama-molecule ashukumisayo njenge-CD80 kanye ne-4-1BBLLokhu kukhombisa okubili kuqinisa ukusebenza kwamaseli e-T futhi kuthuthukisa ukumelana kwawo nendawo enobutha yesimila, kunciphisa ingozi yokukhathala kusenesikhathi. USadelain ufingqa lo mqondo ngokugcizelela ukuthi amaseli e-CAR-T kanye nezinto eziphuma kuwo "izidakamizwa eziphilayo" ezingakhula ngaphakathi kwesiguli, ngokungafani nokwelashwa kwamakhemikhali okuvamile, umzimba okuqeda ngokushesha.
Umphumela uba ama-lymphocyte aguquliwe ahlangana ukusabela okukhulu ekutholeni ama-antigen “afihliwe” enekhono elingcono lokusinda nokuqhubeka nokusebenza ngaphakathi "kwesigodlo" sesimila. Ngamazwi ochwepheshe abaningana, lokhu kungaba isizukulwane esilandelayo samaseli e-CAR-T, okuhloswe ngqo ukunqoba izithiyo zezimila eziqinile.
Imiphumela yangaphambi kokwelashwa: ukususwa kwesimila kumamodeli egundane
Lapho ukubonakaliswa kwe-CD70 sekuchazwe futhi kwasungulwa amaseli e-HIT, ithimba lahlola isu kumamodeli asuselwa esigulini ane- umdlavuza wezinso, wesibeletho kanye ne-pancreaticLawa mamodeli e-xenograft aphinda ngokwethembeka ubunzima kanye nokungafani kwamathumba abantu, ngakho-ke abhekwa njengethuluzi elidingayo lapho kuhlolwa izindlela zokwelapha zokuhlola.
Kulezi zivivinyo, Izinhloso ze-CAR-T ezijwayelekile yi-CD70 Bakwazile ukuqeda ngempumelelo amaseli ane-antigen ephezulu, kodwa bashiya ama-subpopulation anamazinga aphansi kakhulu noma abonakala engekho. Le ngxenye esele yayanele ukuthi isimila siqhubeke sikhula noma siphinde sivele ngokuhamba kwesikhathi, okuhambisana nemiphumela emincane ebonwe ezivivinyweni zomtholampilo zangaphambilini.
Lapho zisetshenziswa esikhundleni salokho amaseli e-anti-CD70 HITUkuziphatha kwashintsha kakhulu. Emagundwini anezimila zezinso, i-pancreatic, kanye ne-ovarian, abacwaningi bachaza i- "ukuqothulwa okuphelele nokuhlala njalo" komdlavuzaAmaseli e-HIT aphinde athola futhi asusa amaseli anokubonakaliswa kwe-CD70 okuphansi kakhulu, ngaleyo ndlela avimbela ukuphuma kwesimila esivamile.
Idatha iphakamisa ukuthi i-CD70 ikhiqizwa ngokweqile kakhulu ku- izilonda ezisakazekilenjenge-metastases yamaphaphu evela kumdlavuza wezinso. Kweminye yale modeli, ukuphathwa okukodwa kwamaseli e-HIT kwakwanele ukufeza ukunyamalala kwesimila, into ababhali abayiqokomisa njengenye yemiphumela ethembisayo kakhulu yomsebenzi.
Izifundo zokuphepha zangaphambi kokwelashwa nazo zibalulekile. Ukuhlaziywa kwezinto ezingaphezu kuka- Izinhlobo ezingu-30 zezicubu ezinempilo Lokhu kubonisa ukuthi i-CD70 ayivezwa kakhulu ngaphandle komongo wesimila, ngaphandle kwamanye amaseli omzimba lapho esebenza. Akukho ukwanda kobuthi okubonwe kunalokho okuchazwe kumaseli e-CAR-T asevele evunyelwe. Noma kunjalo, ochwepheshe bezifo ezifana U-Ignacio Melero (I-University of Navarra Clinic) ikhombisa ukuthi ukususwa kwamangqamuzana athile omzimba kungaba nemiphumela yezokwelapha okuzodinga ukubhekwa ngokucophelela.
Ushintsho lomqondo ekwelashweni kwe-CAR-T kwamathumba aqinile
Ochwepheshe abaningana ababonisiwe bayavuma ukuthi intshisekelo yocwaningo ayigcini nje ekuhlosweni kwe-CD70 uqobo, kodwa ukuthi yethula umqondo ohlukile onethonya elibanzi ekwakhiweni kwezindlela zokwelapha amasosha omzimba ezimila eziqinile. Njengoba kufingqiwe ULuis Álvarez-VallinaLo msebenzi, oholwa yinhloko ye-immunotherapy e-CNIO-HMarBCN, uphakamisa ukuthi Inkinga akuyona kakhulu ukungabikho kwe-antigen eqondiwekodwa ukuntuleka kokuzwela kwama-receptor amanje.
Lokhu kuchazwa kabusha kuvula umnyango wokubuyekeza amanye ama-antigen alahliwe ngenxa ye- ukungafani okubonakalayo okweqileUma ngempela kukhona ukubonakaliswa okusalile okusabalele, isihluthulelo singase sibe sekwakheni ama-receptor azwela kakhulu, kuhlanganiswe namasu e-epigenetic avimbela isimila ukuthi "singanciphisi ivolumu" yezinhloso zaso.
Ababhali bafika ngisho nasekuphakamiseni ukuthi i-CD70 iyi- inhloso ye-pan-tumoral amandla, njengoba kutholakale ngokungafani ezimila eziqinile ezingaphezu kwamashumi amabili, okuhlanganisa i-glioblastoma kanye ne-pancreatic adenocarcinomaLe ndlela izosebenza futhi njengemodeli yendlela yokuhlonza ezinye "izinhloso ezifihliwe" lokho kuze kube manje akubonwanga.
U-Álvarez-Vallina uveza ukuthi lolu cwaningo “luhambisana kahle nobufakazi bangaphambilini” nokuthi iziphetho zalo zisekelwa idatha eqinile, yize ephikelela ngokuthi sikhuluma ngalo izifundo zangaphambi kokwelashwa ezinemikhawulo engokwemveloUma ibheka “ezweni langempela,” ilindele ukwanda kwekhathalogi yezinhloso ezingaba khona ezinhlamvini eziqinile, izinguquko ezindleleni zokukhetha iziguli, kanye ubunzima obukhulu bokulawula, kanye nengozi yobuthi uma ukuzwela kuthathwa ngokweqile.
Abanye ochwepheshe bakhomba ukuthi lesi sihloko sika Isayensi igcina a izinga elihle lendlela yokusebenza nokuthi isitatimende sabezindaba esihambisana naso sibonisa ngokunembile umlayezo oyinhloko, yize kungase kuthambekele ekwenzeni lula kakhulu uhlobo "lomdlavuza we-pan" lwe-CD70 kanye nelebula "lokuzwela kakhulu" elisetshenziswa kuma-receptor, empeleni eliqhathaniswa nomklamo we-CAR ojwayelekile oqiniswe nge-CD80/4-1BBL co-stimulation.
Imiphumela eSpain naseYurophu: ukufinyelela, izindleko kanye nomthethonqubo
Umthelela ongaba khona wezindlela zokwelapha ze-CAR-T ezisebenzayo zokulwa nezimila eziqinile ubaluleke kakhulu ezinhlelweni zokunakekelwa kwempilo ezifana ne- ISpanishi neYurophulapho lezi zindlela zokwelapha sezihlanganisiwe kakade, yize zinezimpawu ezikhawulelwe kumdlavuza we-hematological. ESpain, isibonelo, kukhona izindlela zokwelapha ezinhlanu ze-CAR-T zezentengiselwano ezixhaswe yi-National Health System ngokumelene nama-leukemia, ama-lymphoma kanye nama-myelomas, ngaphezu kwezindlela zokwelapha ezimbili zezemfundo ezakhiwe e-Hospital Clínic yaseBarcelona.
Lezi zindlela zokwelapha zine- izindleko eziphakeme kakhulu ngesiguli ngasinyeLezi zindleko zingafinyelela noma zidlule u-€300.000 wezinketho zezimboni, futhi zibe cishe u-€90.000 kweminye imisebenzi yezemfundo. Ukwandiswa okungenzeka kwemodeli kuya ezimila eziqinile, ezivame kakhulu, kungadinga ukucabanga kabusha ngale ndlela. amasu okuxhasa ngezimali, amandla okukhiqiza kanye nezindlela zokubeka phambili ngaphakathi kwezinhlelo zomphakathi.
Ngesikhathi esifanayo, ukuthuthukiswa kwezindlela zokwelapha ezisekelwe kuma-HIT receptor kuletha izinselele ezengeziwe zokulawula. ukwanda kobuzwe Lokhu kuhilela ukubonisa ngokuningiliziwe ukuthi akwandisi ingozi yobuthi obukhulu ngaphandle kwesimila. Izinhlangano zaseYurophu nezezwe cishe zizodinga lokhu. izinhlelo zokuqapha zesikhathi eside kanye nemiklamo yokuhlola ecophelelayo kakhulu ukunciphisa izingozi ezigabeni zokuqala.
Abacwaningi abahilelekile kulo mkhakha, njengososayensi wezifo zomzimba UManel Juan E-Hospital Clinic eBarcelona, bayazisa leli cebo elisha njenge- ubufakazi obuqinile bomqondo okungahlanganiswa nezinye izindlela (ama-antibodies, i-immunotherapy evamile, imithi ye-epigenetic) ukuthuthukisa izimpendulo ezifweni eziqinile. Kodwa bagcizelela ukuthi kusadingeka ulwazi olwengeziwe mayelana imiphumela emibi engaba khona ezicutshini ezinempilo kanye nokuthi la maseli azoziphatha kanjani ebunzimeni bezinto eziphilayo zomuntu.
Uma ukusebenza kwayo kuqinisekiswa, iYurophu kuzodingeka futhi ibhekane nezinkinga ezifana nokuthi ukukhiqizwa okuhlukaniswe ngokwezindawo uma kuqhathaniswa nokukhiqizwa okuhlanganisiwe Lokhu kwelashwa kwamaseli kufaka phakathi ukuqeqeshwa kwezikhungo zezibhedlela, ukuxhumanisa phakathi kwamazwe, kanye nezingxoxo zamanani nemboni, kanye nentuthuko engaba khona ye amapulatifomu ezemfundo zomphakathi okufanayo nalezo esezivele zisetshenziswa eCatalonia nakwezinye izifunda.
Ukusuka elabhorethri ukuya emtholampilo: isinyathelo esilandelayo
Njengamanje, ukusebenza ngamaseli e-anti-CD70 HIT kusesigabeni sokuqala. ngaphambi kokwelashwa okuqondileUSadelain ngokwakhe uyavuma ukuthi inselele enkulu esheshayo ukufeza uxhaso lwezimali luyadingeka ukuqala izivivinyo zemitholampilo kubantu nokuhlanganisa ingqalasizinda yokukhiqiza enkulu ehlangabezana nezidingo zekhwalithi.
Izifundo zokuqala zabantu zihlelwe, ngokusho kwethimba laseColumbia, ngo iziguli ezine-glioblastoma, i-acute myeloid leukemia, umdlavuza we-ovarian, kanye nomdlavuza we-pancreaticNakuba kulindeleke ukuthi kuzoqala ngokugxila enkombeni eyodwa noma ezimbili. Kunoma ikuphi, lokhu kungaba yizilingo ze- isigaba sokuqala (I/II), igxile kakhulu ekuhloleni ukuphepha kanye nomthamo, kunokubonisa ukusebenza kahle okuqinisekile.
Ngesikhathi esifanayo, abacwaningi basebenza ku- izindlela zokuthola ngcono ye-CD70 kumasampula eziguli, njengoba isinqumo sokuthi obani abangazuza ekwelashweni sizoncika ekuhloleni ngokunembile leso "sigcawu" sokuziveza. Ukufakwa kwamasu okuthwebula izithombe athuthukisiwe kanye nokuhlaziywa kwe-genomic kungaba yisihluthulelo ekukhetheni abantu abane- amathuba aphezulu okuphendula.
Ababhali kanye nochwepheshe abazimele bayavuma ukuthi, yize imiphumela "ikhuthaza kakhulu", kusenesikhathi kakhulu ukwenza izibikezelo mayelana nayo ukuhumusha kwangempela emtholampiloIzindlela eziningi zokwelapha umdlavuza ezibonise ukusebenza kahle okukhulu kumamodeli egundane ziye zahluleka ngenxa yobunzima bomzimba womuntu kanye nezidingo zomthetho.
Noma kunjalo, umsebenzi uvuselele intshisekelo yomphakathi wesayensi kanye nomkhakha wezokwelapha ku Amaseli e-CAR-T okwelapha izimila eziqinileUma izivivinyo zabantu ziqinisekisa ingxenye enkulu yale miphumela yangaphambi kokwelashwa, i-oncology ingathola ithuluzi elisha lokubhekana nomdlavuza onesimo esibi kakhulu, njengokuthi i-pancreatic adenocarcinoma, izimila ezithile zezinso, noma i-glioblastomaizindawo lapho izinketho zamanje zisencane kakhulu.
Uma kubhekwa konke, ucwaningo ngamaseli e-anti-CD70 HIT luqinisa umqondo wokuthi ikusasa le- Ama-immunotherapy eselula ezimila eziqinile Kuhilela ukwandisa ukuzwela kwama-receptor, ukuqonda kangcono i-biology yalezi zinhloso, nokuhlanganisa lawa masu nezinye izindlela zokwelapha, njalo nokuhlolwa okuqinile kwezokwelapha ukuze kuhlukaniswe intshiseko efanelekile nezithembiso ezingakaqinisekiswa.