ari Masero eCAR-T e mamota akasimba Vari zvakare pakati pemakakatanwa esainzi mushure mezvidzidzo zvakatevedzana zve preclinical zvakatungamirwa neColumbia University zvinoratidza shanduko yeparadigm. Seti yezvidzidzo zvakaburitswa mu sainzi tsanangura shanduro yekurapa kwemasero iyi inonyanya kunzwa inokwanisa kuwana nekuparadza bundu reitsvo, pancreatic uye ovarian mumamodeli ekuyedza, chimwe chinhu chainzi hachigoneke kusvika pari zvino.
Panguva iyo mishonga yeCAR-T yatove chikamu chekurapa kwevakawanda kenza yeropa MuSpain nedzimwe nyika dzeEurope, zvabuda izvi zvinovhurazve hurukuro pamusoro pe maitiro ekushandisa nzira iyi kune kenza yenhengo dzakasimbaizvo zvinotsanangura huwandu hwakawanda hwezvirwere zvegomarara. Nyanzvi dzinogamuchira kufambira mberi kuri kuitika, asi dzinonyevera kuti izvi zvidzidzo zvepamberi pekiriniki uye dzinokurudzira kungwarira: mibvunzo ichiri kusapindurwa nezve chepfu, mitemo, mari, uye kusarudzwa kwevarwere.
Sei kurapwa kweCAR-T kwakakundikana mukurapa bundu rakasimba
Kurapa kwemasero eCAR-T kwakatanga senzira yekurapa "Mushonga mupenyu"MaT lymphocytes anotorwa mumuviri wemurwere, ogadziriswa murabhoritari kuti aone puroteni yekenza, obva adzorerwa kuti awane uye aparadze bundu. Nzira iyi yakachinja nzira yezvirwere zvakasiyana-siyana zveleukemia nelymphomas, zvichiita kuti kuderedzwa kwenguva refu kwemasero eropa kunyangwe kune vanhu vakamboedza dzimwe nzira dzekurapa.
Zvisinei, kusvetuka kubva muropa kuenda kunhengo dzakasimba Dambudziko iri rave riripo kwemakore anopfuura gumi. Kusiyana nekenza yeropa, uko masero ese egomarara anoratidza chinangwa chimwe chete (seCD19), magomarara akaomarara anoratidza chiratidzo chegomarara. kusiyana kukuruMamwe masero anoburitsa antigen yakawanda, mamwe mashoma, uye mamwe anoita seasingabudisi zvachose. Rudzi urwu rwe "mosaic" runoita kuti zvive nyore kuti chikamu chebundu chirambe chiri kure nekurapwa uye pakupedzisira chidzoke.
Uyezve, bundu iri pacharo rinoshanda senzira yekudzivirira "Nhare" yakaoma kupindaZvipingamupinyi zvemuviri zvinotadzisa kupinda kwemasero eT, zviratidzo zvinodzvinyirira masoja emuviri zvinoaderedza, uye mamiriro ekuzvimba anoderedza kurarama kwawo. Muchiitiko ichi, miedzo yekutanga nemasero eCAR-T achitarisa bundu rakasimba yakawana mhedzisiro iri nyore uye, kazhinji, inosuwisa.
Imwe yemapuroteni akanga ataurwa kuti angangoshandiswa yaive CD70, avo vakaonekwa mukenza dzakawanda, kunyanya mu itsvo, mazamu, bundu reuropi uye pancreasDambudziko nderekuti zvidzidzo zvechinyakare zvakaratidza kuti chikamu chimwe chete chemasero ari mubundu rega rega chaive neCD70, izvo zvakaderedza kushanda kwaro senzira imwe chete yekurapa. Miedzo yekiriniki nemasero ekurwisa CD70 CAR-T mukenza yemasero erenal yakapararira, semuenzaniso, yakaguma nekusashanda zvakanaka, pakati pe6% ne21%.
CD70, kubva pachinangwa "chisina kurongeka" kuenda pachinangwa chebundu repamuviri
Chikwata chinotungamirwa nenyanzvi yezvirwere zvemuviri Michel SadelainMunhu wekare mukuvandudzwa kwemishonga yeCAR-T, akasarudza kuongorora zvizere basa reCD70. Muongorori uyu akaongororawo zvakadzama basa reCD70. Sophie Hanina Zvakatanga nepfungwa iri nyore asi inovhiringidza: zvichida masero mazhinji anoonekwa se "CD70-negative" aive neprotein, asi padanho rakaderera zvekuti akapukunyuka nzira dzekuziva dzakajairika uye kuzivikanwa kwemasero eCAR-T akajairika.
Kubudikidza maikorosikopu yepamusoro uye kuongororwa kwe fluorescence mumamodeli anobva kuvarwere (xenografts), boka iri rakaona kuti mamiriro acho ezvinhu akanga asina kufanana nezvaifungidzirwa kare. Kuonekwa kweCD70 kwakaumbwa chiratidzo chinoenderera mberiKubva pamazinga akakwirira zvikuru kusvika pahuwandu husingaonekwe, asi huripo. Kunyangwe masero airatidzika kunge asina simba akaratidza CD70 yakawanda kupfuura ayo jini rakanga rabviswa zvachose murabhoritari.
Chidzidzo ichi chinotarisawo mashandiro ari shure kwekutaura uku kwakaderera. Vanyori vanobatanidza chiitiko ichi ne Kunyaradzwa kwe epigenetic kwakaitwa neEZH2 uye chiratidzo chehistone H3K27me3, chakabatana nekudzvinyirirwa kwemajini. Mumasero ane CD70 yakaderera zvakanyanya, kuwedzerwa kwezviratidzo izvi zvinodzvinyirira kwakaonekwa mumutsigiri wemajini. EZH2 payakadziviswa, kutaura kweCD70 kwakawedzera, zvichisimbisa pfungwa yekuti bundu "rinodzima" chinangwa kuti risapinde mudziviriro yemuviri.
Zvichibva padata iri, tsvakiridzo iyi inokurudzira kududzirwa patsva kwe "heterogeneity" yegomarara rekare: pachinzvimbo chegomarara rine masero akanaka kana asina kunaka eCD70, pangave gradation yakadzorwa ne epigeneticallyIzvi zvinotibvumira kudzoreredza pfungwa yeCD70 se chinangwa chekenza yepan chero bedzi paine ma receptors anokwanisa kuona kunyange mazinga iwayo akasara aripo.
HIT: chizvarwa chitsva chevanogamuchira zvinhu zvakanyatsonaka
Chinokosha pakufambira mberi chiri mumhando itsva iyi yemugamuchiri. Boka reColumbia rakagadzira chinonzi Masero eHIT (HLA-Independent T cell receptor), kushanduka-shanduka kwemasero eCAR-T akajairika anotevedzera zviri nani nzira yechisikigo iyo masero eT anoziva maantigen.
Kusiyana nemaCAR echinyakare, ayo anoda huwandu hwakanyanya hweantigen inotarirwa Kuti zvishande, maHIT receptors akagadzirwa kuti aite zvinoenderana nehuwandu hwezvinhu. CD70's "yakaderera zvakanyanya"Vanyori vanotsanangura masero aya semhando ye "high-precision sensor" inokwanisa kuona "kuchema" uko kare kwaingonzwika "kuchema".
Kuti vawedzere kushanda kwavo, vaongorori vakasanganisa maHIT receptors ne mamorekuru anosimudzira mafambiro emhepo akadai seCD80 ne4-1BBLKupa zviratidzo zviviri uku kunosimbisa kushanda kwemasero eT uye kunovandudza kuramba kwawo kurwisa mamiriro ekunze ane bundu, zvichideredza njodzi yekuneta nekukurumidza. Sadelain anopfupikisa pfungwa iyi nekusimbisa kuti masero eCAR-T nezvinobuda maari "mishonga mhenyu" inogona kuwedzera mukati memurwere, kusiyana nekurapa kwemakemikari kwechinyakare, uko muviri unobvisa nekukurumidza.
Mhedzisiro yacho i lymphocytes dzakagadziriswa dzinosanganisa hypersensitivity yekuwana maantigen "akavanzika" vane simba riri nani rekurarama uye kuramba vachishanda mukati me "castle" yebundu. Mumashoko enyanzvi dzinoverengeka, iyi ndiyo ingave chizvarwa chinotevera chemasero eCAR-T, yakanangana nekukunda zvipingamupinyi zvemabundu akaoma.
Mhedzisiro yekiriniki isati yatanga: kubviswa kwebundu mumamodeli emakonzo
Pakangoonekwa kuratidzwa kweCD70 uye masero eHIT agadzirwa, timu yakaedza nzira iyi mumamodheru anobva kuvarwere ane kenza yeitsvo, ovarian uye pancreaticMamodheru aya e xenograft anotevedzera zvakajeka kuomarara uye kusiyana kwemagomarara evanhu, uye nekudaro anoonekwa sechishandiso chinoda simba pakuongorora nzira dzekurapa dzekuedza.
Mumiedzo iyi, Chinangwa cheCAR-T chemazuva ese cheCD70 Vakakwanisa kubvisa masero ane antigen yakawanda zvinobudirira, asi vakasiya mapoka mashoma ane huwandu hwakaderera kana kuti husina kuonekwa zvachose. Chikamu ichi chakasara chakakwana kuti bundu rirambe richikura kana kuonekazve nekufamba kwenguva, zvichienderana nemigumisiro mishoma yakaonekwa mumiedzo yekiriniki yapfuura.
Pazvakashandiswa panzvimbo pezvo masero ekurwisa CD70 HITMaitiro acho akachinja zvakanyanya. Mumakonzo ane bundu reitsvo, pancreatic, uye ovarian, vaongorori vanotsanangura a "Kubviswa zvachose uye kusingaperi" kwegomararaMasero eHIT akaonawo uye akabvisa masero ane CD70 yakaderera zvakanyanya, zvichiita kuti adzivise kubuda kwegomarara.
Ruzivo rwunoratidza kuti CD70 inonyanya kutengeswa zvakanyanya mu zvipembenene zvinopararirazvakaita sekenza yeitsvo inopararira mumapapu. Mune mamwe emamodheru aya, kushandiswa kamwe chete kwemasero eHIT kwaive kwakakwana kuti bundu ripere, chimwe chinhu chinosimbiswa nevanyori sechimwe chezvakawanikwa zvinovimbisa zvikuru mubasa iri.
Zvidzidzo zvekuchengetedza zvisati zvaitwa zvekiriniki zvine basa rakaenzana. Kuongororwa kwezvinopfuura Mhando makumi matatu dzenyama ine hutano Izvi zvinoratidza kuti CD70 hairatidzike zvakanyanya kunze kwebundu, kunze kwemamwe masero emuviri anodzivirira zvirwere paanoshanda. Hapana kuwedzera kwechepfu kwakaonekwa kupfuura zvakatsanangurwa kune masero eCAR-T akatotenderwa. Kunyangwe zvakadaro, nyanzvi dzekudzivirira muviri dzakadai se Ignacio Melero (Yunivhesiti yeNavarra Clinic) inoratidza kuti kubviswa kwemamwe masero ekudzivirira muviri kunogona kuva nemigumisiro yekiriniki inofanira kutariswa nokungwarira.
Kuchinja kwepfungwa mukurapa kweCAR-T kwegomarara rakasimba
Nyanzvi dzakawanda dzakabvunzwa dzinobvumirana kuti kufarira kwechidzidzo ichi hakungogumiri pachinangwa cheCD70 chete, asi kuti chinopa pfungwa huru ine simba guru mukugadzirwa kwemishonga yekudzivirira zvirwere yemamota akaomarara. Sezvakapfupikiswa Luis Álvarez-VallinaBasa iri, rinotungamirwa nemukuru we immunotherapy pa CNIO-HMarBCN, rinoratidza kuti Dambudziko harisi kunyanya kusavapo kweantigen inotarirwaasi kusanzwa kwemareceptors aripo.
Kududzirwa patsva uku kunovhura mukana wekuongorora mamwe maantigen akange araswa nekuda kwe kusiyana kwakanyanya kuri pachenaKana paine kupararira kwemasero emasero, chinhu chikuru chinogona kunge chiri mukugadzira ma receptors anonzwa zvakanyanya, pamwe chete nemaitiro e epigenetic anodzivirira bundu kuti risaderedze huwandu hwemasero ari kutsvagwa.
Vanyori vanosvika pakutaura kuti CD70 ibhuku re chinangwa chebundu repanyika kugona, tichifunga kuti yakaonekwa zvakasiyana mumabundu anopfuura makumi maviri akasimba, kusanganisira glioblastoma uye pancreatic adenocarcinomaMaitiro aya aizoshandawo semuenzaniso wenzira dzekuziva zvimwe "zvinangwa zvakavanzika" izvo kusvika pari zvino hazvina kuonekwa.
Álvarez-Vallina anotaura kuti chidzidzo ichi "chinoenderana zvakanaka neuchapupu hwekare" uye kuti mhedziso yacho inotsigirwa nedata rakasimba, kunyange hazvo achisimbirira kuti tiri kutaura nezvazvo zvidzidzo zvepamberi pekiriniki zvine zvipingamupinyi zvepakutangaIchitarisa ku "nyika chaiyo," inotarisira kuwedzera kwekarogu yezvinangwa zvinogona kuwanikwa mumabundu akaoma, shanduko musarudzo dzevarwere, uye kuoma kukuru kwemitemo, pamwe chete nenjodzi yekukuvadzwa kana munhu akanyanya kubatwa nechirwere ichi.
Dzimwe nyanzvi dzinoti chinyorwa chakanyorwa na sainzi anochengeta a nzira dzakanaka dzekuita uye kuti kuburitswa kwenhau kwakabatana kunoratidza zviri pachena meseji huru, kunyangwe zvingaita kuti CD70 ive nyore kunzwisisa "kenza yepan-pan" uye "label" ye "ultrasensitive" inoshandiswa kumareceptors, iyo inofananidzwa chaizvo nekugadzirwa kweCAR kwakajairika kwakasimbiswa neCD80/4-1BBL co-stimulation.
Zvazvinoreva kuSpain neEurope: mukana wekuwana, mutengo uye mutemo
Kukanganisa kunogona kuitika kwemishonga yeCAR-T inoshanda pakurwisa bundu rakasimba kunonyanya kukosha muzvirongwa zvehutano zvakaita se Spanish neEuropeanuko mishonga iyi yakatobatanidzwa, kunyangwe paine zviratidzo zvegomarara reropa chete. Semuenzaniso, muSpain, kune mishonga mishanu yekutengeserana yeCAR-T inotsigirwa nemari neNational Health System kurwisa leukemias, lymphomas uye myelomas, pamwe chete nemishonga miviri yedzidzo yakagadzirwa paHospital Clinic yeBarcelona.
Kurapa uku kune mutengo wakakwira zvikuru pamurwereMutengo uyu unogona kusvika kana kudarika €300.000 yesarudzo dzemaindasitiri, uye ungasvika €90.000 kune mamwe mapurojekiti edzidzo. Kuwedzerwa kwemuenzaniso uyu kusvika kumabundu akaoma, ayo akajairika, kunoda kufunga patsva nezvenzira iyi. nzira dzekubhadhara mari, kugona kugadzira zvinhu uye zvinodiwa kuti zvinhu zviitwe pakutanga mukati mehurongwa hweveruzhinji.
Panguva imwe cheteyo, kugadzirwa kwemishonga inobva kuHIT receptor kunopa mamwe matambudziko ekutonga. kuwedzera kunzwisisika Izvi zvinosanganisira kuratidza zvakadzama kuti hazviwedzere njodzi yekukuvadzwa zvakanyanya kunze kwebundu. Masangano eEurope nenyika anogona kuda izvi. zvirongwa zvekutarisa kwenguva refu uye magadzirirwo ekuyedza akanyatsonaka kuderedza njodzi pakutanga.
Vatsvaguriri vanobatanidzwa mubasa iri, vakaita sachiremba wezvirwere zvemuviri Manel Juan Kuchipatara cheBarcelona, vanokoshesa nzira itsva iyi senzira humbowo hwakasimba hwepfungwa izvo zvinogona kusanganiswa nedzimwe nzira (masoja ekudzivirira chirwere, immunotherapy yechivanhu, mishonga ye epigenetic) kuvandudza mhinduro dzemabundu akaoma. Asi vanosimbirira kuti ruzivo rwakawanda ruchiri kudiwa pamusoro pe migumisiro yakaipa inogona kuitika pamitezo ine hutano uye nezvekuti masero aya achaita sei mukuoma kwechinhu chinorarama.
Kana kushanda kwayo kukasimbiswa, Europe inofanirawo kugadzirisa nyaya dzakadai se kugadzirwa kwenzvimbo dzakasiyana-siyana kana kuenzaniswa nekugadzirwa kwenzvimbo imwe chete Kurapa kwemasero uku kunosanganisira kudzidziswa kwezvipatara, kudyidzana pakati penyika, uye kutaurirana kwemitengo neindasitiri, pamwe nekuvandudzwa kunogona kuitika kwe mapuratifomu edzidzo yeruzhinji zvakafanana nezviri kutoitwa kare muCatalonia nedzimwe nzvimbo.
Kubva murabhoritari kuenda kukiriniki: danho rinotevera
Parizvino, kushanda nemasero e-anti-CD70 HIT kuri muchikamu chekutanga. kunyatsogadzirira kurapwaSadelain pachake anobvuma kuti dambudziko guru riripo nderekuzadzisa mari inodiwa kutanga miedzo yekiriniki muvanhu uye kubatanidza zvivakwa zvikuru zvekugadzira zvinosangana nezvinodiwa zvemhando yepamusoro.
Zvidzidzo zvekutanga zvevanhu zvakarongwa, sekureva kwechikwata cheColumbia, mu varwere vane glioblastoma, acute myeloid leukemia, kenza yemazamu, uye kenza yepancreaticKunyangwe zvichitarisirwa kuti zvichatanga nekutarisa pane chimwe kana zviviri zviratidzo. Chero zvazvingava, izvi zvingave miedzo ye danho rekutanga (I/II), yakatarisana zvakanyanya nekuongorora kuchengetedzeka uye mwero wemushonga, pane kuratidza kushanda kwayo kwakasimba.
Panguva imwe chete, vaongorori vari kushanda pa nzira dzekuongorora nadzurudzo yeCD70 mumienzaniso yevarwere, sezvo sarudzo yekuti ndiani angabatsirwa nekurapa ichizoenderana nekuongorora nemazvo "spectrum" iyoyo yekutaura. Kubatanidzwa kwehunyanzvi hwepamusoro hwekufungidzira uye ongororo dzemajini kunogona kuva chinhu chakakosha pakusarudza vanhu vane mukana wepamusoro wekupindura.
Vanyori nenyanzvi dzakazvimirira vanobvumirana kuti, kunyange hazvo mhedzisiro yacho "ichikurudzira zvikuru", kuchiri mangwanani-ngwanani kutaura nezvenyaya yacho. shanduro chaiyo kukirinikiKurapa kwakawanda kwegomarara kwakaratidza kushanda kwakanaka mumamodheru embeva kwakazotadza kushanda nekuda kwekuoma kwemuviri wemunhu uye zvinodiwa nemitemo.
Kunyange zvakadaro, basa iri rakamutsazve kufarira kwenharaunda yesainzi nebazi rezvekurapa mune zvekurapa. Masero eCAR-T ekudzivirira bundu rakasimbaKana miedzo yevanhu ikasimbisa chikamu chikuru chemhedzisiro iyi isati yasvika pakiriniki, oncology inogona kuwana chishandiso chitsva chekurapa kenza ine fungidziro yakaipa kwazvo, senge pancreatic adenocarcinoma, mamwe mabundu eitsvo, kana glioblastomanzvimbo uko sarudzo dziripo dziri shoma zvikuru.
Kana zvabatanidzwa, tsvakiridzo yemasero ekurwisa CD70 HIT inosimbisa pfungwa yekuti remangwana re Masero ekudzivirira muviri mumatumbu akaoma Zvinosanganisira kuwedzera kunzwisiswa kwemasero eropa, kunzwisisa zviri nani biology yezvinotarirwa, uye kusanganisa nzira idzi nedzimwe nzira dzekurapa, nguva dzose nekuongorora kwakasimba kwekiriniki kuti kusiyanisa kufarira kunonzwisisika kubva kune zvipikirwa zvisati zvaratidzwa.