Juni 2022: Ngokwemiphumela yocwaningo olusanda kushicilelwa ngabakwa Imithi yeStanford kumagundane, ukwelashwa komdlavuza okusebenzisa amaseli omzimba esiguli ashintshwe ufuzo ukuze ahlasele amangqamuzana omdlavuza kuphephile futhi kusebenza kangcono uma kungashintshwa futhi kuvalwe ngomuthi odluliselwa ngomlomo.
Ukwelashwa kokuqala, manje okuvame ukubizwa ngokuthi i-CAR-T cell therapy, kubonise impumelelo ephawulekayo ekulweni nezinhlobonhlobo zomdlavuza wegazi. Kodwa-ke, ngenxa yokuthi ezinye iziguli zinokusabela komzimba kumangqamuzana aklanyelwe okungenzeka abulale, ukwelashwa kwe-CAR-T ngokuvamile kugcinelwe ukusetshenziswa kuphela ngemva kokuba ezinye izindlela zokwelapha sezihloliwe kuqala.
Iphinde ibe nezinga eliphansi lempumelelo ekwelapheni iziguli ezinezimila eziqinile, njengalezo ezitholakala kumdlavuza wobuchopho nowamathambo. Abacwaningi bakholelwa ukuthi lokhu kungenxa yokuthi amangqamuzana e-CAR-T asengozini yokuthola inani eliningi lokubonisa izimpawu, okuwenza aphelelwe amandla ngaphambi kokuba akwazi ukuqeda izimila eziqinile. Ngaphezu kwalokho, ngokungafani nomdlavuza wegazi, kunzima ukuhlonza izinhloso zamangqamuzana ezimila eziqinile. Lokhu okuhlosiwe kwamangqamuzana kufanele kube khona kuphela kumaseli omdlavuza futhi hhayi esicutsheni esivamile ukuze kube yizinketho zokwelapha eziphumelelayo.
Abacwaningi e-Stanford baqhamuke nokwelashwa kweseli ye-CAR-T eshintshiwe abayibiza nge-SNIP CAR-T. Lokhu kwelashwa kwenziwa kusebenze ngokuthatha umuthi womlomo wesifo sokusha kwesibindi kohlobo iFood and Drug Administration eselunikeze ukukhanya okuluhlaza ukuze lusetshenziswe kubantu. (Amaseli e-SNIP CAR-T awasebenzi uma umuthi unganikiwe.)
Lezo ziguli ezisengozini yokuba nokusabela okungekuhle kumaseli ashintshiwe ngofuzo zivikelwa indlela engaphephile ebizwa ngokuthi ikhono lokusebenzisa umuthi ukulungisa izinga lomsebenzi wamaseli ngemva kokuba ebuyiselwe esigulini. Abacwaningi baphinde bathola ukuthi amaseli e-CAR-T ashintshiwe asebenza kahle kakhulu ekulweni nomdlavuza oqinile kumagundane aselabhorethri. Bacabanga ukuthi lokhu kungase kube njalo ngoba amangqamuzana aba nezikhathi zokuphumula ezimfushane neziphindaphindiwe ngenkathi imithi yansuku zonke igaywa emizimbeni yezilwane.
UCrystal Mackall, MD, uProfessor Womndeni wakwa-Ernest kanye no-Amelia Gallo kanye noprofesa wezifo zezingane kanye nezokwelapha, uthe basungule indlela yokwelapha ye-CAR-T “elawulwa kude” engenziwa ngokwezifiso isiguli ngasinye. “Lawa maseli e-CAR-T ashintshwe ngokofuzo awaphephile nje kuphela, kodwa futhi anamandla futhi aguquguqukayo kunamaseli e-CAR-T akhiwa ekuqaleni. Iwuhlelo oluhle lobuchwepheshe obusezingeni eliphezulu zonke izinto ezibhekwayo.”
UMackall ungumbhali omkhulu walolu cwaningo futhi lwashicilelwa ku-inthanethi ngo-Ephreli 27 kujenali Cell. Umbhali oyinhloko wocwaningo nguLouai Labanieh, ongumfundi oneziqu.
NgokukaLabanieh, “Ngamangala ngezinga amaseli e-SNIP CAR-T abengcono ngalo kunokwelashwa okuvamile kwe-CAR-T.” "Amangqamuzana e-SNIP CAR-T aphulukise ngokuphelele amagundane anezimila eziqinile emathanjeni nasesimiso sezinzwa," ngokungafani nokwelashwa okuvamile kwe-CAR-T, okwakuwukwehluleka okuphelele.
Ngenxa yokuthi i-FDA isivele iyinike isibusiso sayo emithini yomlomo ekhuthaza ukusebenza kwamaseli e-SNIP CAR-T, abacwaningi banethemba lokuthi bazokwazi ukuqala izivivinyo zomtholampilo kubantu abanamathumba aqinile phakathi nezinyanga ezingama-24 ezizayo.
Ukubeka amaseli omzimba ukusebenza
Amaseli e-CAR-T angamaseli omzimba abizwa ngokuthi ama-T cell aqoqwa esigulini futhi enziwe ngofuzo elabhorethri ukuze abone futhi ahlasele amangqamuzana omdlavuza nge-molecule ethile endaweni yawo. Lawa maseli abe esesetshenziselwa ukwenza amaseli e-CAR-T. Amaseli e-CAR-T angasetshenziswa ukwelapha iziguli. Ngemva kwalokho, ama-antigen aphinde afakwe esigulini ukuze alwe nesifo. Lapho i-receptor kuseli ye-CAR-T ibophezela kulokho okuhlosiwe kuseli lomdlavuza, iqala ukusabela kweketanga ngaphakathi kweseli ye-CAR-T ethumela isignali engqamuzaneni ukubulala ingqamuzana lomdlavuza.
I-Food and Drug Administration (FDA) inikeze imvume yokuqala yokusetshenziswa kwe-CAR-T cell therapy ngo-2017 yokwelapha i-acute lymphoblastic leukemia ezinganeni nakubantu abadala. Kusukela ngaleso sikhathi, iphinde yavunyelwa ukuthi isetshenziswe kubantu abadala abahlushwa ezinye izinhlobo zomdlavuza wegazi, njenge-myeloma eminingi kanye nezinhlobo ezimbalwa ezihlukene ze-lymphoma. Amaseli e-CAR-T abona amanye ama-molecule noma okuqondiwe kwamangqamuzana amabili esikhundleni selilodwa okwamanje ahlolwa abacwaningi. Uhlobo lwangempela lokwelapha luqondise i-molecule engaphezulu kwamaseli omdlavuza ebizwa ngokuthi i-CD19.
Umgomo kaLabanieh kwakuwukuklama uhlelo lwe-CAR-T okuthi, uma amaseli esebuyiselwe esigulini, akwazi ukugadwa futhi alungiswe kalula. Lokhu wakwenza ngokwethula iphrotheni yegciwane eyaziwa ngokuthi i-protease kumaseli e-CAR-T. Isamukeli se-CAR-T, esisohlangothini lwe-cytoplasmic lolwelwesi lweseli, lugoqwe yile protease, ephinde ivimbe i-cascade ebonisa izimpawu eziqala umsebenzi wokubulala wamaseli. I-protease ingenziwa ingasebenzi ngokusebenzisa umuthi i-grazoprevir, ogunyazwe ukusetshenziswa ekwelapheni i-hepatitis C. Amaseli awalali lapho umuthi ungekho, kodwa ngokushesha lapho usukhona, aqala ukusebenza futhi aqale ukuqeda umdlavuza. amaseli emzimbeni.
Uma ingekho i-grazoprevir, u-Labanieh nozakwabo babonise ukuthi amaseli e-SNIP CAR-T awasebenzi kumagundane aselabhorethri. Ngakolunye uhlangothi, i-protease ikwazile ukuvinjelwa futhi amaseli e-SNIP CAR-T akwazi ukwenziwa asebenze lapho i-grazoprevir inikezwa amagundane ngomlomo. Kumodeli yegundane lobuthi obubulalayo obubangelwa i-CAR-T, amagundane alashwe ngamaseli e-SNIP CAR-T akwazi ukululama ngemva kokunqanyulwa kokwelashwa kwe-grazoprevir. Lokhu kubonise ukuthi uhlelo lunamandla okusebenza njengendlela ephephile ezigulini kunokwelashwa okuvamile kwe-CAR-T.
NgokukaLabanieh, “imizamo yangaphambilini yokwakha amangqamuzana e-CAR-T alawuleka izidakamizwa iye yakhiqiza amasistimu aqinile noma avuzayo.” Kungokokuqala ngqa ukuthi sikwazi ukushuna umsebenzi wabo ngezinga elithile.
Ngaphezu kwalokho, uMackall uthe "uma uhlelo lwe-SNIP CAR-T olunomthamo ogcwele we-grazoprevir luvuliwe, lusebenza ngokugcwele." “Futhi uma i-grazoprevir isihambile, akusekho ukwelashwa. Lokhu kubaluleke kakhulu ezigulini ezihlushwa ubuthi. Sinekhono lokumisa amaseli ukuthi akhiqize, okungathengela isiguli isikhathi esithile ukuze sibe ngcono. Iningi lamanye amaswishi okuphepha enzelwe ukususa amaseli e-CAR-T ngokuphelele noma acishwe unomphela. Kungenzeka ukuthi isiguli sizophumelela ekwelashweni, kodwa ngeke selapheke umdlavuza waso.
Ukwelashwa kwezimila eziqinile
Lapho abacwaningi behlola ikhono lamaseli e-SNIP CAR-T ukulwa nomdlavuza oqinile kumagundane, bathola ukuthi asebenza kahle kakhulu kunokwelapha okuvamile kwe-CAR-T. Ezimweni eziningi, abacwaningi bakwazi ukwelapha amagundane ayenomdlavuza wobuchopho owaziwa ngokuthi i-medulloblastoma noma umdlavuza wethambo owaziwa ngokuthi i-osteosarcoma.
Ngokungalindelekile, bathole nokuthi ukulungisa umthamo we-grazoprevir kwenza amaseli e-CAR-T abandlulule kakhulu, aqondisa umsebenzi wawo wokubulala kumaseli omdlavuza anamazinga aphezulu e-molecule eqondiwe ngenkathi kugcinwa izicubu ezijwayelekile ezinamazinga aphansi e-molecule efanayo. Lokhu kwaba ukutholakala okubalulekile ngoba kuchaza ukuthi amaseli e-CAR-T akwazi kanjani ukuhlukanisa phakathi kwamangqamuzana omdlavuza kanye nezicubu ezivamile. Ngokusho kwabacwaningi, ikhono lobunjiniyela be-CAR-T cell ukubona ama-molecule aqondiwe nawo akhona kumaseli anempilo anamandla okuthuthukisa kakhulu ikhono lomuntu lokulwa nezimila eziqinile zomuntu.
UMackall uchaze lokhu “njengento engenzeka ekhangayo ngempela.” “Uma sikwazi ukwehlisa ukusebenza kwamaseli e-SNIP CAR-T ngokulungisa umthamo we-grazoprevir, lapho-ke sizokwazi ukuhlukanisa ngokunembe kakhulu ukwelashwa kwesiguli ngasinye. Lokhu kuzovimbela ubuthi noma kuqhuba amaseli e-CAR-T ukuthi abulale amangqamuzana omdlavuza kunezicubu ezivamile. Sikholelwa ukuthi lokhu kwelashwa komdlavuza kungokwesizukulwane esilandelayo futhi kuzoguqula umkhakha wamaseli e-CAR-T.
Abanye ababhali abavela eStanford bahlanganisa uRobbie Majzner, MD, uprofesa osizayo wezifo zezingane; izazi ze-postdoctoral uDorota Klysz noSean Yamada-Hunter, PhD; usosayensi omkhulu wocwaningo okuthiwa u-Elena Sotillo, PhD; abacwaningi besayensi yokuphila uChris Fisher, u-Kaithlen Pacheco, u-Meena Malipatlolla, u-Johanna Theruvath, no-Peng Xu, MD, PhD; Jose Vilches-Moure, DVM, PhD,
Lolu cwaningo lwenziwe lwaba nokwenzeka ngoxhaso lweNational Institutes of Health (izibonelelo U54 CA232568-01, DP2 CA272092, kanye U01CA260852), National Science Foundation, Stand Up 2 Cancer, Parker Institute for Cancer Immunotherapy, Lyell Immunopharma, the Virginia and DK Ludwig Fund for Cancer Research, Cancer Research Institute, German Cancer Aid, nabanye.
Mayelana nalolu cwaningo, u-Labanieh, Mackall, Majzner, kanye no-Lin bonke bafakwe ohlwini lwabaqambi ngokubambisana kulungelo lobunikazi. UMackall ungomunye wabasunguli bezinkampani ezintathu okwamanje ezisebenzela ukuthuthukisa izindlela zokwelapha ezisekelwe ku-CAR-T. Lezi zinkampani yi-Lyell Immunopharma, Syncopation Life Sciences, kanye ne-Link Cell Therapies. U-Labanieh ungumxhumanisi we-Syncopation Life Sciences ngaphezu kokuba umsunguli wenkampani. U-Labanieh, uMajzner, Sotillo, kanye no-Weber bonke bangabaxhumanisi be-Lyell Immunopharma kanye nabanikazi bamasheya enkampanini.
Ukuze uthole ulwazi chofoza lapha.
