Umzimba wakho unezinhlobo ezahlukene zamaseli ezimhlophe egazi. Olunye uhlobo, i -lymphocyte , lufika ezinhlotsheni ezimbili eziyinhloko: i-B-cell ne-T-cell. Lapha, esimweni sokwelashwa komdlavuza, sithinteka kakhulu kulolu hlobo lwesibili, i-T-cell.
Ngakho-ke, yimuphi ukwelashwa kwe-T-cell ye-anti-receptor (CAR)? Ngamafuphi, kuyindlela yokwelashwa okuphezu kwezintambo ezenza izakhi zofuzo zibe ngcono ekuqapheliseni nasekuhlaseleni umdlavuza ngaphakathi.
Ngenye yezinhlobo eziningi ze-immunotherapies ezihlolwe. Uma unesithakazelo ku-biotechnology ngemuva kwalolu hlobo lwezokwelapha, incazelo eningiliziwe yokuthi indlela ye-CAR T-cell yokwelapha isebenza ngayo ngale ndlela.
Lapha, kugxilwe kulezi "zindlela zokwelapha" nezinye izindlela zokwelapha ezisebenza ngeT-cells-amasosha omzimba omzimba wakho-ukulwa nomdlavuza ngokuqaphela nokuhlasela amangqamuzana omzimba. Ezinye izindlela zokwelapha zomdlavuza ezisebenzisa ama-T-cells omzimba wakho sezivumile kakade, kanti abanye kulindeleke ukuba balandele maduzane.
Ukulondoloza Indlela Yokwelashwa Okusekelwe Emzimbeni
Ukucubungula amasosha omzimba wakho ukuzama ukulwa nomdlavuza akuyona into entsha. Eqinisweni, kunezibonelo zendlela zokwelapha ezinjalo (ezigxila ekuphenduleni kwe-T-cell) ezitholile imvume ye-FDA: i-sipuleucel-T, i-ipilimumab, ne-blinatumomab, isibonelo.
Ukwelapha | Uhlobo lomdlavuza | I-Immune System Action |
I-Sipuleucel-T (Nikeza) | Amacala athile omdlavuza wesandulela ngculazi |
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Ipilimumab (Yervoy) | Amacala athile omdlavuza wesikhumba obulalayo we-melanoma |
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I-Blinatumomab (iBlincyto) | Isandulela se-B-cell ephindaphindiwe noma ekhanyelayo (i-ALL) kubantu abadala nabantwana |
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Omunye wabo, i-sipuleucel-T, izwakala kakhulu njengelashwa lwe-CAR T-cell ngoba isebenzisa amangqamuzana omzimba wakho omzimba aqoqwe kuqala egazini ngalinye bese esetshenziselwa i-laboratory; ziyasebenza futhi zenziwe ukuba ziphendule ngokwengeziwe kumangqamuzana e-tumor, bese zifaka emuva egazini njengegazi.
I-Sipuleucel-T ibhekwa ngokuthi "i-autologous vaccine," noma "i-autologous cell immunotherapy", kodwa hhayi ukwelashwa kwe-CAR T-cell kusukela amangqamuzana omzimba omzimba aqeqeshelwe ukuphendula, kunokuba abe nezakhi zofuzo ukuphendula amangqamuzana omzimba .
Ama-inhibitors wokuhlola omzimba omzimba njenge-ipilimumab (ngenhla) asebenza ngezinqubo ezihlukahlukene zokuzivikela komzimba wakho "zokusebenzisa amabhuleki," noma "ukushaya umshini wokugesi" emzimbeni womzimba, ukuze uzame ukuzivikela ngokuvikela umzimba wakho ngokumelene nomdlavuza. Ipilimumab yisinye isibonelo somuthi osebenza ngale ndlela. Esinye isibonelo se-inhibitor ye-immune checkpoint i-pembrolizumab (i-Keytruda), ehlose i- "switch on-off" yamaseli e-T, okuthiwa i-PD-1.
Izindlela zokwelapha ze-CAR-T: Yiqiniso "Izidakamizwa Zokuphila"
Kodwa-ke, imithi yokwelapha ye-CAR-T, ngokusobala, iyinto yawo ehlukile. Ama-T-cell akhishwa emzimbeni wakho, ahlelwe izakhi zofuzo ukuze aqaphele kangcono futhi abulale amangqamuzana e-tumor, bese esetjenziswa kabusha njengendlela yokwelashwa okuphilayo. Amaseli angenziwa futhi akhule ezinsukwini ezimbalwa ezinsukwini ezingu-21 bese ephindaphinda egazini.
I-CAR T-cell therapy ayilona uhlobo lwezokwelapha olungasetshenziswa ngaphambi kokuzama ezinye izindlela zokwelashwa-okungenani, hhayi okwamanje. Lezi zindlela zokwelapha ezintsha zivame ukuvela eqinisweni elibi ukuthi, ngeziguli ezinezifo eziseduze, isifo somdlavuza wendabuko, kuhlanganise nokuhlinzwa, i-chemotherapy, kanye nokwelashwa kwemisebe, ngokuvamile kuvame ukusebenza ngokulinganiselwe.
Ngakho-ke, kuze kube manje, izindlela zokwelapha ze-CAR-T zitholakale kuphela ezigulini ezibhalisile ezivivinyweni zomtholampilo, njengoba ukwelashwa kuthathwa njengophenyo e-US, kodwa lokhu kungashintsha maduzane. Imithi yokwelapha ye-CAR-T ingaba i-FDA evunyelwe futhi itholakale ngaphandle kwezilingo zomtholampilo ngokushesha nje ngo-2017-2018.
Uhlu oluthile lwabaqashi abakhulu abathuthukiswa emitholampilo balandela.
CTL019 (tisagenlecleucel) ngu-Novartis
I-CTL019 iyi-CD19-ethize ye-anti-receptor receptor (CAR) -yakhelwe ukwelashwa kwe-T-cell.
Ake siqale ngokukhipha umusho owedlule: i-CD19 iyi-molecule ngamaseli omzimba omzimba okuthiwa yi-B-cells, futhi lawa maseli angabangela izinhlobo ezithile ze- leukemia ne-lymphoma .
Umthamo owodwa we-CTL019 uye waletha ukukhipha isikhathi eside kanye nokuphulukiswa okungenzeka (asazi okwamanje) kwizibalo eziningi ezifundweni eziphelelwa ukhetho lwezokwelapha.
Nansi ukuhlaselwa kwezifo lapho i-CTL019 ithathwa khona njengamanje:
- I-CTL019 ithole ukubizwa kwe-FDA Breakthrough Therapy yokwelapha iziguli ezikhulile ezine-B-cell lymphoma (DLBCL) ephindaphindiwe / ekhanyelayo. (I-Lymphomas ngokuvamile ihlukaniswe ngamaqembu amabili ayisisekelo: i-Hodgkin non-Hodgkin. Uhlobo oluvame kakhulu lwe-non-Hodgkin lymphoma yi-DLBCL).
- I-CTL019 iphinde ivume ukuphathwa kokwelashwa okuphindaphindiwe noma okukhukhumezayo kanye neziguli ezindala ezincane ezine-B-cell acute lymphoblastic leukemia (YONKE).
I-CTL019 yamukelwe ngokuvota (10-0) ngokuvunywa yi-FDA ye-Oncologic Drugs Advisory Committee, okusho ukuthi izinto zibukeka zithembisa ukugunyazwa kwayo. I-Novartis ihlose i-CTL019 ukuthi ivunyelwe ukwelashwa kwe-B-cell ephindaphindiwe noma ephikisayo YONKE kuzo iziguli ezinganeni kanye nabantu abadala. I-leukemia ingumdlavuza wenani lomntwana oyedwa, futhi YONKE ifomu elivame kakhulu, elibhekene namaphesenti angama-25 e-kansa yengane. Kunezinhlobo ezahlukene ZONKE, kuhlanganise ne-B-cell NONKE ne-T-cell NONKE, futhi ama-subtypes angaphakathi angase athathe ama-prognoses awo.
I-CTL019 okwamanje ibuyekezwa ngokubaluleka futhi ukuvunyelwa okwesikhashana kuzokwenza ukuthi kube yilapho ikhambi lokuqala le-CAR-T elitholakala khona. Ukwelashwa kwe-CAR T-cell kuyotholakala kuphela ngenani elincane labantwana kanye nabantu abadala abano-leukemia abangaphenduli ekunakekelweni okujwayelekile. Lezi ziguli zinezifo eziphuthumayo, kodwa ekuhlolweni okuvivinya kakhulu ukwelashwa cishe emazweni ayishumi nambili, amaphesenti angu-83 weziguli azongena ekuxoxweni. Ngemva konyaka, izingxenye ezimbili kwezintathu zahlala njalo.
Ngenxa yokuthi ukwelashwa akubhuli nje kuphela uketshezi lwe-B kuphela kodwa futhi kunezifo ezinempilo, ezilwa nezifo, iziguli zidinga ukwelashwa ukuze zivikeleke ekutheleleni. Bathola ukugonywa kwama-immune globulins njalo ezinyangeni ezimbalwa njengendlela yokuzivikela.
Omunye wemiphumela emibi kakhulu ebizwa ngokuthi i-cytokine release syndrome, okubangela ukukhulelwa okukhulu kanye nezimpawu ezifana nezifo eziwumkhuhlane ukuthi kwezinye izimo kungaba yingozi kangangokuba isiguli sigcina ekunakekeleni okukhulu. Okunye okukhathazeka okukhulu yi-neurotoxicity, engabangela ukudideka okwesikhashana noma ukuvuvukala kobuchopho obubulalayo.
Ukuze uzame ukuqinisekisa ukuphepha kwesiguli, i-Novartis ayihlezi ukukhishwa komkhiqizo ojwayelekile, isidakamizwa sinyatheliswa ngokubanzi futhi ngokufutheka ngangokunokwenzeka. Le nkampani esikhundleni sayo izobeka izikhungo zezokwelapha ezingu-30 kuya ku-35 ukuphatha ukwelashwa. Abaningi babo bahlanganyele ekuvivinyweni komtholampilo, futhi bonke bathole ukuqeqeshwa okubanzi.
I-Axicabtagene Ciloleucel nguKite Pharma
Isekelwe eSanta Monica, eCalifornia, iKite Pharma yinkampani egxile kwi-CAR kanye ne-T-cell receptor ezakhiwe ngezindlela zokwelashwa zamaseli. I-Kite ihlakulela ukwelashwa kwe-CAR T-cell okuthiwa i-axicabtagene ciloleucel, okwamanje iphinde ibuyekezwe ngokuyinhloko e-US ngokuphathwa kweziguli ezinezinhlupho ezingenayo i-Hodgkin lymphoma (NHL). Iziguli ezine-NHL ezihlukumezayo zibhekene nesimo sokubikezela ngokucacile ngamathuba angu-50 kuphela okuphila ezinyangeni eziyisithupha. Lokhu kugcizelela isidingo sezempilo esiphuthumayo salezi ziguli.
Njenge-CTL019, i-axicabtagene ciloleucel iphinde ihlose i-antigen CD19, iphrotheni evezwe esitokisini se-B-cell lymphomas nama-leukemi. Amaseli we-T wesiguli asetshenziselwa ukuveza i-chimeric receptor (CAR) ukukhomba i-antigen CD19.
Esikhathini senqubo yokuthuthukiswa kwezidakamizwa nokuvunywa, i-axicabtagene ciloleucel inephrofayili efanayo naleyo ye-CTL019, ngoba ukugxila ekubhekeni kwezidakamizwa ezivela ku-B-cell, kodwa i-B cell NONKE ayibonakali njengengxenye yokuthuthukiswa kwayo emtholampilo ngalesi sikhathi.
Nansi ukuhlaselwa kwezifo lapho i-axicabtagene ciloleucel ithathwa khona njengamanje:
- I-Axicabtagene ciloleucel inikezwe isimo sokuqokwa kwe-Thethrough Treatment Designation ye-B-cell lymphoma enkulu (DLBCL) enkulu, i-transformed follicular lymphoma (TFL), kanye ne-B-cell lymphoma (PMBCL) ye-mediaminal mediastinal (PMBCL) eyisekela le-US FDA kanye ne-Priority Medicines (PRIME) I-DLBCL e-EU.
Ukwamukelwa njenge-Breakthrough Therapy yi-FDA kusekelwa idatha evela ku-ZUMA-1 Isigaba sesivivinyo sesi-2 esihlangene nesiphelo sokugcina sokulinganisa izinga lokuphendula (ORR) eliqoshiwe ngemuva kokukhipha okukodwa kwe-axicabtagene ciloleucel ngamaphesenti angu-82 (p <0.0001). Ekulandeleni okuphakathi kwamaphesenti angu-8.7, iziguli ezingu-44 zinezimpendulo eziqhubekayo, ezihlanganisa iziguli ezingu-39 ezimpendulo ngokugcwele (CR).
Izenzakalo ezivamile ezimbi zihlanganisa ukwehliswa kwamaseli anempilo alwa nokutheleleka futhi asize igazi ligule. Njengoba nge-CTL019, enye yemiphumela emibi kakhulu ebizwa ngokuthi i-cytokine release syndrome, ebangela ukushisa okukhulu kanye nezimpawu ezifana nemikhuhlane ukuthi kwezinye izimo kungaba yingozi kangangokuthi isiguli siphelela ekunakekeleni okukhulu. I-encephalopathy ingabangela ukudideka okwesikhashana noma ukuvuvukala kobuchopho obubulalayo. Kube nokufa abathathu kulo lonke icala lokubhaliswa hhayi ngenxa yokuqhubeka kwezifo, okwenzeka kuzo ezimbili, okwakubhekwa kuhlobene ne-axicabtagene ciloleucel. Nakulokhu, ukuthuthukiswa kwemitholampilo yalezi zidakamizwa kulindeleke ukuba uqhubeke ngokuqapha.
I-GoCAR-T, i-Candidate for Tumor Tumors yi-Bellicum Pharmaceuticals
I-Houston, i-Texas-based Bellicum Pharmaceuticals, Inc., inezidakamizwa zezidakamizwa ezibandakanya i-BPX-601 (i-GoCAR-T, izibilini eziqinile, ezenzelwe inkinobho yokusebenza yokusebenza iMC ukuthuthukisa ukusebenza, isigaba I), ne-BPX-701 -ukungapheli kwesifo se-TCR, ngenxa yezicubu eziqinile , ezenzelwe ukushintshwa kwe-CaspaCIDe, isigaba I).
Ngakho, kusho ukuthini lokho konke? Ngokuyinhloko, leli qembu lisebenza ekucwengeni ubuchwepheshe be-CAR T-cell ukuze buze umtholampilo aphinde alawule ngaphezulu impendulo ye-T cell. Amaseli we-GoCAR-T aklanyelwe kuphela ukuthi acushiwe ngokugcwele lapho evezwa kokubili amangqamuzana omdlavuza kanye ne -ejenti ebizwa ngokuthi i-rimiducid. Ngakho-ke, umhlengikazi uzokwazi ukulawula izinga lokusebenza kwamaseli e-CAR ngokushintsha isimo sokuphatha okubi, kodwa ukubulawa kwamangqamuzana kuzobe kusenzeka ngendlela encike ekudleni.
Abanye abakhethiweyo
I-Juno yinkampani manje egxile kuJCAR017, umkhiqizo we-CAR-T ohlose i-CD19. UJuno ubheka ukuthola i-JCAR017 emakethe ngasekupheleni kuka-2018 we-NHL. Le nkampani ihlangene no-Celgene kule mizamo.
I-ZIOPHARM Oncology inomkhiqizo othize we-CD19 futhi isebenza nge-CD33 ethize ye-CAR T-cell therapy yokuvuvukala / ukuphikisana komzimba we-myeloid leukemia (AML). I-NantKwest iyinkampani ye-immunotherapy egxile ekusebenziseni umbulali wemvelo (NK) amangqamuzana ukuphatha umdlavuza, izifo ezithathelwanayo nezifo ezivuthayo.
Iplatifomu ye-NK yenkampani yenzelwe ukudala iseli ukufa ngokumelene nomdlavuza noma amangqamuzana anegciwane ngezindlela ezintathu ezihlukene zokusebenza-ukubulawa okuqondile usebenzisa i-NK cells (aNK) esebenzayo; ukubulawa kwe-antibody-mediated ngokusebenzisa i-haNKs, nokubulala okusetshenzisiwe okusetshenzisiwe kusetshenziswa i-taNKs.
Izwi elivela
Eminye yemiphumela yokuqala ye-CAR-T ye-cell therapy iye yaba mnandi kakhulu, inikeza izindlela zokwelashwa ezintsha kumaqembu eziguli azange aziphathe ngale ndlela ngaphambili. Kubuye kube nokuhluleka, noma kunjalo, nokuncane kokuxazululwa kwezinkinga ukuze lezi zindlela zokwelashwa ziphumelele ngangokunokwenzeka ngezinga elincane lokushisa.
Njengoba abacwaningi befunda kabanzi mayelana nokuphendula komzimba okuhlangene nakho kulezi zindlela zokwelapha, kanye nomthelela emilonyeni yezifiso, isithombe esicacile sezingozi nezinzuzo kufanele siphume.
> Imithombo:
> Wang M, Yin B, Wang HY, Wang RF. Ukuthuthukiswa kwamanje ku-T-cell-based-based immunotherapy. Immunotherapy . 2014; 6 (12): 1265-1278.
> Bhoj VG, Arhontoulis D, Wertheim G, et al. Ukuphikelela kwamaseli e-plasma ahlala isikhathi eside nokuzivikela komzimba kubantu abasabela ekwelashweni kwe-CAR T-cell eqondiswa yi-CD19. Igazi. 2016; 128 (3): 360-370.
> I-Kite ithola ukubuyekezwa okubalulekile kwe-US Food and Drug Administration ye-Axicabtagene Ciloleucel. http://ir.kitepharma.com/releasedetail.cfm?releaseid=1028075 Ifinyelelwe ngoJulayi 2017.
> Morris EC, Stauss HJ. Ukwenza ngcono i-T-cell ye-receptor gene therapy ye-hematologic malignancies. Igazi . 2016; 127 (26): 3305-3311.
> Ipaki JH, Geyer MB, i-Brentjens RJ. Izindlela zokwelapha ze-hematologic ze-CAR T-CD19 ezihloselwe i-CD19: ukuhumusha imiphumela yomtholampilo kuze kube yimanje. Igazi . 2016; 127 (26): 3312-3320.