izindaba

I-Chimeric antigen receptor (CAR) Ukwelashwa kwe-T cell sekuphenduke ukwelashwa okubalulekile kwezifo ze-hematological eziphindaphindiwe noma eziphikisayo. Njengamanje, kunemikhiqizo eyisithupha ye-auto-CAR T egunyazwe ukumakethwa e-United States, kuyilapho kunemikhiqizo emine ye-CAR-T esohlwini lwase-China. Ngaphezu kwalokho, izinhlobonhlobo zemikhiqizo ye-CAR-T ye-autologous ne-allogeneic isathuthukiswa. Izinkampani ezenza imithi enale mikhiqizo yesizukulwane esilandelayo zisebenzela ukuthuthukisa ukusebenza kahle nokuphepha kwezindlela zokwelapha ezikhona ze-hematological malignancies kuyilapho ziqondise izimila eziqinile. Amaseli e-CAR T nawo ayathuthukiswa ukuze aphathe izifo ezingezona eziyingozi njengezifo ezizimele.

Izindleko ze-CAR T ziphezulu (okwamanje, izindleko ze-CAR T/CAR e-United States ziphakathi kuka-370,000 no-530,000 wamadola ase-US, futhi imikhiqizo eshibhe kakhulu ye-CAR-T e-China ingu-999,000 yuan/imoto). Ngaphezu kwalokho, izehlakalo eziphezulu zokusabela okunobuthi obunzima (ikakhulukazi i-grade 3/4 immunoeffector cell-related neurotoxic syndrome [ICANS] kanye nesifo sokukhululwa kwe-cytokine [CRS]) kube yisithiyo esikhulu kubantu abahola kancane – nabahola kancane ukuthi bathole ukwelashwa kwamaseli e-CAR T.

Muva nje, i-Indian Institute of Technology Mumbai kanye ne-Mumbai Tata Memorial Hospital ngokubambisana ukuthuthukisa umkhiqizo omusha we-CD19 CAR T (NexCAR19), ukusebenza kwawo kufana nemikhiqizo ekhona, kodwa ukuphepha okungcono, okubaluleke kakhulu ukuthi izindleko ziyingxenye eyodwa kweshumi kuphela yemikhiqizo efanayo yase-United States.

Njengemithi yokwelapha emine kweyisithupha ye-CAR T egunyazwe yi-US Food and Drug Administration (FDA), i-NexCAR19 nayo ihlose i-CD19. Kodwa-ke, emikhiqizweni egunyazwe ukuthengisa e-United States, ucezu lwama-antibody ekupheleni kwe-CAR ngokuvamile luvela kumagundane, okunciphisa ukuphikelela kwalo ngoba amasosha omzimba akubona njengelinye izwe futhi ekugcineni alususe. I-NexCAR19 yengeza iphrotheni yomuntu ekugcineni kwe-antibody yegundane.

Ucwaningo lwelabhorethri luye lwabonisa ukuthi umsebenzi we-antitumor wezimoto "zomuntu" uqhathaniswa nezimoto ezitholakala ku-murine, kodwa ngamazinga aphansi okukhiqizwa kwe-cytokine. Ngenxa yalokho, iziguli zinengozi enciphile yokuthola i-CRS eqinile ngemva kokuthola ukwelashwa kwe-CAR T, okusho ukuthi ukuphepha kuyathuthukiswa.

Ukuze kuncishiswe izindleko, ithimba labacwaningi bakwa-NexCAR19's lenze, lahlola futhi lakhiqiza umkhiqizo ngokuphelele e-India, lapho ukusebenza ishibhile kunasemazweni anemali engenayo ephezulu.
Ukwethula i-CAR kuma-T cell, abacwaningi ngokuvamile basebenzisa ama-lentivirus, kodwa ama-lentivirus ayabiza. E-United States, ukuthenga ama-lentiviral vector anele okuhlolwa kwabantu abangu-50 kungabiza u-$800,000. Ososayensi enkampanini yokuthuthukisa i-NexCAR19 bazenzele bona imoto yokulethwa kwezakhi zofuzo, behlisa izindleko ngendlela emangalisayo. Ngaphezu kwalokho, ithimba labacwaningi baseNdiya lithole indlela eshibhile yokukhiqiza amangqamuzana aklanywe ngobuningi, ukugwema ukusetshenziswa kwemishini ezibizayo ezenzakalelayo. I-NexCAR19 njengamanje ibiza cishe u-$48,000 iyunithi ngayinye, noma ingxenye yeshumi yezindleko zozakwabo wase-US. Ngokusho kwenhloko yenkampani eyathuthukisa i-NexCAR19, izindleko zomkhiqizo kulindeleke ukuthi zehliswe ngokuzayo.

Okokugcina, ukuphepha okuthuthukisiwe kwalokhu kwelashwa uma kuqhathaniswa neminye imikhiqizo egunyazwe i-FDA kusho ukuthi iziguli eziningi azidingi ukululama egunjini labagula kakhulu ngemva kokuthola ukwelashwa, okuqhubeka kwehlisa izindleko ezigulini.

U-Hasmukh Jain, udokotela oncologist wezokwelapha e-Tata Memorial Centre eMumbai, ubike ukuhlaziywa kwedatha okuhlanganisiwe kwesivivinyo seSigaba 1 neSigaba 2 se-NexCAR19 emhlanganweni waminyaka yonke we-American Society of Hematology (ASH) 2023.
Uhlolo lweSigaba 1 (n=10) lwaluyisikhungo esisodwa esiklanyelwe ukuhlola ukuphepha kwemithamo yeseli ye-CAR T engu-1×107 kuya ku-5×109 ezigulini ezine-B-cell lymphoma enkulu ebuyele emuva/ephikisayo (r/r DLBCL), eguqula i-follicular lymphoma (tFL), kanye ne-primary mediastinal big-cell lymphoma (PMB). Uhlolo lweSigaba 2 (n=50) bekuwucwaningo lwengalo eyodwa, olugxile ezindaweni eziningi olwabhalisa iziguli ≥ezineminyaka engu-15 ubudala ezine-r/r B-cell malignancies, okuhlanganisa i-B-cell lymphomas enolaka ne-occult kanye ne-acute lymphoblastic leukemia. Iziguli zanikezwa i-NexCAR19 ezinsukwini ezimbili ngemuva kokuthola i-fludarabine kanye ne-cyclophosphamide. Umthamo okuhlosiwe wawungu-≥5×107/kg amaseli e-CAR T. Isiphetho esiyinhloko kwakuyizinga lokuphendula lenhloso (ORR), kanti izindawo zokugcina zesibili zazihlanganisa ubude besikhathi sokuphendula, izehlakalo ezimbi, ukusinda kwe-progression-free survival (PFS), kanye nokusinda sekukonke (OS).
Iziguli ezingama-47 zelashwa nge-NexCAR19, ezingama-43 kuzo ezithole umthamo ohlosiwe. Isamba seziguli ezingama-33/43 (78%) ziqede ukuhlolwa kwangemva kokumnika izinsuku ezingama-28. I-ORR ibingu-70% (23/33), lapho ama-58% (19/33) athole impendulo ephelele (CR). Eqenjini le-lymphoma, i-ORR yayingama-71% (17/24) kanti i-CR yayingu-54% (13/24). Eqenjini le-leukemia, izinga le-CR lalingu-66% (6/9, i-MRD-negative ezimweni ezi-5). Isikhathi sokulandelela esimaphakathi seziguli ezihlolekayo kwakuyizinsuku ezingama-57 (izinsuku ezingama-21 kuye kwezingama-453). Ekulandeleni kwezinyanga ezi-3 - neziyi-12, zonke iziguli eziyisishiyagalolunye kanye nengxenye yesithathu yeziguli zigcine ukuxola.
Akukho ukufa okuhlobene nokwelashwa. Asikho ezigulini ebenanoma yiliphi izinga le-ICANS. Iziguli ezingama-22/33 (66%) zakha i-CRS (61% grade 1/2 kanye no-6% grade 3/4). Ngokuphawulekayo, awekho ama-CRS angaphezu kwebanga lesi-3 ayekhona eqenjini le-lymphoma. I-cytopenia yeBanga lesi-3/4 yayikhona kuzo zonke izimo. Ubude besikhathi esimaphakathi se-neutropenia kwakuyizinsuku eziyi-7. Ngosuku lwama-28, i-neutropenia yebanga lesi-3/4 yabonwa ezigulini eziyi-11/33 (33%) kanye ne-thrombocytopenia yebanga lesi-3/4 ezigulini eziyi-7/33 (21%). Isiguli esisodwa kuphela (3%) esidinga ukungeniswa egunjini labagula kakhulu, iziguli ezi-2 (6%) zazidinga ukwesekwa kwe-vasopressor, iziguli eziyi-18 (55%) zithole i-tolumab, ne-median ye-1 (1-4) kanye neziguli ezi-5 (15%) zithole ama-glucocorticoids. Ubude bokuhlala obumaphakathi kwakuyizinsuku eziyi-8 (izinsuku eziyi-7-19).
Lokhu kuhlaziya okuphelele kwedatha kukhombisa ukuthi i-NexCAR19 inephrofayili enhle yokusebenza ngempumelelo nezokuphepha kuma-r/r B-cell malignancies. Ayinayo i-ICANS, ubude besikhathi obufushane be-cytopenia, kanye nezinga eliphansi le-CRS yebanga lesi-3/4, okuyenza ibe omunye wemikhiqizo yokwelashwa kwamaseli e-CD19 CAR T ephephe kakhulu. Umuthi usiza ukuthuthukisa ukusetshenziswa kalula kwe-CAR T cell therapy ezifweni ezihlukahlukene.
Ngo-ASH 2023, omunye umbhali wabika ngokusetshenziswa kwezinsiza zezokwelapha esivivinyweni sesigaba 1/2 kanye nezindleko ezihlobene nokwelashwa kwe-NexCAR19. Izindleko zokukhiqiza ezilinganiselwe ze-NexCAR19 ezigulini ezingama-300 ngonyaka kumodeli yokukhiqiza ehlakazekile ngokwesifunda zilinganiselwa ku-$15,000 isiguli ngasinye. Esibhedlela sezemfundo, isilinganiso sezindleko zokuphathwa komtholampilo (kuze kufike ekulandeleni kokugcina) isiguli ngasinye singaba ngu-$4,400 (cishe u-$4,000 we-lymphoma kanye no-$5,565 we-B-ALL). Cishe amaphesenti angu-14 kuphela alezi zindleko ezokulala esibhedlela.