iindaba

I-Chimeric antigen receptor (CAR) Unyango lwe-T cell luye lwaba lunyango olubalulekileyo lwe-hematological malignancies ephindaphindiweyo okanye echasayo. Okwangoku, kukho iimveliso ezintandathu ze-auto-CAR T ezivunyiweyo ukuba zithengiswe e-United States, ngelixa kukho iimveliso ezine ze-CAR-T ezidweliswe e-China. Ukongeza, iintlobo ezahlukeneyo ze-autologous kunye ne-allogeneic CAR-T iimveliso ziphantsi kophuhliso. Iinkampani zamachiza kunye nezi mveliso zesizukulwana esilandelayo zisebenzela ukuphucula ukusebenza kunye nokhuseleko lwezonyango ezikhoyo kwi-hematological malignancies ngelixa zijolise kwi-tumor eqinile. Iiseli ze-CAR T nazo ziphuhliswa ukunyanga izifo ezinganyangekiyo ezifana nezifo ezizimelayo.

Iindleko zeCAR T ziphezulu (okwangoku, iindleko zeCAR T / CAR e-United States ziphakathi kwe-370,000 kunye ne-530,000 yeedola zase-US, kwaye iimveliso ze-CAR-T ezingabizi kakhulu e-China ziyi-999,000 yuan / imoto). Ngaphezu koko, izehlo eziphezulu zokusabela okuyityhefu kakhulu (ingakumbi ibakala le-3/4 le-immunoeffector cell-related neurotoxic syndrome [ICANS] kunye ne-cytokine release syndrome [CRS]) ibe ngumqobo omkhulu kubantu abaphantsi – nabanomvuzo ophakathi ukuba bafumane unyango lweseli ye-CAR T.

Kungekudala, i-Indian Institute of Technology Mumbai kunye ne-Mumbai Tata Memorial Hospital ngokubambisana nokuphuhlisa imveliso entsha ye-CD19 CAR T (NexCAR19), ukusebenza kwayo kufana nemveliso ekhoyo, kodwa ukhuseleko olungcono, eyona nto ibalulekileyo kukuba iindleko ziyingxenye yeshumi kuphela ye-United States yeemveliso ezifanayo.

Njengomane kwezintandathu zonyango ze-CAR T ezivunywe yi-US Food and Drug Administration (FDA), i-NexCAR19 nayo ijolise kwi-CD19. Nangona kunjalo, kwiimveliso ezivunyiweyo kurhwebo e-United States, iqhekeza le-antibody ekupheleni kwe-CAR lidla ngokuphuma kwiimpuku, nto leyo enciphisa ukuzingisa kwayo kuba amajoni omzimba ayayibona njengeyangaphandle kwaye ekugqibeleni iyayicoca. I-NexCAR19 yongeza iprotheni yomntu ekupheleni kwe-antibody ye mouse.

Izifundo zeLabhoratri zibonise ukuba umsebenzi we-antitumor we "Humanized" Iimoto zifaniswa neemoto ze-murine-derived, kodwa ngamanqanaba aphantsi okuveliswa kwe-cytokine. Ngenxa yoko, izigulane zinomngcipheko omncinci wokuphuhlisa i-CRS enzima emva kokufumana unyango lwe-CAR T, oku kuthetha ukuba ukhuseleko luphuculwe.

Ukugcina iindleko ziphantsi, iqela lophando le-NexCAR19's liphuhlise, lavavanya kwaye lenza imveliso ngokupheleleyo eIndiya, apho abasebenzi baphantsi kakhulu kunamazwe anengeniso ephezulu.
Ukwazisa i-CAR kwiiseli T, abaphandi badla ngokusebenzisa iilentiviruses, kodwa iilentivirus ziyabiza. E-United States, ukuthenga ii-lentiviral vectors ezaneleyo kulingo lwabantu abangama-50 kunokubiza i-$800,000. Izazinzulu kwinkampani yophuhliso ye-NexCAR19 zenze isithuthi sokuhanjiswa kwemfuza ngokwazo, zinciphisa kakhulu iindleko. Ukongeza, iqela lophando laseIndiya lifumene indlela efikelelekayo yokuvelisa iiseli eziyinjineli ngobuninzi, ukuthintela ukusetyenziswa koomatshini abazibizayo. I-NexCAR19 okwangoku ixabisa malunga ne-48,000 yeedola ngeyunithi, okanye isahlulo seshumi seendleko zomlingani wayo wase-US. Ngokwentloko yenkampani ephuhlise i-NexCAR19, ixabiso lemveliso kulindeleke ukuba lincitshiswe ngakumbi kwixesha elizayo.

Ekugqibeleni, ukhuseleko oluphuculweyo lonyango xa kuthelekiswa nezinye iimveliso ezivunywe yi-FDA kuthetha ukuba izigulane ezininzi azidingeki ukuba ziphinde zibuyele kwindawo yokunyamekela kakhulu emva kokufumana unyango, ukunciphisa iindleko kwizigulane.

U-Hasmukh Jain, i-oncologist yezokwelapha kwi-Tata Memorial Centre eMumbai, uchaze uhlalutyo lwedatha edibeneyo yeSigaba 1 kunye neSigaba se-2 sovavanyo lwe-NexCAR19 kwi-American Society of Hematology (ASH) i-2023 intlanganiso yonyaka.
Ulingo lweSigaba soku-1 (n = 10) lulingo lweziko elilodwa elenzelwe ukuvavanya ukhuseleko lwe-1 × 107 ukuya kwi-5 × 109 i-CAR T ye-cell doses kwizigulane ezine-relapsed / refractory diffuse enkulu ye-B-cell lymphoma (r / r DLBCL), ukuguqula i-follicular lymphoma (tFL), kunye ne-primary mediastinal B-cell lymphoma (PMB). Ulingo lweSigaba se-2 (n = 50) lwaluyingalo enye, uphando oluninzi olubhalise izigulane ≥iminyaka eyi-15 ubudala kunye ne-r / r B-cell malignancies, kubandakanywa i-B-cell lymphomas enobudlova kunye ne-occult kunye ne-acute lymphoblastic leukemia. Izigulane zanikwa i-NexCAR19 iintsuku ezimbini emva kokufumana i-fludarabine kunye ne-cyclophosphamide. I-dose ekujoliswe kuyo yayiyi-≥5 × 107 / kg iiseli ze-CAR T. Isiphelo esiphambili sasiyinqanaba lempendulo yenjongo (ORR), kwaye isiphelo sesibini sibandakanya ixesha lokuphendula, iziganeko ezimbi, ukusinda okungenasiphelo (PFS), kunye nokusinda ngokubanzi (OS).
Iyonke yezigulana ezingama-47 zanyangwa nge-NexCAR19, ezingama-43 kuzo zafumana ithamo ekujoliswe kulo. Iyonke izigulane ezingama-33/43 (78%) zalugqiba iintsuku ezingama-28 zovavanyo lwasemva kokutofa. I-ORR yayingama-70% (23/33), apho i-58% (19/33) ifumene impendulo epheleleyo (CR). Kwiqela le-lymphoma, i-ORR yayingu-71% (17/24) kunye ne-CR yi-54% (13/24). Kwiqela le-leukemia, izinga le-CR laliyi-66% (6/9, i-MRD-negative kwiimeko ezi-5). Ixesha eliqhelekileyo lokulandela izigulane ezivavanywayo zaziyi-57 iintsuku (i-21 ukuya kwii-453 iintsuku). Kwi-3 - kunye ne-12-inyanga yokulandelelana, zonke izigulane ezisithoba kunye neekota ezintathu zezigulane zigcine ukuxolelwa.
Akukho kufa okunxulumene nonyango. Akukho namnye wabaguli owayenalo naliphi na inqanaba le-ICANS. I-22/33 (66%) izigulane zaphuhlisa i-CRS (i-61% ibakala 1/2 kunye ne-6% ibakala 3/4). Ngokucacileyo, akukho CRS ngaphezulu kwebakala 3 ekhoyo kwiqela le-lymphoma. I-cytopenia yeBakala 3/4 yayikhona kuzo zonke iimeko. Ixesha eliphakathi kwe-neutropenia yayiziintsuku ezisi-7. Ngosuku lwe-28, i-grade 3/4 i-neutropenia yabonwa kwizigulane ze-11/33 (33%) kunye ne-grade 3/4 thrombocytopenia yabonwa kwizigulane ze-7/33 (21%). Isigulane esi-1 kuphela (i-3%) esifuna ukungeniswa kwiyunithi yokunyamekela kakhulu, izigulane ze-2 (6%) zifuna inkxaso ye-vasopressor, izigulane ze-18 (55%) zifumene i-tolumab, kunye ne-median ye-1 (1-4) kunye ne-5 izigulane (15%) zafumana i-glucocorticoids. Ubude obuphakathi kokuhlala yayiziintsuku ezisi-8 (iintsuku ezisi-7-19).
Olu hlalutyo olubanzi lwedatha lubonisa ukuba i-NexCAR19 inokusebenza kakuhle kunye neprofayili yokhuseleko kwi-r/r B-cell malignancies. Ayinayo i-ICANS, ixesha elifutshane le-cytopenia, kunye nesiganeko esisezantsi sebanga le-3 / 4 CRS, okwenza kube yenye yezona mveliso zonyango ze-CD19 CAR T ezikhuselekileyo. Ichiza linceda ukuphucula ukusetyenziswa kwe-CAR T yonyango lweseli kwizifo ezahlukeneyo.
Kwi-ASH 2023, omnye umbhali unike ingxelo malunga nokusetyenziswa kwezixhobo zonyango kwisilingo se-1/2 kunye neendleko ezinxulumene nonyango lwe-NexCAR19. Iindleko eziqikelelwayo zemveliso ye-NexCAR19 kwizigulana ezingama-300 ngonyaka kwimodeli yemveliso esasazwe kwingingqi imalunga ne-15,000 yeedola ngesigulana ngasinye. Kwisibhedlele semfundo, i-avareji yeendleko zolawulo lweklinikhi (ukuya kulandelelwano lokugqibela) ngesigulane malunga ne-$ 4,400 (malunga ne-$ 4,000 ye-lymphoma kunye ne-$ 5,565 ye-B-ALL). Kuphela malunga ne-14 pesenti yezi ndleko zokuhlala esibhedlele.