nkhani

Chimeric antigen receptor (CAR) T cell therapy yakhala chithandizo chofunikira cha matenda obwera mobwerezabwereza kapena osagwirizana ndi hematological. Pakadali pano, pali zinthu zisanu ndi chimodzi za auto-CAR T zovomerezedwa kuti zigulitsidwe ku United States, pomwe pali zida zinayi za CAR-T zolembedwa ku China. Kuphatikiza apo, mitundu yosiyanasiyana ya autologous ndi allogeneic CAR-T ikupangidwa. Makampani opanga mankhwala omwe ali ndi mankhwala am'badwo wotsatirawa akuyesetsa kukonza magwiridwe antchito ndi chitetezo chamankhwala omwe alipo a hematological malignancies pomwe akulunjika zotupa zolimba. Ma cell a CAR T akupangidwanso kuti azichiza matenda omwe si owopsa monga matenda a autoimmune.

Mtengo wa CAR T ndi wokwera (pakali pano, mtengo wa CAR T/CAR ku United States uli pakati pa madola 370,000 ndi 530,000 aku US, ndipo zotsika mtengo za CAR-T ku China ndi 999,000 yuan/galimoto). Komanso, kuchuluka kwa zinthu zoopsa kwambiri (makamaka grade 3/4 immunoeffector cell-related neurotoxic syndrome [ICANS] ndi cytokine release syndrome [CRS]) zakhala chopinga chachikulu kwa anthu otsika - ndi apakati kuti alandire chithandizo cha cell cha CAR T.

Posachedwapa, Indian Institute of Technology Mumbai ndi Mumbai Tata Memorial Hospital mogwirizana kuti apange latsopano humanized CD19 CAR T mankhwala (NexCAR19), efficacy ndi ofanana ndi zinthu zomwe zilipo, koma chitetezo chabwino, chofunika kwambiri ndi chakuti mtengo ndi gawo limodzi mwa magawo khumi a United States mankhwala ofanana.

Monga njira zinayi mwamankhwala asanu ndi limodzi a CAR T omwe avomerezedwa ndi US Food and Drug Administration (FDA), NexCAR19 imayang'ananso CD19. Komabe, muzinthu zovomerezedwa ndi malonda ku United States, chidutswa cha antibody chomwe chili kumapeto kwa CAR nthawi zambiri chimachokera ku mbewa, zomwe zimalepheretsa kulimbikira kwake chifukwa chitetezo cha mthupi chimazindikira kuti ndi chachilendo ndipo pamapeto pake chimachichotsa. NexCAR19 imawonjezera puloteni yamunthu kumapeto kwa antibody ya mbewa.

Kafukufuku wa ma laboratory asonyeza kuti ntchito ya antitumor ya Magalimoto "opangidwa ndi anthu" ikufanana ndi magalimoto opangidwa ndi murine, koma ndi zochepa zomwe zimapangidwira kupanga cytokine. Zotsatira zake, odwala amakhala ndi chiopsezo chochepa chokhala ndi CRS yoopsa atalandira chithandizo cha CAR T, zomwe zikutanthauza kuti chitetezo chimakula.

Pofuna kuchepetsa ndalama, gulu lofufuza la NexCAR19 linapanga, kuyesa ndi kupanga mankhwala onse ku India, kumene ntchito ndi yotsika mtengo kusiyana ndi mayiko omwe amapeza ndalama zambiri.
Kuti apangitse CAR kukhala ma T cell, ofufuza nthawi zambiri amagwiritsa ntchito ma lentivirus, koma ma lentivirus ndi okwera mtengo. Ku United States, kugula ma lentiviral vector okwanira oyeserera anthu 50 kungawononge $800,000. Asayansi pakampani yopanga NexCAR19 adapanga okha galimoto yobweretsera majini, ndikuchepetsa kwambiri ndalama. Kuphatikiza apo, gulu la kafukufuku waku India lapeza njira yotsika mtengo yopangira ma cell opangidwa mochuluka, kupewa kugwiritsa ntchito makina okwera mtengo. NexCAR19 pakadali pano imawononga pafupifupi $48,000 pagawo lililonse, kapena gawo limodzi mwa magawo khumi a mtengo wa mnzake waku US. Malinga ndi mkulu wa kampani yomwe idapanga NexCAR19, mtengo wazinthuzo ukuyembekezeka kuchepetsedwanso mtsogolo.

Pomaliza, chitetezo chokhazikika cha mankhwalawa poyerekeza ndi zinthu zina zovomerezeka ndi FDA zikutanthauza kuti odwala ambiri safunikira kuchira m'chipinda cha odwala kwambiri atalandira chithandizo, kuchepetsanso ndalama kwa odwala.

Hasmukh Jain, dokotala wa oncologist ku Tata Memorial Center ku Mumbai, adanenanso kusanthula kophatikizana kwa mayeso a Gawo 1 ndi Gawo 2 la NexCAR19 pamsonkhano wapachaka wa American Society of Hematology (ASH) 2023.
Mayesero a Phase 1 (n = 10) anali mayesero apakati omwe adapangidwa kuti ayese chitetezo cha 1 × 107 ku 5 × 109 CAR T mlingo wa maselo a CAR T kwa odwala omwe abwereranso / okana kufalitsa B-cell lymphoma (r / r DLBCL), kusintha follicular lymphoma (tFL), ndi primary mediastinal lalikulu B-cell lymphoma (PMB). Mayesero a Phase 2 (n = 50) anali mkono umodzi, kafukufuku wambirimbiri omwe analembetsa odwala ≥15 azaka za r/r B-cell malignancies, kuphatikizapo amphamvu ndi zamatsenga B-cell lymphomas ndi acute lymphoblastic leukemia. Odwala anapatsidwa NexCAR19 patatha masiku awiri atalandira fludarabine kuphatikiza cyclophosphamide. Mlingo wofunikira unali ≥5 × 107/kg maselo a CAR T. Mapeto oyambilira anali kuyankha kwacholinga (ORR), ndipo zomaliza zachiwiri zidaphatikizapo nthawi yakuyankha, zochitika zoyipa, kupulumuka kwaulere (PFS), ndi kupulumuka konse (OS).
Odwala 47 adalandira chithandizo cha NexCAR19, 43 mwa iwo omwe adalandira mlingo womwe akuwafunira. Odwala 33/43 (78%) adamaliza kuwunika kwamasiku 28 pambuyo pa kulowetsedwa. ORR anali 70% (23/33), pomwe 58% (19/33) adapeza yankho lathunthu (CR). Mu gulu la lymphoma, ORR inali 71% (17/24) ndipo CR inali 54% (13/24). Mu gulu la khansa ya m'magazi, mlingo wa CR unali 66% (6/9, MRD-negative muzochitika zisanu). Nthawi yotsatiridwa yapakatikati ya odwala omwe amawunikiridwa inali masiku 57 (masiku 21 mpaka 453). Pakutsata kwa miyezi 3 - ndi 12, odwala onse asanu ndi anayi ndi atatu mwa atatu mwa odwalawa adapitirizabe kukhululukidwa.
Panalibe imfa zokhudzana ndi chithandizo. Palibe odwala omwe anali ndi mulingo wa ICANS. Odwala 22/33 (66%) adapanga CRS (61% kalasi 1/2 ndi 6% kalasi 3/4). Makamaka, palibe CRS pamwamba pa giredi 3 yomwe inalipo mu gulu la lymphoma. Gulu la 3/4 cytopenia linalipo nthawi zonse. Nthawi yapakati ya neutropenia inali masiku 7. Patsiku la 28, grade 3/4 neutropenia idawonedwa mwa odwala 11/33 (33%) ndi grade 3/4 thrombocytopenia idawonedwa mwa odwala 7/33 (21%). Wodwala m'modzi yekha (3%) amafunikira kulandilidwa kuchipinda chosamalira odwala kwambiri, odwala 2 (6%) amafunikira thandizo la vasopressor, odwala 18 (55%) adalandira tolumab, ndi wapakati wa 1 (1-4) ndi odwala 5 (15%) adalandira glucocorticoids. Kutalika kwapakati kunali masiku 8 (masiku 7-19).
Kusanthula kwatsatanetsatane kumeneku kukuwonetsa kuti NexCAR19 ili ndi mphamvu yabwino komanso mbiri yachitetezo mu r/r B-cell malignancies. Ilibe ICANS, nthawi yayifupi ya cytopenia, komanso kuchepa kwa giredi 3/4 CRS, ndikupangitsa kuti ikhale imodzi mwazinthu zotetezeka kwambiri za CD19 CAR T cell therapy. Mankhwalawa amathandiza kupititsa patsogolo kugwiritsa ntchito chithandizo cha CAR T cell mu matenda osiyanasiyana.
Pa ASH 2023, wolemba wina adanenanso za kugwiritsa ntchito zithandizo zamankhwala muyeso la gawo 1/2 komanso mtengo wokhudzana ndi chithandizo cha NexCAR19. Mtengo woyerekeza wa NexCAR19 pa odwala 300 pachaka mumayendedwe obalalika am'deralo ndi pafupifupi $15,000 pa wodwala aliyense. Pachipatala cha maphunziro, mtengo wapakati wa kasamalidwe kachipatala (mpaka kutsata komaliza) pa wodwala aliyense ndi pafupifupi $4,400 (pafupifupi $4,000 ya lymphoma ndi $5,565 ya B-ALL). Pafupifupi 14 peresenti yokha ya ndalamazi ndi zogonera kuchipatala.