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Chimeric antigen receptor (CAR) T cell therapy tau dhau los ua ib qho kev kho mob tseem ceeb rau kev rov ua dua lossis refractory hematological malignancies. Tam sim no, muaj rau 6 auto-CAR T cov khoom tau pom zoo rau kev ua lag luam hauv Tebchaws Meskas, thaum muaj plaub CAR-T cov khoom lag luam teev nyob hauv Suav teb. Tsis tas li ntawd, ntau yam khoom siv autologous thiab allogeneic CAR-T tab tom tsim. Cov tuam txhab tshuaj nrog cov khoom lag luam tiam tom ntej no tau ua haujlwm los txhim kho kev ua tau zoo thiab kev nyab xeeb ntawm cov kev kho mob uas twb muaj lawm rau hematological malignancies thaum tsom cov qog nqaij hlav. CAR T hlwb tseem raug tsim los kho cov kab mob tsis zoo xws li kab mob autoimmune.

Tus nqi ntawm CAR T yog siab (tam sim no, tus nqi ntawm CAR T / CAR hauv Tebchaws Meskas yog nyob nruab nrab ntawm 370,000 thiab 530,000 US las, thiab cov khoom siv CAR-T pheej yig tshaj hauv Suav teb yog 999,000 yuan / tsheb). Ntxiv mus, qhov tshwm sim ntawm cov tshuaj lom neeg mob hnyav (tshwj xeeb yog qib 3/4 immunoeffector cell-related neurotoxic syndrome [ICANS] thiab cytokine release syndrome [CRS]) tau dhau los ua ib qho teeb meem loj rau cov neeg tau nyiaj tsawg thiab nruab nrab kom tau txais CAR T cell kho.

Tsis ntev los no, Indian Institute of Technology Mumbai thiab Mumbai Tata Memorial Tsev Kho Mob hauv kev koom tes los tsim ib qho tshiab humanized CD19 CAR T khoom (NexCAR19), nws cov txiaj ntsig zoo ib yam li cov khoom uas twb muaj lawm, tab sis kev nyab xeeb zoo dua, qhov tseem ceeb tshaj plaws yog tus nqi tsuas yog ib feem kaum ntawm Tebchaws Meskas cov khoom zoo sib xws.

Ib yam li plaub ntawm rau CAR T kho tau pom zoo los ntawm US Food and Drug Administration (FDA), NexCAR19 kuj yog hom phiaj CD19. Txawm li cas los xij, hauv cov khoom lag luam pom zoo hauv Tebchaws Meskas, cov tshuaj tiv thaiv kab mob hauv qhov kawg ntawm CAR feem ntau yog los ntawm cov nas, uas txwv nws qhov kev pheej hmoo vim tias lub cev tiv thaiv kab mob lees paub nws txawv teb chaws thiab nws thiaj li tshem tawm. NexCAR19 ntxiv cov protein tib neeg mus rau qhov kawg ntawm nas antibody.

Cov kev tshawb fawb hauv chav kuaj pom tau hais tias cov kev ua haujlwm antitumor ntawm "tib neeg" Tsheb yog piv rau cov tsheb uas tau los ntawm murine, tab sis nrog qis qis ntawm kev tsim cov cytokine. Raws li qhov tshwm sim, cov neeg mob muaj qhov txo qis ntawm kev tsim mob hnyav CRS tom qab tau txais CAR T kho, uas txhais tau tias kev nyab xeeb tau zoo dua.

Txhawm rau kom cov nqi qis, NexCAR19' pab pawg tshawb fawb tau tsim, sim thiab tsim cov khoom lag luam hauv Is Nrias teb, qhov chaw ua haujlwm pheej yig dua hauv cov tebchaws tau nyiaj ntau.
Txhawm rau qhia CAR rau hauv T hlwb, cov kws tshawb fawb feem ntau siv lentiviruses, tab sis lentiviruses kim. Hauv Tebchaws Meskas, kev yuav cov kab mob lentiviral txaus rau 50 tus neeg sim tuaj yeem raug nqi $ 800,000. Cov kws tshawb fawb ntawm lub tuam txhab kev txhim kho NexCAR19 tau tsim cov noob xa tsheb rau lawv tus kheej, txo cov nqi ntau heev. Tsis tas li ntawd, pab pawg tshawb fawb Indian tau pom txoj hauv kev pheej yig dua los tsim cov tshuab tsim hluav taws xob ntau, zam kev siv cov tshuab siv hluav taws xob kim. Lub NexCAR19 tam sim no raug nqi txog $ 48,000 toj ib chav, lossis ib feem kaum ntawm tus nqi ntawm nws cov neeg Asmeskas. Raws li lub taub hau ntawm lub tuam txhab uas tsim NexCAR19, tus nqi ntawm cov khoom xav tias yuav raug txo ntxiv rau yav tom ntej.

Thaum kawg, kev txhim kho kev nyab xeeb ntawm kev kho mob no piv rau lwm cov khoom lag luam pom zoo los ntawm FDA txhais tau hais tias cov neeg mob feem ntau tsis tas yuav rov qab los hauv chav saib xyuas mob hnyav tom qab tau txais kev kho mob, txo nqi ntxiv rau cov neeg mob.

Hasmukh Jain, kws kho mob oncologist ntawm Tata Memorial Center hauv Mumbai, tau tshaj tawm cov ntaub ntawv sib koom ua ke ntawm Theem 1 thiab Theem 2 kev sim ntawm NexCAR19 ntawm American Society of Hematology (ASH) 2023 lub rooj sib tham txhua xyoo.
Theem 1 mus sib hais (n=10) yog ib qho kev sim ib leeg tsim los kuaj kev nyab xeeb ntawm 1 × 107 rau 5 × 109 CAR T cell koob tshuaj rau cov neeg mob uas rov qab los / refractory diffuse loj B-cell lymphoma (r / r DLBCL), hloov pauv follicular lymphoma (tFL), thiab thawj mediastinal loj B-CL lymphoma ). Theem 2 mus sib hais (n=50) yog ib leeg-caj npab, multicenter txoj kev tshawb fawb uas cuv npe cov neeg mob ≥15 xyoo nrog r/r B-cell malignancies, nrog rau aggressive thiab occult B-cell lymphomas thiab mob lymphoblastic leukemia. Cov neeg mob tau muab NexCAR19 ob hnub tom qab tau txais fludarabine ntxiv rau cyclophosphamide. Lub hom phiaj koob tshuaj yog ≥5 × 107 / kg CAR T hlwb. Lub ntsiab lus kawg yog lub hom phiaj teb tus nqi (ORR), thiab cov ntsiab lus thib ob suav nrog lub sijhawm teb, cov xwm txheej tsis zoo, kev muaj sia nyob tsis muaj sia nyob (PFS), thiab kev ciaj sia tag nrho (OS).
Tag nrho ntawm 47 tus neeg mob tau kho nrog NexCAR19, 43 ntawm cov neeg tau txais lub hom phiaj koob tshuaj. Tag nrho ntawm 33/43 (78%) cov neeg mob ua tiav 28-hnub kev ntsuas tom qab txhaj tshuaj. ORR yog 70% (23/33), uas 58% (19/33) ua tiav cov lus teb (CR). Hauv cov qog ntshav qog ntshav, ORR yog 71% (17/24) thiab CR yog 54% (13/24). Hauv cov kab mob leukemia, CR tus nqi yog 66% (6/9, MRD-tsis zoo hauv 5 kis). Lub sijhawm nruab nrab ntawm kev soj ntsuam rau cov neeg mob ntsuas tau yog 57 hnub (21 txog 453 hnub). Thaum 3 - thiab 12-hli kev soj ntsuam, tag nrho cuaj tus neeg mob thiab peb-plaub ntawm cov neeg mob tau tswj xyuas kev tshem tawm.
Tsis muaj kev kho mob ntsig txog kev tuag. Tsis muaj ib tus neeg mob twg muaj qib ntawm ICANS. 22/33 (66%) cov neeg mob tsim CRS (61% qib 1/2 thiab 6% qib 3/4). Qhov tseem ceeb, tsis muaj CRS saum qib 3 muaj nyob hauv cov qog ntshav qog ntshav. Qib 3/4 cytopenia muaj nyob rau hauv txhua kis. Lub sijhawm nruab nrab ntawm neutropenia yog 7 hnub. Hnub 28, qib 3/4 neutropenia tau pom hauv 11/33 cov neeg mob (33%) thiab qib 3/4 thrombocytopenia tau pom hauv 7/33 cov neeg mob (21%). Tsuas yog 1 tus neeg mob (3%) yuav tsum tau nkag mus rau chav saib xyuas mob hnyav, 2 tus neeg mob (6%) xav tau kev txhawb nqa vasopressor, 18 tus neeg mob (55%) tau txais tolumab, nrog qhov nruab nrab ntawm 1 (1-4) thiab 5 tus neeg mob (15%) tau txais glucocorticoids. Qhov nruab nrab ntev ntawm kev nyob yog 8 hnub (7-19 hnub).
Qhov kev ntsuam xyuas ntawm cov ntaub ntawv no qhia tau hais tias NexCAR19 muaj qhov ua tau zoo thiab kev nyab xeeb profile hauv r / r B-cell malignancies. Nws tsis muaj ICANS, lub sijhawm luv ntawm cytopenia, thiab qis dua ntawm qib 3/4 CRS, ua rau nws yog ib qho kev nyab xeeb tshaj plaws CD19 CAR T cell kho cov khoom. Cov tshuaj pab txhim kho qhov yooj yim ntawm kev siv CAR T cell kho nyob rau hauv ntau yam kab mob.
Ntawm ASH 2023, lwm tus kws sau ntawv tau tshaj tawm txog kev siv cov peev txheej kho mob hauv theem 1/2 sim thiab cov nqi cuam tshuam nrog NexCAR19 kev kho mob. Tus nqi tsim khoom kwv yees ntawm NexCAR19 ntawm 300 tus neeg mob hauv ib xyoos hauv cov qauv tsim tawm hauv cheeb tsam yog kwv yees li $ 15,000 rau ib tus neeg mob. Hauv tsev kho mob kev kawm, tus nqi nruab nrab ntawm kev tswj xyuas kev kho mob (mus txog qhov kev soj ntsuam zaum kawg) rau ib tus neeg mob yog li $4,400 (kwv yees $ 4,000 rau lymphoma thiab $ 5,565 rau B-ALL). Tsuas yog li ntawm 14 feem pua ​​​​ntawm cov nqi no yog rau kev nyob hauv tsev kho mob.