Chimeric antigen receptor (CAR) T cell therapy yave yakakosha kurapwa kune inodzokororwa kana refractory hematological malignancies. Parizvino, kune zvitanhatu zveauto-CAR T zvigadzirwa zvakatenderwa kumusika muUnited States, nepo kune ina CAR-T zvigadzirwa zvakanyorwa kuChina. Mukuwedzera, zvakasiyana-siyana zve autologous uye allogeneic CAR-T zvigadzirwa zviri pasi pekuvandudzwa. Makambani emishonga ane zvigadzirwa zvechizvarwa chinotevera ari kushanda kuti avandudze kushanda uye kuchengetedzeka kwemishonga iripo yehematological malignancies ichinangana nemamota akasimba. Masero eCAR T ari kugadzirwa zvakare kuti arape zvirwere zvisingaite sezvirwere zvinotapurira muviri.
Mutengo weCAR T wakakwira (parizvino, mutengo weCAR T/CAR muUnited States uri pakati pe370,000 ne530,000 US madhora, uye zvakachipa zveCAR-T zvigadzirwa muChina i999,000 yuan/mota). Uyezve, kuwanda kwemaitiro ehupfu hwakanyanya (kunyanya giredhi 3/4 immunoeffector cell-related neurotoxic syndrome [ICANS] uye cytokine release syndrome [CRS]) chave chipingamupinyi chikuru kuvanhu vashoma - uye vepakati kuti vawane CAR T cell therapy.
Munguva pfupi yapfuura, Indian Institute of Technology Mumbai neMumbai Tata Memorial Hospital mukubatana kugadzira chigadzirwa chitsva cheCD19 CAR T (NexCAR19), kushanda kwayo kwakafanana nezvigadzirwa zviripo, asi kuchengeteka kuri nani, chinonyanya kukosha ndechekuti mutengo unongova chikamu chimwe chete chegumi cheUnited States zvigadzirwa zvakafanana.
Senge ina pamatanhatu eCAR T marapirwo akatenderwa neUS Food and Drug Administration (FDA), NexCAR19 zvakare inotarisa CD19. Zvakadaro, muzvigadzirwa zvinotenderwa nekutengeserana muUnited States, chipande chekudzivirira utachiona chiri kumagumo eCAR chinowanzobva kumakonzo, izvo zvinodzikisira kushingirira kwacho nekuti masoja emuviri anozviona seyekunze uye anozopedzisira azvibvisa. NexCAR19 inowedzera puroteni yemunhu kumagumo embeva antibody.
Zvidzidzo zverabhoritari zvakaratidza kuti basa reantitumor re "vanhu" Motokari inofananidzwa nemotokari yakagadzirwa nemurine, asi nemazinga akaderera ekugadzirwa kwe cytokine. Nekuda kweizvozvo, varwere vane njodzi yakadzikira yekukudziridza CRS yakaoma mushure mekugamuchira CAR T kurapwa, zvinoreva kuti kuchengetedzwa kunovandudzwa.
Kuti mutengo udzike, boka rekutsvagisa reNexCAR19 rakagadzira, rakaedza nekugadzira chigadzirwa chose muIndia, uko kushanda kwakachipa pane munyika dzine mari yakawanda.
Kuunza CAR muT masero, vaongorori vanowanzo shandisa lentiviruses, asi lentiviruses inodhura. MuUnited States, kutenga malentiviral vectors akakwana ekuedza kwevanhu makumi mashanu kunogona kuita madhora mazana masere ezviuru. Masayendisiti kukambani yekusimudzira yeNexCAR19 vakagadzira mota yekutakura majini ivo pachavo, vachidzikisa zvakanyanya mitengo. Pamusoro pezvo, timu yekuIndia yekutsvagisa yakawana nzira yakachipa yekugadzira masero akagadzirwa, kudzivirira kushandiswa kwemichina inodhura. Iyo NexCAR19 parizvino inoita madhora zviuru makumi mana nemasere payuniti, kana chegumi chemutengo wemumwe wayo wekuUS. Sekureva kwemukuru wekambani yakagadzira NexCAR19, mutengo wechigadzirwa unotarisirwa kudzikiswa mune ramangwana.
Chekupedzisira, kuchengetedzeka kwakavandudzwa kwekurapa uku kana zvichienzaniswa nezvimwe zvakatenderwa neFDA-zvinoreva kuti varwere vazhinji havadi kupora muchikamu chekuchengetedza kwakanyanya mushure mekugamuchira kurapwa, zvichiwedzera kudzikisira mitengo yevarwere.
Hasmukh Jain, chiremba oncologist paTata Memorial Center muMumbai, akashuma ongororo yakasanganiswa yeData 1 uye Phase 2 miedzo yeNexCAR19 pamusangano wepagore weAmerican Society of Hematology (ASH) 2023.
The Phase 1 trial (n = 10) yaiva imwe-center test yakagadzirirwa kuedza kuchengetedzwa kwe1 × 107 kusvika 5 × 109 CAR T cell doses muvarwere vane relapsed / refractory diffuse yakakura B-cell lymphoma (r / r DLBCL), kushandura follicular lymphoma (tFL), uye primary mediastinal hombe B-cell lymphoma (PMB). Chiyero cheChikamu chechipiri (n = 50) chaive chidzidzo cheruoko rumwe, chidzidzo chakawanda chakanyoresa varwere ≥makore gumi nemashanu ezera vane r/r B-cell malignancies, kusanganisira ane hutsinye uye occult B-cell lymphomas uye acute lymphoblastic leukemia. Varwere vakapihwa NexCAR19 mazuva maviri mushure mekugamuchira fludarabine pamwe necyclophosphamide. Chiyero chakanangwa chaive ≥5 × 107/kg CAR T masero. Mhedzisiro yekutanga yaive yechinangwa chekupindura mwero (ORR), uye magumo ekupedzisira aisanganisira nguva yekupindura, zviitiko zvakashata, kufambira mberi-kusina kupona (PFS), uye kupona kwese (OS).
Huwandu hwevarwere makumi mana nevanomwe vakarapwa neNexCAR19, makumi mana nevatatu vavo vakagamuchira iyo yaitarisirwa dosi. Huwandu hwevarwere ve33/43 (78%) vakapedza 28-day post-infusion assessment. ORR yaive 70% (23/33), iyo 58% (19/33) yakawana mhinduro yakakwana (CR). Muchikwata che lymphoma, ORR yaiva 71% (17/24) uye CR yaiva 54% (13/24). Muchikwata cheleukemia, chiyero cheCR chaiva 66% (6/9, MRD-negative mu5 kesi). Iyo yepakati yekutevera nguva yevarwere vanoyerwa yaive mazuva makumi mashanu nenomwe (21 kusvika 453 mazuva). Pa3 - uye 12-mwedzi yekutevera, varwere vapfumbamwe vose uye zvikamu zvitatu zvevarwere vakachengetedza kuregererwa.
Pakanga pasina nzufu dzine chekuita nekurapa. Hapana wevarwere aive nechero level yeICANS. 22/33 (66%) varwere vakagadzira CRS (61% giredhi 1/2 uye 6% giredhi 3/4). Zvikuru, hapana CRS pamusoro pegiredhi 3 yaivepo mune lymphoma cohort. Giredhi 3/4 cytopenia yaivepo mune zvese zviitiko. Nguva yepakati neutropenia yaive mazuva manomwe. Pazuva 28, giredhi 3/4 neutropenia yakaonekwa mune 11/33 varwere (33%) uye giredhi 3/4 thrombocytopenia yakaonekwa mune 7/33 varwere (21%). Murwere 1 chete (3%) aidiwa kuti apinde mukamuri yekuchengeta zvakanyanya, varwere ve2 (6%) vaida rubatsiro rwevasopressor, varwere gumi nemasere (55%) vakagamuchira tolumab, nepakati pe1 (1-4) uye 5 varwere (15%) vakagamuchira glucocorticoids. Hurefu hwepakati hwekugara hwaive mazuva masere (7-19 mazuva).
Uku kuwongorora kwakadzama kwedata kunoratidza kuti NexCAR19 ine basa rakanaka uye chengetedzo mbiri mu r/r B-cell malignancies. Iyo haina ICANS, ipfupi nguva yecytopenia, uye yakaderera chiitiko chegiredhi 3/4 CRS, ichiiita imwe yeakachengeteka CD19 CAR T cell therapy zvigadzirwa. Mushonga unobatsira kuvandudza kushandiswa kweCAR T cell therapy muzvirwere zvakasiyana-siyana.
PaASH 2023, mumwe munyori akataura nezvekushandiswa kwezviwanikwa zvekurapa muyedzo yechikamu 1/2 uye mutengo une chekuita neNexCAR19 kurapwa. Mari inofungidzirwa yekugadzira yeNexCAR19 pavarwere mazana matatu pagore mune yedunhu yakaparadzirwa modhi yekugadzira inoita zviuru gumi nezvishanu zvemadhora pamurwere. Pachipatara chedzidzo, avhareji yemutengo wekutarisirwa kwekiriniki (kusvika pakutevera kwekupedzisira) pamurwere ingangoita $4,400 (inenge $4,000 yelymphoma uye $5,565 yeB-ALL). Zvikamu gumi nezvina kubva muzana chete zvemitengo iyi ndezvekugara muchipatara.
Nguva yekutumira: Kubvumbi-07-2024