'Mele oa hau o na le mefuta e sa tšoaneng ea lisele tse tšoeu tsa mali Mofuta o mong, lymphocyte , o na le mefuta e 'meli e meholo: B-cell le T-cell. Mona, tabeng ea phekolo ea kankere, re ameha haholo ka mofuta oo oa bobeli, T-cell.
Kahoo, phekolo ea T-cell ea chimeric antigen receptor (CAR) ke efe? Ka bokhutšoaane, ke phekolo ea mantlha ea hore liphatsa tsa lefutso li fetole li-T-cell tse molemo ho lemoha le ho hlasela kankere kahare.
Ke e 'ngoe ea mefuta e mengata ea li-immunotherapies e hlahlojoang. Haeba u thahasella theknoloji ea baeloji ka mor'a mofuta ona oa phekolo, tlhaloso e qaqileng ea kamoo CAR T-cell therapy e sebetsang kateng e fana ka maikutlo.
Mona, ho tsepamisitsoe maikutlo ho tsena "mekhoa ea phekolo ea bophelo" le mekhoa e meng ea phekolo e sebetsang ka li-T-lisele-mele ea 'mele ea' mele ea hau ea ho itšireletsa mafung-ho loantša kankere ka ho lemoha le ho hlasela lisele tsa 'mele. Litsela tse ling tsa kankere tse sebelisang lisele tsa T-mele tsa hau li amohetsoe, 'me tse ling li lebeletsoe hore li latele kapele.
Ho etsa Tsela e Nang le Litlhare Tse Thehiloeng ho 'mele
Ho senya tsamaiso ea 'mele ea' mele ea hau ea ho itšireletsa mafung ho leka ho loantša kankere hase ntho e ncha ka ho feletseng. Ha e le hantle, ho na le mehlala ea phekolo e joalo (e lebisang tlhokomelong ea T-cell) e seng e fumane tumello ea FDA: sipuleucel-T, ipilimumab, le blinatumomab, ka mohlala.
Phekolo | Mofuta oa Kankere | Tsamaiso ea Ts'ebetso ea 'mele |
Sipuleucel-T (Tlatsetsa) | Maemong a mang a kankere e tsoetseng pele ea prostate |
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Ipilimumab (Yervoy) | Maemong a mang a lefu la kankere ea letlalo la malanoma |
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Blinatumomab (Blincyto) | Ho khutlela morao kapa ho hanyetsa B-cell precursor acute lymphoblastic leukemia (ALL) ho batho ba baholo le bana |
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E 'ngoe ea tsona, sululeucel-T, e utloahala hantle joaloka phekolo ea T-cell ea CAR hobane e sebelisa lisele tsa hau tsa' mele tse qalang ho bokelloa ho tsoa mali maling 'me li sebetsanoa le laboratori; li ts'ebetsoe 'me li entsoe hore li amohelehe haholoanyane lisele tsa' mele, ebe li kenngoa ka mali maling.
Sipuleucel-T e nkoa e le "ente ea autologous" kapa "autologous cellular immunotherapy", leha ho le joalo, e seng phekolo ea CAR T-cell ho tloha ha lisele tsa 'mele tsa' mele li koetlisoa ho arabela, ho e-na le hore li be le liphatsa tsa lefutso ho arabela lisele tsa 'mele .
Li-immune checkpoint inhibitors tse kang ipilimumab (ka holimo) li sebetsa ka mekhoa e fapaneng ea tsamaiso ea 'mele oa hau ea' mele ea ho "sebelisa li-brake," kapa "ho otla khase" ea 'mele oa' mele, ho leka ho sebelisa tšireletso ea 'mele ea hao khahlanong le kankere. Ipilimumab ke mohlala o le mong feela oa phekolo e sebetsang ka tsela ena. Mohlala o mong oa thibeliso ea 'mele oa ho itšireletsa mafung ke inembitor (pembrolizumab (Keytruda), e leng sepheo sa "switch on-off" bakeng sa T-cell, e bitsoang PD-1.
Litšebeletso tsa Meriana ea CAR-T: 'Nete "Lithethefatsi Tse Phelang"
Leha ho le joalo, lihlahisoa tsa lik'hemik'hale tsa CAR-T, ke ka ho hlaka hore li entsoe ka ho khetheha. L-lisele li tlosoa 'meleng oa hao, li hlophisitsoe ka liphatsa tsa lefutso ho lemoha le ho bolaea lisele tsa' mele, ebe li boela li hlahisoa e le phekolo e phelang. Lisele li ka etsoa 'me li hōlileng ka matsatsi a seng makae tse 21' me joale li kenngoa ka mali.
CAR T-cell therapy hase mofuta oa phekolo o ka sebelisoang pele o leka mefuta e meng ea phekolo-bonyane, eseng hona joale. Lithethefatsi tsena tse ncha li atisa ho hlaha ka lebaka la bobe ba hore, bakeng sa bakuli ba nang le mafu a morao-rao, mekhoa ea kankere ea setso, ho akarelletsa le ho buuoa, chemotherapy, le phekolo ea mahlaseli, hangata e fana ka katleho e fokolang.
Kahoo ho fihlela joale, litlhare tsa CAR-T li fumaneha feela ho bakuli ba ngolisitseng litekong tsa meriana, kaha mekhoa ea phekolo e nkoa e le lipatlisiso United States, empa sena se ka fetoha haufinyane. Litšebeletso tsa lisele tsa CAR-T li ka fetoha FDA tse amohelehang le tse fumanehang ka ntle ho liteko tsa kliniki hang ka 2017-2018.
Lethathamo le lekhutšoanyane la likhetho tse kholo tse ntseng li ntlafatsoa ke lingaka.
CTL019 (tisagenlecleucel) ke Novartis
CTL019 ke CD19-e khethehileng chimeric antigen receptor (CAR) e thehiloeng ho T-cell therapy.
A re qale ka ho hlakola polelo e fetileng: CD19 ke molek'hule lisele tse ling tsa 'mele tsa' mele tse bitsoang B-cell, 'me lisele tsena li ka ba mohloli oa mefuta e meng ea leukemia le lymphoma .
Tekanyetso e le 'ngoe ea CTL019 e tliselitse ho fokotsa nako e telele' me mohlomong e phekola (ha re tsebe) ho bakuli ba bangata ba lithuto tse neng li tsoa mefuteng ea phekolo.
Mona ke ho fokotseha ha maloetse ao CTL019 e ntseng e nkoa hona joale:
- CTL019 e fumane FDA Breakthrough Therapy bakeng sa ho phekola bakuli ba baholo ba nang le ts'oaetso e khutšoanyane ea B-cell lymphoma (DLBCL). (Ka tloaelo li-lymphomas li aroloa ka lihlopha tse peli tsa motheo: Hodgkin le bao e seng Hodgkin. Mofuta o tloaelehileng oa bao e seng Hodgkin lymphoma ke DLBCL).
- CTL019 e boetse e ea ho amoheloa bakeng sa phekolo ea bana ba khutlisitsoeng morao kapa ba nang le ts'oaetso le bacha ba baholo ba nang le B-cell acute lymphoblastic leukemia (ALL).
CTL019 e amohetse tumello e lekaneng (10-0) ea tumello e tsoang ho Komiti ea Boeletsi ba Litlhare tsa Oncologic ea FDA, e bolelang hore lintho li shebahala li tšepisa ho amoheloa ka ho feletseng. Novartis e ikemiselitse hore CTL019 e amohelehe bakeng sa phekolo ea ho khutlisetsoa morao kapa ho hanyetsa B-cell ALL ho bakuli ba bakuli le bacha ba baholo. Lefuemia ke kankere ea palo ea bana, 'me ALL ke mofuta o tloaelehileng ka ho fetisisa, o ikarabellang bakeng sa likarolo tse 25 tsa kankere ea bongoaneng. Ho na le mefuta e sa tšoaneng ea ALL, ho akarelletsa le B-cell ALL le T-cell ALL, mme li-subtypes ka hare li ka 'na tsa nka li-prognoses tsa tsona.
Hona joale CTL019 e ntse e hlahlojoa pele 'me tumello e nakong e tla etsa hore e be eona ea pele ea lefuba la CAR-T e ka fumanoang. Kalafo ea T-cell ea CAR e tla fumaneha feela bakeng sa palo e nyenyane ea bana le ba baholo ba nang le kankere ea mali ha ba arabele tlhokomelo e tloaelehileng. Bakuli bana ba atisa ho hlaseloa, empa ka tekong ea bohlokoa ea ho hlahloba kalafo linaheng tse ka bang 12, karolo ea 83 lekholong ea bakuli e ile ea e-ba kotsing. Selemo hamorao, tse peli ho tse tharo li ile tsa lula joalo.
Hobane phekolo eo e senya lisele feela tsa B le likokoana-hloko, le mefuta e fapaneng ea likokoana-hloko, bakuli ba hloka phekolo ho ba sireletsa tšoaetsong. Ba fumana tšoaetso ea immune globulins likhoeli tse seng kae feela e le tekanyo ea ho itšireletsa.
E 'ngoe ea litla-morao tse tloaelehileng e bitsoa cytokine release syndrome, e bakang feberu e matla le matšoao a kang a mafu a maemong a mang a ka ba kotsi haholo hoo mokuli a qetellang a le tlhokomelo e matla. Ntho e 'ngoe e tšoenyang e kholo ke lefu la neurotoxicity, e ka fella ka pherekano ea nakoana kapa e ka' nang ea baka ho ruruha ha boko.
Ho leka ho netefatsa tšireletso ea mokuli, Novartis ha e rere sehlahisoa se tloaelehileng, se nang le lithethefatsi se sutumelitsoeng ka hohle le ka mabifi kamoo ho ka khonehang. Khamphani e tla khetholla litsi tsa bongaka tse 30 ho ea ho tse 35 ho fana ka phekolo. Ba bangata ba bona ba ile ba kenya letsoho tekong ea bongaka, 'me bohle ba fumane koetliso e pharaletseng.
Axicabtagene Ciloleucel ke Kite Pharma
Ho tloha Santa Monica, California, Kite Pharma ke k'hamphani e lebisang tlhokomelo ea CAR le T-cell receptor e entsoeng ka theknoloji ea sele. Kite e hlahisa therapy ea CAR T-cell e bitsoang axicabtagene ciloleucel, eo hona joale e leng tlas'a tlhahlobo ea pele ho US bakeng sa phekolo ea bakuli ba nang le mabifi a se nang Hodgkin lymphoma (NHL). Bakuli ba nang le NHL e nang le mabifi ba hlasetsoeng ka bohale ba hlaheloa ke polelo e hlabang ka karolo ea 50 feela ea monyetla oa ho phela likhoeli tse tšeletseng. Sena se totobatsa tlhokahalo e potlakileng ea bongaka bakeng sa bakuli bana.
Joaloka CTL019, axicabtagene ciloleel e boetse e hlasela antigen CD19, protheine e hlalositsoeng seleng ea B-cell lymphomas le leukemias. Lisele tsa T tsa mokuli li ikemiselitse ho hlalosa mokelikeli oa anti-immergen (CAR) bakeng sa ho lebisa antigen CD19.
Tlhahisong ea lithethefatsi le ts'ebeliso ea tumello, axicabtagene ciloleucel e na le boemo bo tšoanang le ba CTL019, ka hore ho lebisitsoe tlhokomelo ho lipolelo tse nang le B-cell, empa B cell ALL ha e bonahale e le karolo ea tsoelo-pele ea eona ea meriana ka nako ena.
Mona ho theoha ha maloetse ao axicabtagene ciloleel e nkoa e le hona joale:
- Tšebeliso ea phekolo ea lefuli ea Axicabtagene e entsoe ka boemo bo botle ba B-cell lymphoma (DLBCL), transformed follicular lymphoma (TFL), le methapo e ka sehloohong ea B-cell lymphoma (PMBCL) ka tšehetso ea tsamaiso ea US FDA le Priority Medicines (PRIME) DLBCL ho EU.
Ho amoheloa e le Thethrough Breakthrough ka FDA ho tšehetsoa ke boitsebiso bo tsoang tekong ea ZUMA-1 Phase 2 e nang le ntlha ea ho qetela ea tekanyo ea ho arabela sepheo (ORR) e tlalehiloeng ka mor'a ho tšoaetsoe feela ha axicabtagene ciloleucel ka liphesente tse 82 (p <0.0001). Ka mor'a ho nka likhoeli tse 8.7 ho latela mekhoa ea boipheliso, bakuli ba 44 lekholong ba ne ba e-na le karabo e tsoelang pele, e neng e akarelletsa karolo ea 39 lekholong ea bakuli ba arabelang ka botlalo (CR).
Liketsahalo tse tloaelehileng tse bohloko li akarelletsa ho senyeha ha lisele tse phetseng hantle tse loantšang tšoaetso le ho thusa mali ho koala. Joaloka le CTL019, e 'ngoe ea litla-morao tse tloaelehileng e bitsoa cytokine release syndrome, e bakang feberu e matla le matšoao a kang a mafu a maemong a mang a ka ba kotsi haholo hoo mokuli a qetellang a le tlhokomelo e matla. Encephalopathy e ka fella ka ho ferekanngoa ha nakoana kapa ho ba le ho ruruha ha boko ba boko. Ho ne ho e-na le batho ba bararo ba shoeleng nakong ea nyeoe ea ho ngolisa eseng ka lebaka la tsoelo-pele ea maloetse, e leng liketsahalo tse peli, tse nkoang li amana le axicabtagene ciloleucel. Hape, ntlafatso ea litlhare tsa lithethefatsi ena e lebeletsoe hore e tsoele pele ka tlhokomelo.
GoCAR-T, Mokhethoa bakeng sa Likokoana-hloko tse Tiileng ka Bellicum Pharmaceuticals
Houston, Texas e thehiloeng ho Bellicum Pharmaceuticals, Inc., e na le likhetho tsa lithethefatsi tse kenyeletsang BPX-601 (sekhetho sa GoCAR-T, bakeng sa lihlahala tse tiileng, tse entsoeng ka ho fetola ha iMC ho ts'oanela ho sebetsa hantle, karolo ea I), le BPX-701 (e phahameng sekhetho sa TCR, bakeng sa lihlahala tse tiileng , tse entsoeng ka phetoho ea CaspaCIDe, karolo ea I).
Joale, sohle seo se bolela'ng? Ha e le hantle, sehlopha sena se sebetsa ho hloekisa theknoloji ea T-cell ea CAR hore e tle e fe mooki mokuli hore a laola tsela ea karabo ea T-cell. Lisele tsa GoCAR-T li etselitsoe hore li sebetse ka ho feletseng ha li pepesitsoe lisele tsa kankere le moemeli ea bitsoang rimiducid. Ka hona, kalafo, ngaka e tla khona ho laola tekanyo ea ts'ebetso ea lisele tsa CAR-T ka ho fetola kemiso ea tsamaiso ea rimiducid, empa ho bolaea sele ho ne ho ntse ho tla etsahala ka mokhoa o itšetlehileng ka hlahala.
Ba bang ba Canditi
Juno ke khampani e ntseng e lebisa tlhokomelo ho JCAR017, sehlahisoa sa CAR-T se hlaselang CD19. Juno o batla ho fumana JCAR017 'marakeng ho fihlela ka 2018 bakeng sa NHL. Khampani e arohane le Celgene matsatsing ana.
MOSEBETSI A Oncology o na le sehlahisoa se khethehileng sa CD19 'me o sebetsana le therapy ea CAR T-cell e khethehileng ea CD33 bakeng sa ho phekoloa hape / ho hanyetsa lefu la myeloid leukemia (AML). NantKwest ke khamphani ea immunotherapy e tsepamisitseng ho sebelisa bolaea ea tlhaho (NK) lisele tsa ho tšoaroa ke kankere, maloetse a tšoaetsanoang, le mafu a ho ruruha.
Sethala sa NK-based cell se thehiloe ho etsa hore sele e shoe khahlanong le kankere kapa lisele tse nang le tšoaetso ka mekhoa e meraro e fapaneng ea ho bolaea-ho bolaea ka ho toba ho sebelisoa NK cells (aNK); ho bolaea batho ba nang le mefuta-futa ka ho sebelisa li-haNK, le ho bolaoa ka morero oa ho bolaea ka li-taNK.
Lentsoe le Tsoang ho
Tse ling tsa liphello tsa pele tsa kankere ea CAR-T e bile tse thahasellisang haholo, li fana ka phekolo e ncha ho lihlopha tsa bakuli ba kileng ba e-ba le mekhoa e joalo pele. Ho boetse ho bile le mefokolo, leha ho le joalo, le mathata a mangata a ho rarolla mathata ho etsa hore lits'oaetso tsena li atlehe ka hohle kamoo ho khonehang ka bongata ba chefo.
Joalokaha bafuputsi ba ithuta ho eketsehileng mabapi le karabelo ea 'mele ea ho itšireletsa mafung e sebetsanang le mekhoa ena ea phekolo,' me liphello li hlaselang, ho na le setšoantšo se hlakileng sa likotsi le melemo e lokelang ho hlaha.
> Mehloli:
> Lee M Lee, Lee M Lee, Wang Lee, Wang RF. Khatelo-pele ea morao-rao T-cell-based-cancer immunotherapy. Immunotherapy . 2014; 6 (12): 1265-1278.
> Bjj VG, Arhontoulis D, Wertheim G, et al. Ho phehella ha lisele tsa mali tsa nako e telele le tšireletso ea ho itšireletsa ha batho ka bomong ba arabela phetong ea CAR T-cell e tsamaisitsoeng ka CD19. Mali. 2016; 128 (3): 360-370.
> Kite e amohela Tlhahlobo ea Bohlokoa ka ho Fetisisa ea Lijo le Drug ea US bakeng sa Axicabtagene Ciloleucel. http://ir.kitepharma.com/releasedetail.cfm?releaseid=1028075 Fihletsoe ho July 2017.
> Morris EC, Stauss HJ. Ho ntlafatsa phekolo ea liphatsa tsa lefutso ea T-cell bakeng sa maling a lefu la hematologic. Mali . 2016; 127 (26): 3305-3311.
> Park JH, Geyer MB, Brentjens RJ. Meriana ea CAR T-cell e hlalositsoeng ka CD19 bakeng sa likokoana-hloko tsa hematologic: ho hlalosa liphello tsa kliniki ho fihlela joale. Mali . 2016; 127 (26): 3312-3320.