Ho Hlōla Mathata a Kalafo ea CAR-T bakeng sa Kankere ea Mali ea Lisele tsa T

Kalafo ea Chimeric Antigen Receptor T-cell (CAR-T) e ipakile e le phekolo ea bohlokoa bakeng sa mafu a mali a tsoang liseleng tsa B, e fanang ka katleho e phahameng le polokeho. Leha ho le joalo, ts'ebeliso ea eona ho mafu a mali a lisele tsa T, joalo ka T-cell acute lymphoblastic leukemia (T-ALL) le peripheral Lymphoma ea Lisele tsa T (PTCL), e hlahisa liphephetso tse kholo. Bothata bo bong ba mantlha bo ho tšoana ho teng pakeng tsa lisele tsa T tse kotsi le lisele tsa T tse tloaelehileng, e leng se etsang hore ho be thata ho shebana le lisele tse nang le mofetše feela ntle le ho senya lisele tsa T tse phetseng hantle. Sena se fella ka ketsahalo e tsejoang e le "fratricide," moo lisele tsa CAR-T li hlaselang lisele tsa T tse kotsi le tse tloaelehileng, li fokotsa katleho ea phekolo haholo. Ho feta moo, ho se tšoane ha mafu a tšoaetsanoang a lisele tsa T ho thatafatsa ho tsebahatsa lipheo tsa lisele tsa CAR-T tsa bokahohleng, kaha antigen e le 'ngoe e ka 'na ea se ke ea hlahisoa ka ho lekana ho pholletsa le lisele tsohle tsa mofetše.

Litekong tsa bongaka, lisele tsa CAR-T tse shebaneng le li-antigen tsa pan-T tse kang CD5 le CD7 li bontšitse katleho e itseng ho phekoleng mafu a tšoaetsanoang a lisele tsa T. Lipheo tsena li fumanoa holim'a mafu a mangata a tšoaetsanoang a lisele tsa T, empa li boetse li hlaha liseleng tse tloaelehileng tsa T, e leng se lebisang litla-morao tse mpe joalo ka ho fokotseha ha lisele tsa T, ho haella ha sesole sa 'mele, le ho eketseha ha monyetla oa ho tšoaetsoa ke mafu. Ho fokotsa liphephetso tsena, bafuputsi ba shebane le li-antigen tse itseng tse "thibetsoeng" tsa sele ea T, tse kang CD4, CD30, CD37, le CCR4. Li-antigen tsena li khetha haholoanyane ho lihlopha tse itseng tsa lisele tsa T, tse ka fokotsang kotsi ea fratricide le ho boloka ts'ebetso e tloaelehileng ea 'mele ea ho itšireletsa mafung. Leha ho le joalo, lipatlisiso mabapi le li-antigen tsena tse thibetsoeng li ntse li le mehatong ea pele, 'me khetho e hlokolosi ea mokuli e bohlokoa ho fumana sepheo se loketseng ka ho fetisisa bakeng sa nyeoe ka' ngoe.

Leano le leng le ntseng le hlahlojoa le kenyeletsa nts'etsopele ea lisele tsa CAR-T tse nang le allogeneic, tse nkiloeng ho bafani ba phetseng hantle ho fapana le bakuli ka bobona. Lisele tsa CAR-T tse nang le allogeneic li ka fetoloa liphatsa tsa lefutso ho thibela tšilafalo ea hlahala le ho fokotsa kotsi ea lefu la graft-versus-host (GvHD), e leng bothata bo tloaelehileng libakeng tsa ho kenngoa ha lisele. Leha ho le joalo, lisele tsena li tobana le liphephetso tse kang ho lahloa ha sesole sa 'mele, e leng se ka fokotsang katleho ea tsona ea nako e telele. Ho sebetsana le sena, mekhoa ea ho hlophisa liphatsa tsa lefutso joalo ka CRISPR/Cas9 le ho hlophisa motheo e ntse e hlahlojoa ho fetola lisele tsa CAR-T, e leng se etsang hore li sebetse hohle le ho sireletseha haholoanyane bakeng sa bakuli. Ho hlophisa motheo, haholo-holo, ho fana ka mokhoa o mong o tšepisang ho fetola liphatsa tsa lefutso tsa setso, kaha ho qoba likotsi tse amanang le ho robeha ha DNA ea likhoele tse peli, ho fokotsa chefo ea liphatsa tsa lefutso le ho ntlafatsa boemo ba polokeho ba mekhoa ea phekolo ea CAR-T.

Ho sa tsotellehe tsoelo-pele ena, ho ntse ho e-na le liphephetso tse 'maloa. Hangata lisele tsa CAR-T ha li khone ho boloka nako e telele 'meleng, e leng se ka lebisang ho khutleleng ha lefu hape. Ka mor'a kalafo ka lisele tsa CAR-T tse shebaneng le CD7, mohlala, lisele tsa T tse se nang CD7 li ka hlaha 'me tsa hanela ho bolaoa ha lisele tsa CAR-T, e leng se thatafatsang phekolo le ho feta. Bafuputsi ba ntse ba batlisisa litsela tsa ho ntlafatsa bophelo bo bolelele le katleho ea lisele tsa CAR-T, ho kenyeletsoa ho kopanya phekolo ea CAR-T le mekhoa e meng ea phekolo, joalo ka ho fetisetsa lisele tsa stem, ho kopanya le ho boloka pholiso. Mokhoa ona, o tsejoang e le "therapy ea ho koala," o ka fana ka lera le eketsehileng la tšireletso khahlanong le ho khutlela morao, haholo-holo ho bakuli ba nang le moroalo o moholo oa hlahala.

Mathata a latelang kalafo ea CAR-T, ho kenyeletsoa le cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), le tšoaetso ea menyetla, le tsona ke libaka tse tšoenyang. Ho fokotseha ha lisele tsa T, haholo-holo, ho siea bakuli ba kotsing ea ho tsosolosoa ha tšoaetso e patehileng joalo ka vaerase ea Epstein-Barr (EBV) le cytomegalovirus (CMV), ha khatello ea moko oa masapo e ka lebisa ho cytopenia e telele. Ho fokotsa likotsi tsena, bafuputsi ba ntse ba batlisisa litsela tsa ho ntlafatsa polokeho le katleho ea lisele tsa CAR-T, joalo ka ho hlahisa li-switch tsa polokeho le ho sebelisa mekhoa e mekhutšoanyane ea kalafo ho fokotsa litla-morao.

Ka kakaretso, leha phekolo ea CAR-T e entse mehato e meholo kalafong ea kankere ea mali ea lisele tsa T, liphephetso tse amanang le ho shebana le li-antigen, mathata a sesole sa 'mele, le ho phehella ha nako e telele li ntse li le teng. Lipatlisiso tse tsoelang pele le boqapi theknolojing ea CAR-T, ho kenyeletsoa nts'etsopele ea mekhoa ea phekolo ea sepheo se habeli, mekhoa ea ho hlophisa liphatsa tsa lefutso, le khetho e nepahetseng haholoanyane ea mokuli, li bohlokoa ho notlolla bokhoni ba ho qetela ba phekolo ea CAR-T ho phekoleng mofetše oa lisele tsa T. Ha liteko tsa bongaka li ntse li tsoela pele ho hlahloba maano a macha, tšepo ke hore phekolo ea CAR-T e tla fetoha ho fana ka likhetho tsa kalafo tse tšoarellang le tse sireletsehileng haholoanyane bakeng sa bakuli ba nang le mofetše ona o thata.