Ukoyisa Imingeni kwi-CAR-T Therapy ye-T-Cell Blood Cancers

Unyango lwe-Chimeric Antigen Receptor T-cell (CAR-T) lubonakalise ukuba lolona nyango lubalaseleyo kwi-B-cell-derived hematological monicancies, olubonelela ngempumelelo ephezulu kunye nokhuseleko. Nangona kunjalo, ukusetyenziswa kwalo kwi-T-cell monicancies, njenge-T-cell acute lymphoblastic leukemia (T-ALL) kunye ne-peripheral I-T-Cell Lymphoma (PTCL), inika imingeni ebalulekileyo. Enye yezona ngxaki ziphambili kukufana phakathi kwee-T-cells ezinobungozi kunye nee-T-cells eziqhelekileyo, okwenza kube nzima ukujolisa kuphela kwiiseli ezinomhlaza ngaphandle kokonakalisa ii-T-cells eziphilileyo. Oku kuphumela kwisiganeko esaziwa ngokuba yi-"fratricide," apho iiseli ze-CAR-T zihlasela zombini ii-T-cells ezinobungozi kunye neziqhelekileyo, nto leyo ethintela kakhulu ukusebenza kakuhle konyango. Ngaphezu koko, ukungafani kwee-T-cell mollusnancies kwenza kube nzima ukuchongwa kweethagethi zeeseli ze-CAR-T, njengoko i-antigen enye ekujoliswe kuyo isenokungabonakaliswa ngokufanayo kuzo zonke iiseli zomhlaza.

Kwizilingo zeklinikhi, iiseli ze-CAR-T ezijolise kwii-antigen ze-pan-T ezifana ne-CD5 kunye ne-CD7 zibonakalise impumelelo ethile ekunyangeni ii-T-cell monoancies. Ezi njongo zifumaneka kumphezulu wee-T-cell monoancies ezininzi, kodwa zikwavela kwiiseli ze-T eziqhelekileyo, nto leyo ekhokelela kwiziphumo ebezingalindelekanga ezinje ngokuphelelwa ziiseli ze-T, ukungabikho komzimba, kunye nokwanda kokuchaphazeleka kusulelo. Ukunciphisa le mingeni, abaphandi bagxile kwii-antigen ze-T-cell ezithile "ezithintelweyo", ezifana ne-CD4, i-CD30, i-CD37, kunye ne-CCR4. Ezi antigens zikhetha ngakumbi kwii-subset ezithile zeeseli ze-T, ezinokunciphisa umngcipheko we-fratricide kwaye zigcine ukusebenza okuqhelekileyo komzimba. Nangona kunjalo, uphando kwezi antigens ezithintelweyo lusekwinqanaba lokuqala, kwaye ukukhetha ngononophelo isigulane kubalulekile ukumisela eyona njongo ifanelekileyo kwimeko nganye.

Elinye icebo eliphandwayo libandakanya ukuphuhliswa kweeseli ze-allogeneic CAR-T, ezithathwe kubanikeli abaphilileyo kunakwizigulane ngokwazo. Iiseli ze-allogeneic CAR-T zinokuhlelwa ngokwezakhi zofuzo ukuthintela ukungcoliswa sisimila kunye nokunciphisa umngcipheko wesifo se-graft-versus-host (GvHD), ingxaki eqhelekileyo kwiindawo zokufakelwa. Nangona kunjalo, ezi seli zijongene nemingeni efana nokungafunwa komzimba, okunokunciphisa ukusebenza kwazo ixesha elide. Ukujongana noku, iindlela zokuhlela izakhi zofuzo ezifana ne-CRISPR/Cas9 kunye nokuhlela isiseko ziyahlolwa ukuze kuguqulwe iiseli ze-CAR-T, okwenza zisebenze ngokubanzi kwaye zikhuseleke ngakumbi kwizigulane. Ukuhlela isiseko, ngakumbi, kunika enye indlela ethembisayo yokuhlela izakhi zofuzo zendabuko, njengoko kuthintela iingozi ezinxulumene nokuqhekeka kwe-DNA yemicu emibini, ukunciphisa ubuthi bezakhi zofuzo kunye nokuphucula iprofayili yokhuseleko lwezonyango ze-CAR-T.

Nangona kukho olu tshintsho, kukho imingeni emininzi eseleyo. Iiseli ze-CAR-T azikwazi ukugcina ixesha elide emzimbeni, nto leyo enokubangela ukuphinda isifo sibuyele esiqhelweni. Emva konyango ngeeseli ze-CAR-T ezijoliswe kwi-CD7, umzekelo, iiseli ze-T-negative ze-CD7 zinokuvela kwaye zimelane nokubulawa kweeseli ze-CAR-T, nto leyo eyenza kube nzima ngakumbi unyango. Abaphandi baphanda iindlela zokuphucula ixesha elide nokusebenza kweeseli ze-CAR-T, kubandakanya ukudibanisa unyango lwe-CAR-T kunye nezinye iindlela zonyango, ezifana nokufakelwa kweeseli ze-stem, ukuqinisa nokugcina ukuxolelwa. Le ndlela, eyaziwa ngokuba yi-"bridging therapy," inokubonelela ngolunye ulwahlulo lokhuseleko ekuphindeni kwakhona, ngakumbi kwizigulana ezinomthwalo omkhulu wesimila.

Iingxaki ezilandela unyango lwe-CAR-T, kuquka i-cytokine release syndrome (CRS), i-immune effector cell-associated neurotoxicity syndrome (ICANS), kunye nezifo ezichaphazela amathuba, nazo zizinto ezixhalabisayo. Ukuncipha kweeseli ze-T, ngakumbi, kushiya izigulana zisengozini yokuvuselelwa kwezifo ezifihlakeleyo ezifana ne-Epstein-Barr virus (EBV) kunye ne-cytomegalovirus (CMV), ngelixa ukucinezelwa komongo wethambo kunokukhokelela kwi-cytopenia ende. Ukunciphisa ezi ngozi, abaphandi baphanda iindlela zokuphucula ukhuseleko kunye nokusebenza kakuhle kweeseli ze-CAR-T, njengokungenisa utshintsho lokhuseleko kunye nokusebenzisa iindlela zonyango ezimfutshane ukunciphisa iziphumo ebezingalindelekanga.

Lilonke, nangona unyango lwe-CAR-T lwenze inkqubela ebalulekileyo kunyango lomhlaza wegazi we-T-cell, imingeni enxulumene nokujoliswa kwe-antigen, iingxaki zenkqubo yomzimba yokuzikhusela, kunye nokuqina kwexesha elide isasele. Uphando oluqhubekayo kunye nophuhliso kwitekhnoloji ye-CAR-T, kubandakanya uphuhliso lwezonyango ezijolise kabini, iindlela zokuhlela izakhi zofuzo, kunye nokukhetha isigulane ngokuchanekileyo, kubalulekile ekuvuleni amandla okugqibela onyango lwe-CAR-T ekunyangeni umhlaza we-T-cell. Njengoko uvavanyo lweklinikhi luqhubeka nokuphonononga amaqhinga amatsha, ithemba kukuba unyango lwe-CAR-T luya kutshintsha lubonelele ngeendlela zonyango ezihlala ixesha elide nezikhuselekileyo kwizigulane ezineemhlaza ezinengxaki.