Ukunqoba Izinselele Ekwelashweni Kwe-CAR-T Kwama-T-Cell Blood Cancers
Ukwelashwa kwe-Chimeric Antigen Receptor T-cell (CAR-T) kuye kwabonakala kuyindlela yokwelapha eyinhloko yezifo ezibangelwa yigazi ezibangelwa yi-B-cell, okunikeza ukusebenza kahle nokuphepha okuphezulu. Kodwa-ke, ukusetshenziswa kwayo ezifweni ezibangelwa yigazi ezibangelwa yi-T-cell, njenge-T-cell acute lymphoblastic leukemia (T-ALL) kanye ne-peripheral I-T-Cell Lymphoma (PTCL), iveza izinselelo ezinkulu. Enye yezinkinga eziyinhloko ifana phakathi kwama-T-cell anobungozi nama-T-cell ajwayelekile, okwenza kube nzima ukuhlasela amaseli anomdlavuza kuphela ngaphandle kokulimaza ama-T-cell anempilo. Lokhu kuphumela esimeni esaziwa ngokuthi “i-fratricide,” lapho amaseli e-CAR-T ehlasela ama-T-cell anobungozi kanye nama-T-cell ajwayelekile, okunciphisa kakhulu ukusebenza kahle kokwelashwa. Ngaphezu kwalokho, ukungafani kwezifo ezibangelwa amagciwane e-T kwenza kube nzima ukuhlonza izisulu zamaseli e-CAR-T ajwayelekile, njengoba i-antigen eyodwa eqondiwe ingase ingavezwa ngokufanayo kuwo wonke amaseli omdlavuza.
Ezivivinyweni zemitholampilo, amaseli e-CAR-T ahlose ama-antigen e-pan-T njenge-CD5 ne-CD7 abonise impumelelo ethile ekwelapheni umdlavuza we-T-cell. Lawa ma-target atholakala ebusweni be-T-cell monosages eziningi, kodwa futhi abonakala kumaseli e-T ajwayelekile, okuholela emiphumeleni emibi emibi njengokuncipha kwamaseli e-T, ukuntuleka kwamasosha omzimba, kanye nokwanda kokuthambekela ekuthelelekeni. Ukuze kuncishiswe lezi zinselele, abacwaningi bagxile kuma-antigen e-T-cell athile “avinjelwe”, njenge-CD4, i-CD30, i-CD37, kanye ne-CCR4. Lawa ma-antigen akhetha kakhulu ama-subset athile amaseli e-T, okungase kunciphise ingozi ye-fratricide futhi kulondoloze ukusebenza okuvamile komzimba. Kodwa-ke, ucwaningo ngala ma-antigen avinjelwe lusesezigabeni zokuqala, futhi ukukhetha isiguli ngokucophelela kubalulekile ukuze kunqunywe i-target efanele kakhulu yecala ngalinye.
Elinye isu elihlolwayo lihilela ukuthuthukiswa kwamaseli e-CAR-T a-allogeneic, atholakala kubanikeli abanempilo kunasezigulini uqobo. Amaseli e-CAR-T a-allogeneic angahlelwa ngokwezakhi zofuzo ukuvimbela ukungcoliswa kwesimila nokunciphisa ingozi yesifo se-graft-versus-host (GvHD), okuyinkinga evamile ezindaweni zokufakelwa. Kodwa-ke, lawa maseli abhekene nezinselele ezifana nokwenqatshwa kwamasosha omzimba, okunganciphisa ukusebenza kwawo kwesikhathi eside. Ukuze kuxazululwe lokhu, amasu okuhlela izakhi zofuzo njenge-CRISPR/Cas9 kanye nokuhlela okuyisisekelo ayahlolwa ukuze kuguqulwe amaseli e-CAR-T, okwenza asebenze kabanzi futhi aphephe kakhulu ezigulini. Ukuhlela okuyisisekelo, ikakhulukazi, kunikeza enye indlela ethembisayo yokuhlela izakhi zofuzo zendabuko, njengoba kugwema izingozi ezihambisana nokuqhekeka kwe-DNA yezintambo ezimbili, ukunciphisa ubuthi bezakhi zofuzo nokuthuthukisa iphrofayili yokuphepha yezindlela zokwelapha ze-CAR-T.
Naphezu kwalokhu kuthuthuka, kusenezinselele eziningana. Amaseli e-CAR-T avame ukungakwazi ukugcina ukuphikelela isikhathi eside emzimbeni, okungaholela ekubuyeleni kwesifo. Ngemva kokwelashwa ngamaseli e-CAR-T aqondiswe ku-CD7, isibonelo, amaseli e-T angenayo i-CD7 angavela futhi amelane nokubulawa kwamaseli e-CAR-T, okwenza kube nzima kakhulu ukwelashwa. Abacwaningi baphenya ngezindlela zokuthuthukisa isikhathi eside nokusebenza kahle kwamaseli e-CAR-T, okuhlanganisa ukuhlanganisa ukwelashwa kwe-CAR-T nezinye izindlela zokwelapha, njengokufakelwa kwamaseli e-stem, ukuqinisa nokugcina ukuxolelwa. Le ndlela, eyaziwa ngokuthi "ukwelashwa kokuvala," inganikeza ungqimba olwengeziwe lokuvikela ekubuyeleni kwesifo, ikakhulukazi ezigulini ezinomthwalo omkhulu wesimila.
Izinkinga ezilandela ukwelashwa kwe-CAR-T, okuhlanganisa i-cytokine release syndrome (CRS), i-immune effector cell-associated neurotoxicity syndrome (ICANS), kanye nezifo ezithinta amathuba, nazo ziyizindawo ezikhathazayo. Ukuncipha kwamaseli e-T, ikakhulukazi, kushiya iziguli zisengozini yokuvuselelwa kwezifo ezifihliwe njengegciwane le-Epstein-Barr (EBV) kanye ne-cytomegalovirus (CMV), kuyilapho ukucindezelwa komnkantsha kungaholela ekukhuleni kwe-cytopenia isikhathi eside. Ukuze kuncishiswe lezi zingozi, abacwaningi baphenya ngezindlela zokuthuthukisa ukuphepha nokusebenza kahle kwamaseli e-CAR-T, njengokwethula ukushintsha kokuphepha nokusebenzisa izindlela zokwelapha ezimfushane ukuze kuncishiswe imiphumela emibi.
Sekukonke, yize ukwelashwa kwe-CAR-T kuye kwenza intuthuko ebalulekile ekwelapheni umdlavuza wegazi we-T-cell, izinselele ezihlobene nokuqondisa ama-antigen, izinkinga zesistimu yomzimba, kanye nokuphikelela kwesikhathi eside zisekhona. Ucwaningo oluqhubekayo kanye nokusungula izinto ezintsha kubuchwepheshe be-CAR-T, okuhlanganisa ukuthuthukiswa kwezindlela zokwelapha ezihloselwe kabili, amasu okuhlela izakhi zofuzo, kanye nokukhethwa kweziguli okunembe kakhudlwana, kubalulekile ekuvuleni amandla okwelapha e-CAR-T ekwelapheni umdlavuza we-T-cell. Njengoba izivivinyo zemitholampilo ziqhubeka nokuhlola amasu amasha, ithemba liwukuthi ukwelashwa kwe-CAR-T kuzothuthuka ukuze kunikeze izinketho zokwelapha ezihlala isikhathi eside neziphephile ezigulini ezinalezi zinhlungu zomdlavuza eziyinselele.