Gutsinda Imbogamizi mu Buvuzi bwa CAR-T ku Kanseri y'amaraso ya T-cell

Uburyo bwo kuvura kanseri ya T-cell (CAR-T) bwagaragaye ko ari uburyo bwiza bwo kuvura kanseri y’amaraso ikomoka ku turemangingo twa B, butanga umusaruro mwiza n’umutekano. Ariko, bukoreshwa mu kuvura kanseri ya T-cell, nka kanseri ya T-cell acute lymphoblastic leukemia (T-ALL) na kanseri yo mu bice by’umubiri. Lymphoma ya T-cell (PTCL), ifite imbogamizi zikomeye. Imwe mu ngorane nyamukuru iri mu gusana hagati y’uturemangingo twa T-seli mbi n’uturemangingo twa T-seli bisanzwe, bigatuma bigorana kwibasira uturemangingo twa kanseri gusa tudakoze kwangiza uturemangingo twa T-seli nzima. Ibi bivamo ikintu kizwi nka "fratricide," aho uturemangingo twa CAR-T twibasira uturemangingo twa T-seli mbi n’utusanzwe, bigabanyiriza cyane imikorere y’ubuvuzi. Byongeye kandi, ubwinshi bw’uturemangingo twa T-seli butuma tugorana kumenya uturemangingo twa CAR-T twose, kuko antigen imwe ishobora kutagaragara mu buryo bumwe ku turemangingo twose twa kanseri.

Mu igeragezwa ry’ubuvuzi, uturemangingo twa CAR-T twibasira antijeni za pan-T nka CD5 na CD7 twagaragaje ko twagize icyo tugeraho mu kuvura kanseri ya T-cell. Izi ngingo ziboneka ku buso bwa kanseri nyinshi za T-cell, ariko kandi zigaragara no ku turemangingo twa T dusanzwe, bigatera ingaruka mbi nko kugabanuka kw’uturemangingo twa T, kubura ubudahangarwa bw’umubiri, no kwiyongera k’ubushobozi bwo kwandura. Kugira ngo bagabanye izi mbogamizi, abashakashatsi baribanda ku antijeni za T-cell "zibujijwe" cyane, nka CD4, CD30, CD37, na CCR4. Izi antijeni zitoranya cyane uturemangingo tumwe na tumwe twa T-cells, bishobora kugabanya ibyago byo kwandura fratricide no kubungabunga imikorere y’ubudahangarwa bw’umubiri. Ariko, ubushakashatsi kuri izi antijeni zibujijwe buracyari mu ntangiriro, kandi guhitamo neza abarwayi ni ingenzi kugira ngo hamenyekane intego ikwiye kuri buri kibazo.

Indi ngamba iri gusuzumwa irimo guteza imbere uturemangingo twa CAR-T twitwa allogeneic, dukomoka ku batanga serivisi nziza aho kuba abarwayi ubwabo. Uturemangingo twa CAR-T twitwa allogeneic dushobora guhindurwa mu buryo bwa genetiki kugira ngo hirindwe kwandura kwa kanseri no kugabanya ibyago byo kwanduzwa n’indwara ya graft-versus-host (GvHD), ikibazo gikunze kugaragara mu buryo bwo gutera uturemangingo. Ariko, utwo turemangingo duhura n’imbogamizi nko kwanga ubudahangarwa bw’umubiri, bishobora kugabanya imikorere yatwo mu gihe kirekire. Kugira ngo ibi bikemuke, hari uburyo bwo guhindura uturemangingo nka CRISPR/Cas9 na base editing burimo gusuzumwa kugira ngo hahindurwe uturemangingo twa CAR-T, bigatuma dukoreshwa ku isi hose kandi tukaba twizewe ku barwayi. Base editing, by’umwihariko, itanga ubundi buryo bwiza bwo guhindura uturemangingo gakondo, kuko birinda ibyago bijyana no gucika kwa ADN, kugabanya uburozi bwa genetiki no kunoza umutekano w’ubuvuzi bwa CAR-T.

Nubwo hari iterambere rigaragara, hari imbogamizi nyinshi ziracyahari. Uturemangingo twa CAR-T akenshi ntidushobora gukomeza kubaho igihe kirekire mu mubiri, ibyo bikaba byatuma indwara isubira inyuma. Urugero, nyuma yo kuvurwa hakoreshejwe uturemangingo twa CAR-T twibasiwe na CD7, uturemangingo twa T-negative CD7 dushobora kugaragara no kurwanya kwica uturemangingo twa CAR-T, ibyo bikaba byarushaho kugorana kuvura. Abashakashatsi barimo gukora ubushakashatsi ku buryo bwo kunoza igihe kirekire n'imikorere y'uturemangingo twa CAR-T, harimo guhuza ubuvuzi bwa CAR-T n'ubundi buryo bwo kuvura, nko gutera uturemangingo tw'ingirabuzimafatizo, kugira ngo dukomeze kandi dukomeze koroherwa. Ubu buryo, buzwi nka "bridging therapy," bushobora gutanga ubundi buryo bwo kurinda gusubira inyuma, cyane cyane ku barwayi bafite umutwaro mwinshi wa kanseri.

Ingorane nyuma yo kuvurwa na CAR-T, harimo indwara ya cytokine release syndrome (CRS), indwara y’ubudahangarwa bw’uturemangingo (ICANS), n’indwara z’abarwayi, nabyo ni bimwe mu bintu bihangayikishije. Kugabanuka k’uturemangingo twa T, cyane cyane bituma abarwayi bashobora kongera kugira indwara zihishe nka virusi ya Epstein-Barr (EBV) na virusi ya cytomegalovirus (CMV), mu gihe kugabanuka k’umusemburo w’amagufwa bishobora gutuma habaho cytopenia igihe kirekire. Kugira ngo bagabanye izi ngaruka, abashakashatsi barimo gukora ubushakashatsi ku buryo bwo kunoza umutekano n’imikorere y’uturemangingo twa CAR-T, nko gutangiza uburyo bwo kwirinda no gukoresha uburyo bwo kuvura bugufi kugira ngo bagabanye ingaruka mbi.

Muri rusange, nubwo ubuvuzi bwa CAR-T bwateye intambwe ikomeye mu kuvura kanseri y’amaraso ya T-cells, imbogamizi zijyanye no kwibasira antigens, ingorane z’ubudahangarwa bw’umubiri, no gukomeza igihe kirekire ziracyahari. Ubushakashatsi n’udushya bikomeje mu ikoranabuhanga rya CAR-T, harimo guteza imbere uburyo bwo kuvura indwara ebyiri, uburyo bwo guhindura ingirabuzima fatizo, no guhitamo neza abarwayi, ni ingenzi mu kugaragaza ubushobozi bwa CAR-T mu kuvura kanseri ya T-cells. Mu gihe igeragezwa ry’ubuvuzi rikomeje gushakisha ingamba nshya, icyizere ni uko ubuvuzi bwa CAR-T buzatera imbere bugatanga uburyo bwo kuvura burambye kandi bufite umutekano ku barwayi bafite izi kanseri zikomeye.