I-Iovance Biotherapeutics' yokuqala yohlobo lwayo yokwelashwa kwamasosha omzimba yavunywa yi-FDA. Lokhu kusho ukuthi ukwelashwa kwe-T-cell, okushintshe indlela ezinye izinhlobo zomdlavuza wegazi ezilashwa ngayo, manje kungasetshenziswa ngokuqondile kumathumba aqinile.
Umuthi uwukwelashwa kokuqala komuntu siqu kwe-tumor-infiltrating lymphocyte (TIL) ukungena emakethe. Ibizwa ngokuthi i-Amtagvi noma i-lifileucel. I-FDA yasheshisa inqubo yokugunyazwa ngoLwesihlanu kubantu abane-melanoma ethuthukisiwe asebevele belashwe nge-PD-1 inhibitor noma i-BRAF inhibitor uma isisu inofuzo lwe-BRAF V600.
Intengo yohlu lomuthi iphakeme kancane kunezintengo zemithi yokwelapha yamaseli e-CAR-T yamanje, etholwa abantu abanalesi sifo. umdlavuza wegazi kubiza cishe u-$500,000 noma ngaphansi. Lokho kungenxa yokuthi u-Iovance wayecabanga ukuthi i-Amtagvi yayifaneleka kakhulu njengesidakamizwa sokuqala esigunyazwe lolu hlobo lwe melanoma ngemuva kwe-PD-1, futhi babheka nezinye izidakamizwa ezifanayo, kusho uVogt.
Njengezinye izindlela zokwelapha ze-CAR-T cell, i-Amtagvi yenziwe ngamaseli omzimba athathwe ezigulini ezithile. Amaseli e-TIL asuka esimila esikhishwe isiguli asetshenziswa ukwenza umkhiqizo wokugcina. Lawa maseli abe esekhuliswa ngaphandle komzimba futhi aphinde ajovwe esigulini.
Amasosha omzimba enza amaseli e-TIL ngokwawo, angathola izimpawu eziyingqayizivele ebusweni bamaseli omdlavuza futhi alwe nawo. I-Amtagvi ivele inikeze umzimba ngaphezulu kwalawa maseli omzimba alwa nomdlavuza ngoba amangqamuzana okuzivikela omzimba alahlekelwa ukusebenza kwawo ngokuhamba kwesikhathi.
Ngaphambi kwe-Amtagvi, Ukwelashwa kwe-CAR-T kungalwa kuphela nezinhlobo ezithile zomdlavuza wegazi. Lokhu kungenxa yokuthi izimila eziqinile azinawo ama-biomarker afanele weseli ukuze amaseli e-CAR-T aqondiswe kuwo. Leyo nkinga ingaxazululwa ngokwelashwa kwe-TIL, njengoba amaseli e-TIL ahlelwa ngokwemvelo ukuze athole ama-biomarker omdlavuza.
Ocwaningweni lwengalo eyodwa, i-Amtagvi ebangeni lethamo elinconyiwe manje inciphise izimila kuma-31.5% ezigulini ezingama-73 esezelashwe ngomuthi ophikisana ne-PD-1. U-43.5% walabo abaphendulile base bexolelwe isikhathi esingaphezu konyaka ngemuva kwezinyanga eziyi-18.6 zokulandelela.
Izinga lokuphendula elihlosiwe lalifana ku-31.4% ocwaningweni olusekelwe ngokusebenza ngempumelelo olubheke iziguli eziyi-153. Futhi, u-56.3% wabaphenduli basenazo izimpendulo ngemva konyaka. Ukubuyekezwa okusha ekuhlaziyweni okuhlanganisiwe kubonise ukuthi iziguli zaziphila isilinganiso sezinyanga eziyi-13.9, futhi cishe ingxenye yazo yayisaphila ngemva kweminyaka emine. Lolu lwazi alufakiwe kulebula yamanje.
Noma i-Amtagvi iyisinyathelo esikhulu esiya phambili, ayiphelele.
Okokuqala, ngenxa yokuthi i-Amtagvi yenziwe ngamaseli e-TIL ngesimila esanele sesiguli, ngeke isebenze kubantu abangakwazi ukuhlinzwa noma abangenazo izicubu ezanele ezikhishiwe.
Okwesibili, isidakamizwa sifika nesixwayiso esisebhokisini mayelana nokufa okuhlobene nokwelashwa, i-cytopenia enamandla ehlala isikhathi eside, izifo ezinzima, nokulimala kwenhliziyo, amaphaphu, nezinso. Lokhu kusho ukuthi umuthi ungathengwa kuphela ezikhungweni ezithile zokwelapha ngaphakathi ezibhedlela lapho abantu behlala khona. Ilebula yomuthi egunyazwe yi-FDA iphinde ithi iziguli kumele ziqashwe ngeso lokhozi egunjini labagula kakhulu futhi zithole ochwepheshe.
UVogt usasho ukuthi isexwayiso sebhokisi le-Amtagvi singcono kunalokhu okwenzekayo ngama-CAR-Ts amanje. Njengesibonelo, i-Amtagvi ayilawulwa uhlelo lokuphepha oludingwa yi-FDA. Lolu hlelo lubizwa ngokuthi ukubuyekezwa kobungozi kanye namasu okunciphisa. Futhi, umuthi awunazo izexwayiso mayelana ne-cytokine release syndrome noma i-hemophagocytic lymphohistiocytosis, imiphumela emibi emibili yokwelashwa kwamaseli e-CAR-T engaba yingozi kakhulu futhi ibulale imbala.
UVogt uthe bekulindelwe isexwayiso esisebhokisini nokuthi odokotela sebeyazi ukuthi umuthi unjani.
UJim Ziegler, oyisikhulu sezokukhangisa kwa-Iovance, uthe ocingweni inkampani isendleleni yokuba nezikhungo ezingaphezu kuka-50 ezinsukwini ezingaba yikhulu. Izikhungo ezingu-100 sezisunguliwe futhi sezikulungele ukwelapha iziguli uma umuthi usudayiswa.
Kube nezinkinga zokutholakala kwemithi eminingi ye-CAR-T, ikakhulukazi ngesikhathi sokwethulwa. "Sinamandla anele njengoba singena kulawa masayithi ngendlela elawulwayo, eneziyalo," kusho u-Ziegler mayelana nokwethulwa kwe-Amtagvi. Isikhungo sasePhiladelphia lapho inkampani isebenza khona kanye nomkhiqizi wenkontileka oseduze angagcina esebenzela “iziguli eziyizinkulungwane ezimbalwa ngonyaka,” kusho uVogt.
I-WuXi STA, iyunithi ye-WuXi AppTec, esitatimendeni ngoLwesibili ithe isitshalo sayo e-Philadelphia sinikezwe imvume yi-FDA yokuhlola nokwenza i-Amtagvi.
Inqubo yokwenza i-amtagvi ingathatha isikhathi eside. Okwamanje, u-Iovance ucabanga ukuthi isilinganiso sesikhathi esisithathayo ukwenza umkhiqizo—kusukela lapho isimila sifika efektri kuya lapho umkhiqizo osuphelile ukhishwa—kuyoba izinsuku ezingu-34. Ungakhohlwa isikhathi esisithathayo ukuze uthunyelwe.
Abanye abantu bangase babe nenkinga ngesikhathi eside sokulinda. Ucwaningo oluhlanganisiwe lokuphumelela komuthi ekuqaleni lwalubheka iziguli eziyi-189, kodwa ezingama-33 azizange zithole umuthi ngenxa yezinto ezifana neziguli eziyisishiyagalombili ezingawutholi umkhiqizo noma isifo sazo esiba sibi kakhulu noma esifayo.
Futhi, iziguli kufanele zithole ukwelashwa okuningi okuyinkimbinkimbi ngaphambi nangemuva kokuthola i-Amtagvi. Lokhu kwenzelwa ukuthi umzimba ulungele umjovo noma ukwenza amaseli abe nempilo noma ukubhekana nemiphumela engemihle. Futhi, iziguli kufanele zihlale phakathi kwamahora amabili esikhungweni sokwelashwa “amasonto ambalwa” ukuze zibukele imiphumela engemihle. Lezi zinyathelo zizobiza imali eyengeziwe futhi zenze izinto zibe nzima ezigulini.
Abakhokhi bathe bathanda ukunikezwa kwenani le-Amtagvi, yize kubiza kakhulu, kusho uZiegler. Kusuka kulokho u-Iovance akhulume ngakho nabakhokhi ngakho kuze kube manje, inkampani icabanga ukuthi izothola ukutholakala okufanayo nemithi yokwelapha ye-CAR-T yamanje, ngesidingo semvume yangaphambili, esho.
I-FDA igunyaze i-Amtagvi ngenqubo yokubuyekeza esheshayo. I-Iovance futhi yenza ucwaningo lwesigaba sesi-3 ngegama lekhodi elithi TILVANCE-301 ukuze kuqinisekiswe ukuthi umuthi uyasebenza emhlabeni wangempela. Ucwaningo luqhathanisa i-Amtagvi ne-Keytruda, i-PD-1 inhibitor evela ku-Merck & Co., ne-Keytruda iyodwa kubantu abane-melanoma abangakalashwa kuze kube manje.
Bekuyindlela ende nenzima yokwenza isithonjana sika-Amtagvi sisulwe. U-Iovance wayehlele ukufaka ifayela ngo-2020, kodwa kwadingeka aguqule izinhlelo zabo lapho i-FDA iphakamisa ukukhathazeka ngokuhlolwa ababekusebenzisa ukuze babone ukuthi inani ngalinye lokwelapha lisebenza kangakanani. Ngosizo lokuhlolwa, inkampani ikwazile ukuthi isicelo sayo sigunyazwe yi-FDA ngokushesha ngoMeyi 2023. Kodwa i-FDA yabe yelula ukubuyekezwa kwayo ngoba i-ejensi yayingenazo izinsiza ezanele.
Ngesikhathi sokubambezeleka, uVogt wathatha izintambo okwesikhashana njengo-CEO ku-Maria Fardis, Ph.D., owayephethe ngaphambilini. Ukaputeni ozinzile akakakhethwa.
I-Iovance iphinde isebenze ekwelashweni kwe-TIL okubizwa nge-LN-145, ehlolelwa isigaba 2 kumaseli angewona amancane. umdlavuza wamaphaphu ngemuva kwe-PD-1. U-Iovance wathi ngonyaka odlule ukuthi ukuhlolwa okubalulekile kwe-IOV-LUN-202 nakho kungasheshisa inqubo yokukhipha imvume.
I-Amtagvi ikhiqizwa ngokusebenzisa amaseli omzimba esiguli ngasinye, njengokwelashwa kwamaseli e-CAR-T amanje. Umkhiqizo wokugcina udalwa ngokuvuna amaseli e-TIL esiguli engxenyeni yesimila saso esikhishwe ngokuhlinzwa, awanwebe ngaphandle, bese ewabuyisela emzimbeni wesiguli.
Amasosha omzimba akhiqiza amaseli e-TIL angakwazi ukukhomba izimpawu ezithile kumaseli omdlavuza futhi aqale impendulo yokuzivikela komzimba. I-Amtagvi igcwalisa umzimba ngamaseli omzimba alwa nomdlavuza njengoba amaseli akhiqizwa ngokwemvelo eba buthaka ngokukhula.
Ngaphambi kwe-Amtagvi, izindlela zokwelapha ze-CAR-T zazikhawulelwe ekubhekaneni nomdlavuza othile wegazi ngenxa yokungabi bikho kwezinkomba ezifanele zeseli kumathumba aqinile ukuze amaseli e-CAR-T aqondiswe kuwo. Ukwelashwa kwe-TIL ibhekana nenkinga ngokusebenzisa amaseli e-TIL ahlelelwe ukubona izimpawu zomdlavuza.
I-Amtagvi, elawulwa ebangeni lemithamo elivunyelwe ocwaningweni lwengalo eyodwa, iholele ekwehliseni isimila ku-31.5% yeziguli ezingama-73 ezazichayeke ekwelashweni kwe-anti-PD-1. Ngemva kwezinyanga ezingu-18.6, u-43.5% wabahlanganyeli abasabela ekwelashweni babehlale bexolelwe isikhathi esingaphezu konyaka.
Idatha ehlanganisiwe yokuhlolwa evela ezigulini eziyi-153 ibonise izinga lokuphendula elilinganayo lama-31.4%. Ukwengeza, u-56.3% wabahlanganyeli ube nemiphumela ehlala isikhathi eside ngemva konyaka owodwa. Ukubuyekezwa kwakamuva kwedatha ehlanganisiwe kuveze ukuthi iziguli zinezinyanga eziyi-13.9 zokusinda, cishe ingxenye yeziguli isaphila ngemva kweminyaka emine, naphezu kokuthi kungashiwongo kulebula yamanje.
I-Amtagvi, nakuba isungula izinto ezintsha, ayinasici.
Ngenxa yokusetshenziswa kwamaseli e-TIL asuka esimila esigulini, abantu abangakwazi ukuhlinzwa noma abangenazo izicubu ezanele ezikhishwe kabusha abafanelekile ukuthola ukwelashwa kwe-Amtagvi.
Umuthi unesexwayiso esisebhokisini sokushona okuhlobene nokwelashwa, i-cytopenia eqinile eqhubekayo, ukutheleleka okunzima, kanye nokulimala kwenhliziyo nezinso. Umuthi utholakala kuphela ezikhungweni zokwelapha ezithile endaweni yesibhedlela esilaliswayo. Ilebula yomuthi egunyazwe yi-FDA igunyaza iziguli ukuthi ziqashelwe imiphumela engemihle egunjini labagula kakhulu futhi idinga ukuthi ochwepheshe babe khona.
U-Vogt uphikise ngokuthi isexwayiso sebhokisi le-Amtagvi siyintuthuko uma siqhathaniswa nesimo samanje nama-CAR-T akhona. I-Amtagvi ayilawulwa ngaphansi kohlelo lokuphepha olugunyazwe yi-FDA olubizwa ngezinyathelo zokuhlola ubungozi kanye nezinyathelo zokunciphisa. Umuthi awunazo izexwayiso ze i-cytokine release syndrome noma i-hemophagocytic lymphohistiocytosis, okuyimiphumela engathi sína yokwelashwa kwamaseli e-CAR-T.
UVogt uthe bekulindelwe isexwayiso esisebhokisini nokuthi odokotela sebezazi kahle izinto zomuthi.
I-Iovance ifake izikhungo eziqokiwe ezingama-30 ezilungiselwe ukwelapha iziguli lapho umuthi usukhishiwe, ngezinhlelo zokukhuphuka zibe ngaphezu kwezikhungo ezingama-50 phakathi nezinsuku eziyi-100, njengoba kushiwo yisikhulu sezohwebo sase-Iovance, uJim Ziegler.
Izindlela zokwelapha eziningi ze-CAR-T zibhekane nokushoda kokunikezwayo, ikakhulukazi ngesikhathi sokukhishwa kokuqala. U-Ziegler uthe maningi umthamo wokwethulwa kwe-Amtagvi njengoba kancane kancane bengeza lezi zindawo ngendlela elawulwayo nehlelekile. UVogt uthe indawo yale nkampani esePhiladelphia kanye nomkhiqizi wezinkontileka ongumakhelwane banamandla okugcina zelaphe izinkulungwane ezimbalwa zeziguli minyaka yonke.
NgoLwesibili, iWuXi STA, inkampani engaphansi kweWuXi AppTec, imemezele ukuthi indawo yayo yasePhiladelphia ivunyelwe yi-FDA ukuthi ihlole futhi ikhiqize i-Amtagvi.
I-Amtagvi ingase ibe nenqubo ende yokukhiqiza. U-Iovance ulindele ukuthi ubude besikhathi senqubo yokukhiqiza, kusukela ekufikeni kwesimila endaweni yokukhiqiza kuya ekukhululweni komkhiqizo kokugcina, kuzoba yizinsuku ezingama-34. Ngaphandle kwesikhathi sokuthunyelwa.
Ukulinda isikhathi eside kungase kubangele inkinga ezigulini ezithile. Ukuhlaziywa kokusebenza ngempumelelo komuthi ekuqaleni kwakuneziguli eziyi-189, nokho ezingama-33 azizange ziwuthole ngenxa yezizathu ezinjengokwehluleka kokukhiqizwa komkhiqizo ezigulini eziyisishiyagalombili kanye nokuqhubeka kwesifo noma ukufa kweziguli eziyi-11.
Iziguli zithola ukwelashwa okuyinkimbinkimbi ngaphambi nangemuva kokuphathwa kwe-Amtagvi ukuze kuthuthukiswe umzimba ngokufakwa, kuthuthukise ukusebenza kwamaseli, noma ukuphatha imiphumela engemihle. Iziguli kufanele zihlale phakathi kwebanga lamahora amabili lesikhungo sokwelashwa "amasonto ambalwa" ukuze zihlole imiphumela emibi. Lezi zinqubo zizoholela ezindlekweni ezengeziwe kanye nobunzima bomzimba ezigulini.
U-Ziegler uthe abakhokhi bayasivuma isiphakamiso senani le-Amtagvi naphezu kwezindleko zayo eziphezulu. I-Iovance ilindele ukuvikela ukuvikeleka okuqhathaniswa nemithi yokwelapha ye-CAR-T ekhona, enesidingo sangaphambili sokugunyazwa, ngokusekelwe ezingxoxweni zayo nabakhokhi.
I-Amtagvi igunyazwe yi-FDA isebenzisa inqubo yokugunyaza esheshayo. Manje i-Iovance iqedela uhlolo lwesigaba 3 olubizwa nge-TILVANCE-301 ukuze kuqinisekiswe ukusebenza ngempumelelo kokwelapha komuthi. Uhlolo luqhathanisa inhlanganisela ye-Amtagvi ne-Merck & Co.'s PD-1 inhibitor Keytruda nokusebenzisa i-Keytruda iyodwa ezigulini ezingelashiwe ze-melanoma.
Inqubo yokugunyaza ye-Amtagvi yayinzima futhi iyinselele. U-Iovance wayehlele ukuhambisa ifayela ngo-2020 kodwa walihlehlisa ngenxa yemibuzo ye-FDA mayelana nezivivinyo ezisetshenziswa ukukala amandla omthamo ngamunye wokwelapha. NgoMeyi 2023, inkampani yaphumelela ngempumelelo isithiyo sokuhlola futhi isicelo sayo samukelwe yi-FDA ukuze sibuyekezwe kuqala. I-FDA inwebise ukubuyekezwa kwayo ngenxa yezinkinga zezinsiza ejensi.
UVogt wathatha indima yokuba yi-CEO yesikhashana ngo-2021, ethatha isikhundla sika-CEO wangaphambili u-Maria Fardis, Ph.D., ngesikhathi sokubambezeleka. Akekho u-helminman waphakade oqokiwe.
U-Iovance wenza ukwelashwa kwe-TIL okubizwa nge-LN-145, okuqhutshwa isigaba sesi-2 izivivinyo zokwelashwa kumdlavuza wamaphaphu we-post-PD-1 ongewona omncane, ngaphezu kwe-Amtagvi. Ngonyaka odlule, u-Iovance wathi ukuqulwa kwecala okubalulekile kwe-IOV-LUN-202 kungase kuholele ekugunyazweni okusheshayo.
