Thupi lanu liri ndi mitundu yosiyanasiyana ya maselo oyera a magazi. Mtundu umodzi, lymphocyte , umabwera mu mitundu iwiri ikuluikulu: B-cell ndi T-cell. Apa, pa nkhani ya chithandizo cha khansa, timakhudzidwa kwambiri ndi mtundu wachiwiriwu, T-cell.
Nanga, chimeric antigen receptor (CAR) T-cell mankhwala? Mwachidule, ndi njira yopangira mavitamini omwe amachititsa kuti ma T-maselo akhale abwino pakudziwa ndi kupha khansa.
Ndi imodzi mwa mitundu yambiri ya ma immunotherapies yomwe ikufufuzidwa. Ngati muli ndi chidwi ndi sayansi ya zachilengedwe pambuyo pa mtundu uwu wa mankhwala, mndandanda wowonjezereka wa momwe CAR T-cell mankhwala amathandizira kuona.
Pano, cholinga chake chiri pa "mankhwala ochiritsira" komanso mankhwala ena omwe amagwiritsidwa ntchito kupyolera mu T-maselo - thupi lanu la "chitetezo cha mthupi" -kulimbana ndi khansa mwa kuzindikira ndi kuyambitsa maselo otupa. Matenda ena a khansa omwe amagwiritsa ntchito thupi la T-maselo ayamba kuvomerezedwa, ndipo ena akuyembekeza kuti atsatire posachedwa.
Kuwongolera Njira Yothandizira Kuteteza Mthupi
Kusinkhasinkha chitetezo cha mthupi lanu kuyesa kulimbana ndi khansa sikunayambe katsopano. Ndipotu pali zitsanzo za mankhwala ochiritsira (omwe akuyang'ana pa T-cell response) omwe adalandira kale kuvomereza kwa FDA: sipuleucel-T, ipilimumab, ndi blinatumomab, mwachitsanzo.
Chithandizo | Mtundu wa khansa | Chitetezo cha Mthupi |
Sipuleucel-T (Zopatsa) | Matenda ena a kansa ya prostate yapamwamba |
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Ipilimumab (Yervoy) | Matenda ena a khansa yapakhungu ya khansa ya khansa ya khansa |
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Blinatumomab (Blincyto) | Kubwezeretsedwa kapena kusokoneza B-cell precursor pachilendo chachikulu cha mthemphablastic khansa ya m'magazi (ONSE) mwa akuluakulu ndi ana |
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Mmodzi wa iwo, spuleucel-T, amawoneka ngati mankhwala a CAR T-cell m'thupi mwake pogwiritsira ntchito maselo anu okhudzana ndi chitetezo cha mthupi omwe amayamba kusonkhanitsidwa m'magazi pawokha ndikusinthidwa mu labotale; iwo amavomerezedwa ndi kupangidwa kukhala omvera kwambiri maselo otupa, kenaka amalowerera mmagazi monga mankhwala.
Sipuleucel-T imatengedwa ngati "katemera wa autologous," kapena "autologous cell immunotherapy," komabe osati mankhwala a CAR T-cell popeza maselo a chitetezo cha mthupi akuphunzitsidwa kuyankha, osati kuti azigwiritsa ntchito mavitamini a maselo .
Zomwe zimayambitsa matenda a immune monga ipilimumab (pamwambapa) zimagwira ntchito zosiyanasiyana za chitetezo cha mthupi mwa "kugwiritsa ntchito mabeleka," kapena "kugunda mafuta" pa chitetezo cha thupi, kuti ayese kuteteza chitetezo chanu cha mthupi ku khansa. Ipilimumab ndi chitsanzo chimodzi cha mankhwala omwe amagwira ntchito motere. Chitsanzo china cha chitetezo cha mthupi mwa inhibitor ndi pembrolizumab (Keytruda), chomwe chimalimbikitsa "kusinthana" kwa T-maselo, otchedwa PD-1.
Mankhwala a CAR-T: Zoona "Mankhwala Osokoneza Bongo"
Komabe, mankhwala ochiritsira a CAR-T, ndithudi, ali osiyana ndi awo enieni. T-maselo amachotsedwa m'thupi lanu, amawongolera kuti azitha kuzindikira bwino ndi kupha maselo a m'mimba, kenaka amadziwidwanso ngati mankhwala opatsirana. Maselo angapangidwe ndipo amakula mu masiku angapo 21 ndipo kenako amalowetsedwa m'magazi.
CAR T-cell mankhwala si mankhwala omwe angagwiritsidwe ntchito musanayese mankhwala ena-osati, osati panopo. Mankhwalawa atsopano amachokera ku zowawa zomwe, chifukwa odwala omwe ali ndi matenda ochedwa khansa, mankhwala opatsirana khansa, kuphatikizapo opaleshoni, chemotherapy, ndi mankhwala othandizira, nthawi zambiri amapereka mphamvu zochepa.
Kotero, pakalipano, mankhwala a CAR-T akhala akupezeka kwa odwala omwe adaloledwa ku mayesero a zamankhwala, monga momwe chithandizochi chimaonedwa kuti ndifukufuku ku US, koma izi zingasinthe mwamsanga. Mankhwala a CAR-T angakhale FDA ovomerezeka ndipo amapezeka kunja kwa mayesero a kachipatala 2017-2018.
Mndandanda wafupipafupi wa anthu akuluakulu omwe akuwongolera kuchipatala amatsatira.
CTL019 (tisagenlecleucel) ndi Novartis
CTL019 ndi CD19-enieni chimeric antigen receptor (CAR) -yiyikidwa pa T-cell therapy.
Tiyeni tiyambe mwa kutsegula chiganizo chammbuyo: CD19 ndi molekyu pa maselo ena oteteza mthupi omwe amatchedwa B-maselo, ndipo maselowa angakhale magwero a mitundu yambiri ya khansa ya m'magazi ndi lymphoma .
Kuchuluka kwa mlingo umodzi wa CTL019 kwabweretsa kutalika kwa nthawi yaitali ndipo mwinamwake kuchiritsa (sitidziwabe) kwa odwala ochulukirapo omwe amapita kunja kwa chithandizo chamankhwala.
Pano pali kugwidwa kwa matenda omwe CTL019 ikuganiziridwa pakali pano:
- CTL019 inalandira mankhwala a FDA Breakthrough Therapy kuti azitha kuchiza odwala achikulire omwe amatha kubwezeretsa / kutengeka kwakukulu kwa B-cell lymphoma (DLBCL). (Mafupa ammimba amagawidwa m'magulu awiri: Hodgkin ndi osakhala Hodgkin Mtundu wambiri wosakhala Hodgkin lymphoma ndi DLBCL).
- CTL019 imathandizidwanso kuti ayambe kulandira mankhwala ochiritsidwa kapena obwezeretsa ana komanso akuluakulu omwe ali ndi B-cell acute lymphoblastic leukemia (ALL).
CTL019 idalandira voti (10-0) yovomerezeka yovomerezeka kuchokera ku Komiti ya Advocacy Committee ya FDA ya Oncologic Drugs Advisory, kutanthauza kuti zinthu zikuwoneka kuti zikuvomerezedwa kuti zivomerezedwe. Novartis akukonzekera CTL019 kuti avomereze kuchipatala kapena kubwezeretsa B-cell Zonse mwa odwala komanso odwala akuluakulu. Khansa ya m'magazi ndi khansa ya nambala yoyamba, ndipo YONSE ndiyo mawonekedwe ambiri, omwe amachititsa pafupifupi 25 peresenti ya khansa yaunyamata. Pali mitundu yosiyanasiyana ya ZONSE, kuphatikizapo B-cell ALL ndi T-cell ALL, ndipo ma subtypes mkati amatha kunyamula zizindikiro zawo.
CTL019 pakalipano ndikuyang'anitsitsa ndipo kuvomereza kwa nthawi yake kungakhale yoyamba ya CAR-T yothandizira kukhalapo. Thandizo la maselo a CAR likhoza kupezeka kwa ana ang'onoang'ono komanso achichepere omwe ali ndi khansa ya m'magazi samayankha. Odwalawa ali ndi vuto loperewera, koma pachiyeso chachikulu kwambiri poyesera mankhwalawa m'mayiko pafupifupi khumi ndi awiri, odwala 83 peresenti analowa pansi. Chaka chotsatira, magawo awiri pa atatu anakhalabe choncho.
Chifukwa mankhwala samapha osati kokha maselo a B-bulu koma amakhalanso ndi thanzi labwino, mitundu yolimbana ndi majeremusi, odwala amafunikira mankhwala kuti ateteze ku matenda. Amalandira chitetezo cha immune globulins miyezi ingapo ngati njira yotetezera.
Chimodzi mwa zotsatira zofala kwambiri chimatchedwa cytokine release syndrome, chomwe chimayambitsa kutentha kwa malungo ndi zizindikiro monga chimfine chimene nthawi zina chingakhale choopsa kwambiri kuti wodwala amatha kukhala ndi chithandizo chokwanira. Chodetsa nkhaŵa china chachikulu ndi matenda a ubongo, omwe angapangitse kusokonezeka kwa kanthawi kapenanso kutentha kwa ubongo.
Pofuna kuonetsetsa chitetezo cha odwala, Novartis sakukonzekera zopangira mankhwala, ndi mankhwala omwe amawombera mochuluka komanso mwamphamvu ngati n'kotheka. Kampaniyo idzaika malo ochipatala 30 mpaka 35 kuti athe kupereka chithandizo. Ambiri a iwo adayesedwa ku mayesero a zachipatala, ndipo onse aphunzira zambiri.
Ciloleucel ya Axicabtagene ndi Kite Pharma
Kuchokera ku Santa Monica, California, Kite Pharma ndi kampani yomwe imayang'ana pa CAR ndi T-cell yolandira mankhwala opangidwa ndi maselo. Kite ikukulitsa chithandizo cha CAR T-cell chomwe chimatchedwa axicabtagene ciloleucel, yomwe tsopano ikuyang'aniratu ku US kuti ayambe kuchiritsa odwala omwe ali ndi nkhanza zosautsa za mtundu wina osati Hodgkin lymphoma (NHL). Odwala omwe ali ndi nkhanza zoopsa za NHL amayang'aniridwa ndi chifuwa chachikulu ndi 50 peresenti yokhala ndi mwayi wopulumuka miyezi isanu ndi umodzi. Izi zikutsindika zosowa zofunikira zachipatala za odwalawa.
Mofanana ndi CTL019, axicabtagene ciloleucel imalinso antigen CD19, mapuloteni omwe amapezeka m'kati mwa B-cell lymphomas ndi leukemias. Maselo a T odwala amapangidwa kuti afotokoze chimeric antigen receptor (CAR) kuti akonze antigen CD19.
Mu chitukuko cha mankhwala ndi chivomerezo, axicabtagene ciloleucel ali ndi mbiri yofanana ndi ya CTL019, poyang'ana pa malungo omwe ali ndi B-cell, koma B cell ALL sawoneka kuti ndi gawo la chitukuko chake pakadali pano.
Pano pali kuthamanga kwa matenda omwe axicabtagene ciloleucel ikuganiziridwa pakali pano:
- Pulojekiti ya axicabtagene yachipatala yakhala ikupatsidwa mwayi wotchuka wa B-cell lymphoma (DLBCL), transformed follicular lymphoma (TFL), komanso primary mediastinal B-cell lymphoma (PMBCL) ndi thandizo la US FDA ndi Priority Medicines (PRIME) DLBCL mu EU.
Kulandiridwa ngati Breakthrough Therapy ndi FDA kumathandizidwa ndi deta yochokera ku ZUMA-1 Phase 2 yesesero yomwe inagwirizana ndi mapeto a zolinga zowonjezera (ORR) zolembedweratu pambuyo podula limodzi la axicabtagene ciloleucel ndi 82 peresenti (p <0.0001). Pambuyo pa miyezi 8.7, anthu 44 peresenti ya odwala anali kuyankha mobwerezabwereza, kuphatikizapo 39 peresenti ya odwala poyankha kwathunthu (CR).
Zochitika zovuta zomwe zimachitika ndi kuphana kwa maselo abwino omwe amamenyana ndi matenda ndikuthandiza magazi kuti aphimbe. Mofanana ndi CTL019, imodzi mwa zotsatira zoyipa zimatchedwa cytokine release syndrome, yomwe imayambitsa kutentha kwa thupi ndi zizindikiro monga matenda omwe nthawi zina amakhala oopsa kwambiri kuti wodwala amatha kukhala ndi chithandizo chamankhwala. Kuchulukanso kwa matenda kungachititse kuti chisokonezo cha kanthaŵi kapena chithokomiro chikhoza kupha. Panali anthu atatu omwe anaphedwa panthawi yomwe analembera milandu osati chifukwa cha matenda, zomwe zinali zochitika ziwiri, zinayesedwa zogwirizana ndi axicabtagene ciloleucel. Apanso, chitukuko cha mankhwalawa chikuyenera kupitirira mosamala.
GoCAR-T, Wotsatila Matenda Olimba ndi Bellicum Pharmaceuticals
Houston, Texas-based based on Bellicum Pharmaceuticals, Inc., ali ndi odwala mankhwala omwe akuphatikizidwa ndi BPX-601 (mgwirizano wa GoCAR-T, chifukwa chokhala ndi zotupa zolimba, zomwe zimapangidwa ndiMMC activation switch to improve efficiency, phase I), ndi BPX-701 -popopotopera ya TCR, chifukwa cha zotupa zowononga , zomwe zinapangidwa ndi kusintha kwa CaspaCIDe, gawo I).
Kotero, kodi zonsezi zikutanthauza chiyani? Kwenikweni, gulu lino likugwira ntchito yowonongeka kachipangizo cha CAR T-cell kuti icho chidzipatse wodwala kuti azilamulira kwambiri pa yankho la T-maselo. Maselo a GoCAR-T apangidwa kuti athetseketsa bwino pamene akuwonekera ku maselo a khansa ndi wothandizira wotchedwa rimiducid. Choncho, wodwala amatha kulamulira kuchuluka kwa maselo a CAR-T mwa kusintha ndondomeko ya rimiducid administration, koma kupha maselo kungakhale koyendetsa pang'onopang'ono.
Otsatira Ena
Juno ndi kampani yomwe tsopano ikuyang'ana JCAR017, chipangizo cha CAR-T chomwe chimayang'ana CD19. Juno akuyang'ana kuti atenge JCAR017 pamsika kumapeto kwa 2018 kwa NHL. Kampaniyo imayanjana ndi a Celen mu kuyesayesa.
ZIOPHARM Oncology ili ndi mankhwala omwe ali ndi CD19 ndipo ikugwira ntchito pa CD-yeniyeni ya CAR T-cell therapy pofuna kubwezeretsedwa / kutsutsa kwambiri myeloid khansa ya m'magazi (AML). NantKwest ndi kampani yowonongeka yomwe imagwiritsa ntchito opha zachilengedwe (NK) maselo kuti athetse khansa, matenda opatsirana, ndi matenda opweteka.
Nyuzipepala ya NK yothandizira khungu yapangidwa kuti iwonetsere selo imfa yokhudza khansara kapena maselo odwala ndi njira zitatu zosiyana-kupha mwachindunji pogwiritsa ntchito NK cells (aNK); Kupha munthu wothandizira odwala pogwiritsa ntchito njira zopangira ma ARV, komanso kupha anthu okhudzidwa pogwiritsa ntchito taNKs.
Mawu Ochokera
Zina mwa zotsatira zoyambirira kuchokera kuchipatala cha CAR-T zakhala zokondweretsa kwambiri, kupereka mankhwala atsopano kwa magulu a odwala amene sanakhalepo ndi njira zoterezo. Palinso zolephereka, komabe, komanso zovuta zambiri kuti zithandizozi zikhale zogwiritsidwa ntchito mwamsanga ndi poizoni.
Monga momwe ofufuza amadziwira zambiri za chitetezo cha mthupi chomwe chikugwiritsidwa ntchito pa zochiritsira zimenezi, ndipo zomwe zimakhudzidwa ndi malungo omwe akuwunikira, chithunzi chowonekera bwino cha zoopsa ndi zopindulitsa ziyenera kutuluka.
> Zotsatira:
> Wang M, Yin B, Wang HY, Wang RF. Kusintha kwamakono mu T-cell-based-cancer immunotherapy. Immunotherapy . 2014; 6 (12): 1265-1278.
> Bhoj VG, Arhontoulis D, Wertheim G, et al. Kulimbikira kwa maselo a m'magazi a nthawi yaitali komanso chitetezo chaumunthu mwa anthu omwe amatsatira kachidakwa ka CD T-cell yomwe imatsogoleredwa ndi CD19. Magazi. 2016; 128 (3): 360-370.
> Kite ikulandira US Food and Drug Administration Kufunika Kwambiri kwa Axicabtagene Ciloleucel. http://ir.kitepharma.com/releasedetail.cfm?releaseid=1028075 Yapezeka mu July 2017.
> Morris EC, Stauss HJ. Kukulitsa chithandizo cha jini la T-cell chothandizira matenda opatsirana pogonana. Magazi . 2016; 127 (26): 3305-3311.
> Park JH, Geyer MB, Brentjens RJ. Matenda a CAR T-cell omwe amagwiritsidwa ntchito pa CD19 pa zizindikiro za matenda a hematologic: kutanthauzira zotsatira zachipatala mpaka lero. Magazi . 2016; 127 (26): 3312-3320.