{"id":1806,"date":"2019-10-29T08:33:16","date_gmt":"2019-10-29T07:33:16","guid":{"rendered":"https:\/\/www.newslab.sk\/2019\/10\/29\/uloha-imunitnej-odpovede-v-prognoze-kolorektalneho-karcinomu\/"},"modified":"2019-11-04T14:25:59","modified_gmt":"2019-11-04T13:25:59","slug":"uloha-imunitnej-odpovede-v-prognoze-kolorektalneho-karcinomu","status":"publish","type":"post","link":"https:\/\/www.newslab.sk\/en\/uloha-imunitnej-odpovede-v-prognoze-kolorektalneho-karcinomu\/","title":{"rendered":"The role of the immune response in the prognosis of colorectal cancer"},"content":{"rendered":"

*All tables, charts, graphs and pictures that are featured in this article can be found in the .pdf attachment at the end of the paper.<\/strong><\/span><\/p>\n

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\u00davod<\/strong><\/h2>\n

Kolorekt\u00e1lny karcin\u00f3m (CRC) predstavuje v s\u00fa\u010dasnosti z\u00e1va\u017en\u00fd epidemiologick\u00fd probl\u00e9m z h\u013eadiska morbidity a mortality tohto onkologick\u00e9ho ochorenia v slovenskej popul\u00e1cii. Na t\u00fato skuto\u010dnos\u0165 reaguje aj implementovan\u00fd N\u00e1rodn\u00fd onkologick\u00fd program Slovenskej republiky, ktor\u00fd zah\u0155\u0148a od roku 2019 popula\u010dn\u00fd skr\u00edning CRC u os\u00f4b medzi 50. a 70. rokom \u017eivota, S cie\u013eom zlep\u0161enia kontroly, sekund\u00e1rnej prevencie a nadv\u00e4zuj\u00facej lie\u010dby tohto n\u00e1dorov\u00e9ho ochorenia. Pr\u00e1ve v r\u00e1mci \u010fal\u0161ieho overovania terapeutick\u00fdch mo\u017enost\u00ed v s\u00fa\u010dasnosti prebieha diskusia o \u00fa\u010dinnosti a efektivite imunoterapie tzv. checkpoint inhib\u00edtormi u pacientov s CRC.<\/p>\n

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Mechanizmy protin\u00e1dorovej imunitnej odpovede<\/h3>\n

Imunitn\u00e9 odpovede proti n\u00e1dorom maj\u00fa spolo\u010dn\u00e9 \u010drty s odpove\u010fou na cudzorod\u00e9 antig\u00e9ny vr\u00e1tane infek\u010dn\u00fdch agensov. Vroden\u00e9 mechanizmy imunity rozpozn\u00e1vaj\u00fa \u0161pecifick\u00e9 tumorov\u00e9 antig\u00e9ny na povrchu buniek n\u00e1doru mechanizmom, ktor\u00fd je podobn\u00fd rozl\u00ed\u0161eniu antig\u00e9nov cudzorod\u00fdch pre telo. NK-bunky rozpozn\u00e1vaj\u00fa nedostatok MHC-I molek\u00fal na povrchu buniek n\u00e1doru a zap\u00e1jaj\u00fa sa do imunitn\u00fdch odpoved\u00ed akt\u00edvnym odstra\u0148ovan\u00edm t\u00fdchto buniek a aktiv\u00e1ciou subpopul\u00e1ci\u00ed buniek prostredn\u00edctvom uvo\u013e\u0148ovania cytok\u00ednov. Takto aktivovan\u00e9 makrof\u00e1gy a dendritick\u00e9 bunky fagocytuj\u00fa n\u00e1dorov\u00e9 bunky a n\u00e1sledne prezentuj\u00fa ich antig\u00e9ny na svojom povrchu, \u010d\u00edm aktivuj\u00fa \u0161pecifick\u00fa cytolytick\u00fa odpove\u010f sprostredkovan\u00fa T-bunkami. Tieto efektorov\u00e9 T-bunky sa klon\u00e1lne \u0161\u00edria s cie\u013eom \u00fapln\u00e9ho odstr\u00e1nenia n\u00e1doru. N\u00e1dorov\u00e9 bunky preto v reakcii na imunitn\u00fa odpove\u010f podstupuj\u00fa proces selekcie smerom k bunk\u00e1m, ktor\u00e9 maj\u00fa schopnos\u0165 unikn\u00fa\u0165 imunitn\u00e9mu doh\u013eadu prostredn\u00edctvom t\u00fdchto mechanizmov: zn\u00ed\u017een\u00e1 imunogenita, expresia vysokoimunosupres\u00edvneho mikroprostredia a stimul\u00e1cia mikroprostredia bohat\u00e9ho na faktory podporuj\u00face z\u00edskavanie \u017eiv\u00edn, angiogen\u00e9za a prestavba medzibunkovej hmoty(1).<\/p>\n

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Mal\u00edgne bunky \u2013 mechanizmy \u00faniku spod imunitn\u00e9ho doh\u013eadu<\/h3>\n

N\u00e1dorov\u00e9 bunky uplat\u0148uj\u00fa viacero strat\u00e9gi\u00ed, na z\u00e1klade ktor\u00fdch sa sna\u017eia unikn\u00fa\u0165 kontrole imunitn\u00e9ho syst\u00e9mu. Dosiahnu to najm\u00e4 maskovan\u00edm svojho \u0161pecifick\u00e9ho n\u00e1dorov\u00e9ho antig\u00e9nu, ktor\u00fd by bol rozpoznate\u013en\u00fd imunitn\u00fdm syst\u00e9mom. \u010ealej imunogenicita n\u00e1dorovo transformovan\u00fdch buniek je \u00fa\u010dinne zni\u017eovan\u00e1 mut\u00e1ciami v g\u00e9noch k\u00f3duj\u00facich n\u00e1dorov\u00e9 antig\u00e9ny. Mo\u017eno pozorova\u0165 aj pokles, respekt\u00edve stratu MHC molek\u00fal nevyhnutn\u00fdch pre prezent\u00e1ciu n\u00e1dorov\u00fdch antig\u00e9nov T-lymfocytom. Samotn\u00e9 celul\u00e1rne zlo\u017eky imunity s\u00fa vyu\u017e\u00edvan\u00e9 n\u00e1dorov\u00fdmi bunkami. Aktiv\u00e1cia T-lymfocytov je sprostredkovan\u00e1 cez TCR-receptor (obr\u00e1zok 1)<\/em><\/strong>, ktor\u00fd interaguje s antig\u00e9nom naviazan\u00fdm na molekulu MHC na bunk\u00e1ch prezentuj\u00facich antig\u00e9n. Tento sign\u00e1l zais\u0165uje \u0161pecificitu odpovede, ale na samotn\u00fa aktiv\u00e1ciu T-lymfocytov neposta\u010duje. Ako tzv. kostimula\u010dn\u00fd sign\u00e1l sl\u00fa\u017ei interakcia molekuly CD28 a receptora B7 na APC. Nedostato\u010dn\u00e1 sila kostimula\u010dn\u00e9ho sign\u00e1lu sp\u00f4sob\u00ed funk\u010dn\u00fa inaktivitu (anergiu) t\u00fdchto buniek imunity. Anergn\u00e9 T-lymfocyty nemaj\u00fa schopnos\u0165 produkova\u0165 aktiva\u010dn\u00e9 cytok\u00edny, \u010do br\u00e1ni ich dozrievaniu na efektorov\u00e9 bunky. Rozsah imunitnej odpovede je tie\u017e z\u00e1visl\u00fd od interakcie \u010fal\u0161\u00edch receptorov a ligandov, ktor\u00e9 amplifikuj\u00fa alebo, naopak, tlmia procesy aktiv\u00e1cie T-lymfocytov. Signifikantnou inhibi\u010dnou dr\u00e1hou, ktor\u00e1 navodzuje inaktivitu lymfocytov je PD-1\/PD-L1 a ktor\u00e1 je pova\u017eovan\u00e1 za kontroln\u00fd bod imunitn\u00e9ho syst\u00e9mu, tzv. checkpoint, a vo v\u0161eobecnosti t\u00e1to dr\u00e1ha ochra\u0148uje pred vznikom autoimunitn\u00fdch ochoren\u00ed. Zv\u00fd\u0161en\u00e1 aktivita inhibi\u010dnej PD-1\/PD-L1 dr\u00e1hy m\u00f4\u017ee vyvola\u0165 funk\u010dn\u00e9 postihnutie efektorov\u00fdch T-lymfocytov a sp\u00f4sobi\u0165 ich vy\u010derpanie, tzv. exhausting. Tak\u00e9to T-lymfocyty n\u00e1sledne nie s\u00fa schopn\u00e9 \u0161pecifickej cytotoxickej odpovede a cielenej de\u0161trukcie buniek(2).<\/p>\n

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PD-1 receptor a jeho expresia<\/h3>\n

PD-1 je transmembr\u00e1nov\u00fd glykoprote\u00edn patriaci do rodiny prote\u00ednov CD28\/B7 reguluj\u00faci aktivitu T-lymfocytov. Nach\u00e1dza sa predov\u0161etk\u00fdm na aktivovan\u00fdch T- a B-lymfocytoch, NK-bunk\u00e1ch, dendritick\u00fdch bunk\u00e1ch a na lymfocytoch infiltruj\u00facich tumor (TIL). Najd\u00f4le\u017eitej\u0161iu funkciu zast\u00e1va ako inhibi\u010dn\u00fd receptor na T-lymfocytoch. Aktivovan\u00fd T-lymfocyt exprimuje PD-1 na svojom povrchu po rozpoznan\u00ed antig\u00e9nu a produkuje interfer\u00f3ny, ktor\u00e9 indukuj\u00fa expresiu PD-1 v r\u00f4znych tkaniv\u00e1ch. Viazanie PD-1 s jeho ligandom limituje aktivitu T-bunky(3).<\/p>\n

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Ligandy PD-L1 a PD-L2 a ich expresia<\/h3>\n

Ligand receptora programovanej bunkovej smrti PD-L1, taktie\u017e ozna\u010dovan\u00fd CD274 alebo B7-H1, je transmembr\u00e1nov\u00fd prote\u00edn, ktor\u00fd hr\u00e1 podstatn\u00fa \u00falohu v blok\u00e1de imunitn\u00fdch mechanizmov pri procesoch ako kancerogen\u00e9za, autoimunitn\u00e9 ochorenia, ale aj gravidita. Identifikovan\u00fd bol na CD4+ a CD8+ T-bunk\u00e1ch, dendritick\u00fdch bunk\u00e1ch, makrof\u00e1goch, T-regula\u010dn\u00fdch lymfocytoch, epitelov\u00fdch bunk\u00e1ch, endoteli, na bunk\u00e1ch imunitne privilegovan\u00fdch miest, ako je fetoplacent\u00e1rna bari\u00e9ra, a na v\u00e4\u010d\u0161ine n\u00e1dorov\u00fdch buniek. N\u00e1dorov\u00e9 tkanivo \u010dasto vykazuje zv\u00fd\u0161en\u00fa hladinu PD-L1, ktor\u00fa nach\u00e1dzame v lok\u00e1lne ohrani\u010den\u00fdch oblastiach na povrchu buniek a je pravdepodobn\u00e9, \u017ee napom\u00e1ha vznik n\u00e1dorovej tolerancie(4).<\/p>\n

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Klinick\u00fd v\u00fdznam stanovenia kontroln\u00e9ho bodu PD-1\/ PD-L1 v CRC<\/h3>\n

Cielen\u00e1 imunoterapia vyv\u00edjan\u00e1 s cie\u013eom selekt\u00edvnej inhib\u00edcie PD-1\/PD-L1 kontroln\u00e9ho bodu imunity sa sna\u017e\u00ed potencio- va\u0165 schopnos\u0165 organizmu rozpozna\u0165 a de\u0161truova\u0165 n\u00e1dorov\u00e9 bunky, a t\u00fdm prin\u00e1\u0161a nov\u00fd pr\u00edstup v lie\u010dbe pre vybran\u00fdch pacientov s CRC. V s\u00fa\u010dasnosti je na trhu 5 monoklon\u00e1lnych protil\u00e1tok proti PD-1\/PD-L1, ktor\u00e9 registruje U.S. Food and Drug Administration (FDA), respekt\u00edve European Medicines Agency (EMA), s cie\u013eom indik\u00e1ci\u00ed imunoterapie v klinickom sk\u00fa\u0161an\u00ed a demon\u0161truje ich \u00fa\u010dinnos\u0165 zlep\u0161enou terapeutickou reakciou. Ide o atezolizumab, avelumab, durvalumab, nivolumab a pembrolizumab. Hoci sk\u00famanie efektivity tohto typu imunoterapie sa rap\u00eddne vyv\u00edja, nejasn\u00fdm zost\u00e1va definovanie \u00farovne a rozsahu expresie PD-L1 vo vzork\u00e1ch n\u00e1dorov, ktor\u00e1 by pomohla lep\u0161ie identifikova\u0165 pacientov, ktor\u00ed bud\u00fa najviac profitova\u0165 z dan\u00e9ho sp\u00f4sobu lie\u010dby. Pr\u00e1ve takto s\u00fa kreovan\u00e9 testy na detekciu expresie PD-L1 na n\u00e1dorov\u00fdch bunk\u00e1ch a\/alebo bunk\u00e1ch imunity nach\u00e1dzaj\u00facich sa v mikroprostred\u00ed n\u00e1doru(5).<\/p>\n

Overman a spol.(6) publikovali v\u00fdsledky druhej f\u00e1zy \u0161t\u00fa- die CheckMate 142 (NCT02060188), v ktorej bola \u0161tudovan\u00e1 efektivita a bezpe\u010dnos\u0165 terapie nivolumabu v kombin\u00e1cii s ipilimumabom u pacientov s metastatick\u00fdm mismatch-repair deficitn\u00fdm CRC alebo CRC s chromoz\u00f3movou instabilitou (dMMR\/MSI-H). V\u00fdsledky uk\u00e1zali, \u017ee nivolumab a ipilimumab potenciuj\u00fa pre\u017e\u00edvanie bez progresie (PFS) a celkov\u00e9 pre\u017e\u00edvanie (OS) v 12-mesa\u010dnom sledovan\u00ed a s\u00fa s\u013eubnou novou lie\u010debnou modalitou pre pacientov s dMMR\/MSI-H mCRC.<\/p>\n

\u0160t\u00fadia s ozna\u010den\u00edm NCT01988896 hodnotila \u00fa\u010dinok kombin\u00e1cie atezolizumabu a kobimetinibu vo f\u00e1ze Ib pri metastatickom CRC. Do \u0161t\u00fadie boli zahrnut\u00ed jedinci s refrakt\u00e9rnym CRC proti chemoterapii a pacienti s lok\u00e1lne pokro\u010dil\u00fdm metastatick\u00fdm CRC. Testovan\u00e1 terapeutick\u00e1 kombin\u00e1cia uk\u00e1zala priazniv\u00fd bezpe\u010dnostn\u00fd profil a objekt\u00edvna odpove\u010f pozorovan\u00e1 u pacientov s MSS\/MSI-low metastatick\u00fdm CRC priniesla benefit z tejto novej terapeutickej kombin\u00e1cie v subpopul\u00e1cii pacientov refrakt\u00e9rnych na chemoterapiu(7).<\/p>\n

Toh a spol.(8) hodnotili potenci\u00e1l imunoterapie na z\u00e1klade dostupn\u00fdch publik\u00e1ci\u00ed z medic\u00ednskych datab\u00e1z, posudzuj\u00fac PD-1\/PD-L1 v n\u00e1dorovom mikroprostred\u00ed. Prostredn\u00edctvom klinick\u00fdch \u0161t\u00fadi\u00ed, ktor\u00e9 hodnotili PD-1 inhib\u00edtory, sa sna\u017eili verifikova\u0165 predpoklad, \u017ee imunoterapia s pou\u017eit\u00edm PD-1 inhib\u00edtorov je vhodn\u00e1 aj pre CRC. Z ich zisten\u00ed vypl\u00fdva, \u017ee imunoterapia s vyu\u017eit\u00edm PD-1 inhib\u00edtora prin\u00e1\u0161a potenci\u00e1lny benefit u pacientov s MSI-H CRC, nejestvuje v\u0161ak jednozna\u010dn\u00fd d\u00f4kaz, \u017ee tento typ terapie je vhodn\u00fd a prin\u00e1\u0161a benefit pre pacientov s MSS CRC. \u010eal\u0161\u00edm limitom, ktor\u00fd autori pomenovali, bolo, \u017ee neboli zahrnut\u00e9 do porovnania \u0161t\u00fadie s metastatick\u00fdm CRC(8). Siln\u00fa protin\u00e1dorov\u00fa aktivitu pembrolizumabu u lie\u010den\u00fdch pacientov s MSI-H CRC potvrdili \u010fal\u0161ie \u0161t\u00fadie(10). Koganemaru a spol.(9) posudzovali prognostick\u00fd v\u00fdznam PD-L1 expresie u pacientov v III. \u0161t\u00e1diu CRC a hlavn\u00fdm cie\u013eom bolo vyhodnoti\u0165 vz\u0165ah medzi PD-L1 statusom, n\u00e1dorov\u00fdm mikroprostred\u00edm a klinickopatologick\u00fdmi charakteristikami III. \u0161t\u00e1dia. Na stanovenie PD-L1 bola pou\u017eit\u00e1 monoklon\u00e1lna protil\u00e1tka SP142 a ako hranica pre sk\u00f3rovanie n\u00edzkej, respekt\u00edve vysokej expresie bolo stanoven\u00fdch 5 % pozit\u00edvnych buniek. Pacienti s vysokou \u00farov\u0148ou expresie PD-L1 na n\u00e1dorov\u00fdch bunk\u00e1ch mali signifikantne krat\u0161\u00ed \u010das pre\u017e\u00edvania bez choroby oproti pacientom s vysokou \u00farov\u0148ou detegovanej expresie PD-L1 na bunk\u00e1ch infiltruj\u00facich tumor (TIMC), kde bol trend opa\u010dn\u00fd. \u010co sa t\u00fdka pos\u00fadenia PD-L1 expresie vo vz\u0165ahu ku klinickopatologickej charakteristike, n\u00e1dory s vysokou mierou expresie PD-L1 boli sp\u00e1jan\u00e9 s v\u00e4\u010d\u0161\u00edm po\u010dtom metast\u00e1z v lymfatick\u00fdch uzlin\u00e1ch a pokro\u010dilej\u0161\u00edm TNM-stagingom. Autori teda dospeli k z\u00e1veru, \u017ee vysok\u00e1 \u00farove\u0148 expresie PD-L1 na n\u00e1dorov\u00fdch bunk\u00e1ch je preuk\u00e1zate\u013ene asociovan\u00e1 so zlou progn\u00f3zou, naproti tomu vysok\u00e1 \u00farove\u0148 expresie PD-L1 na TIMC je asociovan\u00e1 s dobrou progn\u00f3zou(9).<\/p>\n

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Imunohistochemick\u00e9 stanovenie expresie PD-L1<\/h3>\n

V r\u00e1mci hodnotenia expresie PD-1\/PD-L1 prostredn\u00edctvom IHC je PD-L1 jedn\u00fdm z najd\u00f4le\u017eitej\u0161\u00edch a z\u00e1rove\u0148 najviac \u0161tudovan\u00fdm membr\u00e1nov\u00fdm ligandom. S\u00fahlas vydan\u00fd FDA lie\u010di\u0165 pacientov s metastatick\u00fdm NSCLC pembrolizumabom, pri\u010dom indik\u00e1cia tejto terapie je zalo\u017een\u00e1 na IHC testovan\u00ed pr\u00e1ve PD-L1 expresie, viedol k exponenci\u00e1lnemu n\u00e1rastu v testovan\u00ed met\u00f3dou IHC prostredn\u00edctvom viacer\u00fdch PD-1\/PD-L1 protil\u00e1tok. S\u00fahrnne s\u00fa dostupn\u00e9 viacer\u00e9 anti-PD-L1 protil\u00e1tky a IHC metodiky: Dako 22C3, Dako 28-8, Ventana SP263, Ventana SP142. Terapeutick\u00fdm cie\u013eom je bu\u010f PD-1 receptor na n\u00e1dorov\u00fdch bunk\u00e1ch (pembrolizumab a nivolumab), alebo PD-L1 ligand na T-bunk\u00e1ch (durvalumab a atezolizumab). Chyby pri spracovan\u00ed vzoriek, heterogenita n\u00e1doru alebo testovanie vzoriek tkan\u00edv z\u00edskan\u00fdch v \u010dase diagn\u00f3zy, uprednostnen\u00e9 pred testovan\u00edm v \u010dase progresie alebo relapsu, m\u00f4\u017ee podhodnoti\u0165 alebo, naopak, nadhodnoti\u0165 percentu\u00e1lny podiel n\u00e1dorov\u00fdch buniek vykazuj\u00facich PD-L1 expresiu. \u00darove\u0148 expresie PD-L1 je dynamick\u00e1 a m\u00f4\u017ee sa meni\u0165 po cielenej lie\u010dbe a\/alebo chemoterapii, respekt\u00edve r\u00e1dioterapii(11).<\/p>\n

 <\/p>\n

Ostatn\u00e9 typy n\u00e1dorov a ich reakcia na lie\u010dbu immune checkpoint inhib\u00edtormi<\/h3>\n

Ipilimumab, teda anti-CTLA-4 protil\u00e1tka (CTLA4ab), bol povolen\u00fd FDA s cie\u013eom lie\u010dby metastatick\u00e9ho melan\u00f3mu v roku 2011. N\u00e1sledne bol udelen\u00fd s\u00fahlas pre anti-PD-1 protil\u00e1tky (PD1ab) pembrolizumab a nivolumab v roku 2014. Okrem uveden\u00e9ho lie\u010dba s PD1ab je v s\u00fa\u010dasnosti vyu\u017e\u00edvan\u00e1 pre viacer\u00e9 pokro\u010dil\u00e9 malignity: NSCLC, urotelov\u00e9 malignity, ren\u00e1lne karcin\u00f3my (RCC), skvam\u00f3zny karcin\u00f3m hlavy a krku (SCCHN), karcin\u00f3m \u017eal\u00fadka, hepatocelul\u00e1rny karcin\u00f3m a klasick\u00fd Hodgkinov lymf\u00f3m (cHL). Monoklon\u00e1lne protil\u00e1tky namieren\u00e9 proti PD-L1 (PD-L1ab) atezolizumab (s vyu\u017eit\u00edm pri urotelovom karcin\u00f3me a NSCLC), durvalumab (urotelov\u00fd karcin\u00f3m), avelumab (karcin\u00f3m z Merkelov\u00fdch buniek a urotelov\u00fd karcin\u00f3m) taktie\u017e registrovala FDA. V roku 2017 FDA tie\u017e udelila s\u00fahlas viazan\u00fd s biomarkerom v podobe preuk\u00e1zan\u00e9ho mismatch repair deficitu (dMMR) pre pembrolizumab u pacientov s neresekovate\u013en\u00fdmi alebo metastatick\u00fdmi sol\u00eddnymi n\u00e1dormi a pre CRC s vysokou mierou mikrosatelitovej instability (MSI-H) alebo dMMR. Napriek enormn\u00e9mu pokroku v nasadzovan\u00ed imunoterapeut\u00edk v r\u00e1mci onkologickej terapie odpove\u010f na \u0148u sa l\u00ed\u0161i v jednotliv\u00fdch typoch n\u00e1dorov a jednotliv\u00fdmi skupinami pacientov. Pri melan\u00f3me PD1ab monoterapia m\u00f4\u017ee dosahova\u0165 odpove\u010f na \u00farovni medzi 26 \u2013 32 % a pri kombin\u00e1cii PD1ab a CTLA4ab dosahuje odpove\u010f na \u00farovni viac ako 60 %. Vybran\u00e9 podskupiny pacientov dosahuj\u00fa pretrv\u00e1vaj\u00facu terapeutick\u00fa reakciu pri PD1ab monoterapii a nevy\u017eaduj\u00fa kombinovan\u00fa imunoterapiu, a teda s\u00fa v zna\u010dnej miere chr\u00e1nen\u00ed pred ne\u017eiaducimi \u00fa\u010dinkami tejto lie\u010dby. Tieto skuto\u010dnosti poukazuj\u00fa na potrebu n\u00e1js\u0165 relevantn\u00e9 biomarkery, ktor\u00e9 pom\u00f4\u017eu identifikova\u0165 skupinu pacientov, pre ktor\u00fdch tento typ lie\u010dby bude benefitom, a z\u00e1rove\u0148 pre pacientov prim\u00e1rne rezistentn\u00fdch(12).<\/p>\n

 <\/p>\n

Hodgkinov lymf\u00f3m<\/h3>\n

Genetick\u00e9 zmeny v r\u00e1mci lokusu pre PD-L1\/PD-L2 (9p24.1) vymedzuj\u00fa biologick\u00e9 spr\u00e1vanie cHL. Expresia PD-L1 na Reedovej-Sternbergov\u00fdch bunk\u00e1ch cHL a z\u00e1rove\u0148 PD-L1 expresia v mikroprostred\u00ed lymf\u00f3mu vy\u00fas\u0165uj\u00fa do neefekt\u00edvnej protin\u00e1dorovej odpovede a predstavuj\u00fa tak cHL vhodn\u00fdm cie\u013eom pre blok\u00e1du PD-1. PD1ab nasaden\u00e9 v monoterapii s\u00fa efekt\u00edvne a dobre tolerovan\u00e9 pacientmi s relabuj\u00facim alebo refrakt\u00e9rnym (rel\/ref) cHL, pri\u010dom v\u00e4\u010d\u0161ina pacientov vykazovala objekt\u00edvnu odpove\u010f (pribli\u017ene dve tretiny pacientov) a medi\u00e1n trvania odpovede bol 16,6 mesiaca. Na z\u00e1klade t\u00fdchto \u00fadajov bol nivolumab a pembrolizumab schv\u00e1len\u00fd FDA na \u00fa\u010dely lie\u010dby pokro\u010dil\u00e9ho rel\/ref cHL(13).<\/p>\n

 <\/p>\n

N\u00e1dory z germinat\u00edvnych buniek testes<\/h3>\n

Na podklade objavu nov\u00fdch biomarkerov asociovan\u00fdch s imunitou boli realizovan\u00e9 aj \u0161t\u00fadie na potvrdenie \u00falohy signaliz\u00e1cie PD-1\/PD-L1 v germinat\u00edvnych n\u00e1doroch testes (GCT). Semin\u00f3my aj nonsemin\u00f3mov\u00e9 GCT vykazovali v\u00fdznamn\u00fa expresiu PD-L1(14). Pacienti s n\u00edzkou \u00farov\u0148ou expresie PD-L1 mali zna\u010dne lep\u0161ie PFS a OS. Naproti tomu expresia PD-L1 na lymfocytoch infiltruj\u00facich tumor (TIL) poskytovala vysok\u00fa predikciu v\u00fdsledku v obr\u00e1tenom zmysle. N\u00e1dory s vysokou PD-L1 expresiou na TIL mali preuk\u00e1zate\u013ene lep\u0161iu progn\u00f3zu ako tie s n\u00edzkou PD-L1 expresiou na TIL(15).<\/p>\n

 <\/p>\n

Glioblast\u00f3m<\/h3>\n

Glioblast\u00f3m predstavuje naj\u010dastej\u0161\u00ed prim\u00e1rny mal\u00edgny tumor mozgu, vykazuj\u00faci \u010drty imunosupresie v n\u00e1dorovom mikroprostred\u00ed, pri\u010dom pre rekurentn\u00fd n\u00e1dor nie je dostupn\u00e1 \u0161tandardn\u00e1 lie\u010dba. V \u0161t\u00fadii NCT01375842 sa sledovala bezpe\u010dnos\u0165 a efektivita lie\u010dby atezolizumabom (anti-PD-L1 protil\u00e1tka) pri rekurentnom glioblast\u00f3me. Dlh\u0161ie pre\u017e\u00edvanie bolo spojen\u00e9 so zv\u00fd\u0161en\u00fdm podielom CD4+ T-buniek v n\u00e1doroch. Tieto \u00fadaje nazna\u010duj\u00fa, \u017ee biomarkery ako CD4+ T-lymfocyty a hypermutovan\u00fd status n\u00e1doru m\u00f4\u017eu pom\u00f4c\u0165 k selekcii pacientov, ktor\u00ed m\u00f4\u017eu potenci\u00e1lne profitova\u0165 z lie\u010dby atezolizumabom(16).<\/p>\n

 <\/p>\n

Mal\u00edgny melan\u00f3m a n\u00e1dory uropoetick\u00e9ho traktu<\/h3>\n
    \n
  1. f\u00e1za \u0161t\u00fadie NCT02836795 sledovala bezpe\u010dnos\u0165, tolerabilitu a biologick\u00fa aktivitu JS001 IgG4 humanizovanej monoklon\u00e1lnej anti-PD-1 protil\u00e1tky pri pokro\u010dilom melan\u00f3me a n\u00e1doroch uropoetick\u00e9ho traktu, ktor\u00e9 boli refrakt\u00e9rne proti \u0161tandardnej syst\u00e9movej terapii. Klinick\u00e1 reakcia bola okrem in\u00e9ho korelovan\u00e1 s PD-L1 expresiou na n\u00e1dorov\u00fdch bunk\u00e1ch a pr\u00edtomnos\u0165ou TIL. Monoklon\u00e1lna protil\u00e1tka JS001 bola dobre tolerovan\u00e1 a preukazovala s\u013eubn\u00fa antitumor\u00f3znu aktivitu v urotelovom a ren\u00e1lnom karcin\u00f3me, rovnako aj v akr\u00e1lnych a muk\u00f3znych melan\u00f3moch predt\u00fdm nepresk\u00faman\u00fdch(17).<\/li>\n<\/ol>\n

     <\/p>\n

    Z\u00e1ver<\/h3>\n

    Na z\u00e1klade s\u00fa\u010dasn\u00e9ho stavu znalost\u00ed nemo\u017eno jednozna\u010dne ur\u010di\u0165 efektivitu stanovovania PD-1\/PD-L1 prote\u00ednov pre predikciu terapeutick\u00e9ho \u00fa\u010dinku imunoterapie a pre \u010fal\u0161ie pre\u017e\u00edvanie pacientov s CRC. Dostupn\u00fd je len po\u010detnos\u0165ou mal\u00fd s\u00fabor pacientov v doteraj\u0161\u00edch klinick\u00fdch \u0161t\u00fadi\u00e1ch, kde bola sledovan\u00e1 \u00fa\u010dinnos\u0165 imunoterapie vo vz\u0165ahu k stanovenej miere expresie PD-1\/PD-L1. Nebola ur\u010den\u00e1 hranica (cutoff) pre \u00farove\u0148 vysokej miery expresie t\u00fdchto prote\u00ednov, \u010di u\u017e na n\u00e1dorov\u00fdch bunk\u00e1ch, alebo bunk\u00e1ch imunity vo vzorke CRC. Nemo\u017eno spo\u013eahlivo pos\u00fadi\u0165, \u010di indikovan\u00e1 imunoterapia prin\u00e1\u0161a benefit v podobe celkov\u00e9ho pre\u017e\u00edvania \u010di pre\u017e\u00edvania bez progresie. Ukazuje sa, \u017ee na \u00fa\u010dely \u0161tandardiz\u00e1cie je potrebn\u00e9 zahrn\u00fa\u0165 \u010fal\u0161ie prediktory odhadu terapeutickej odpovede imunoterapie pri CRC. Pozit\u00edvnym prediktorom sa jav\u00ed MSI-H status, ke\u010f\u017ee s\u00fabor pacientov s overen\u00fdm MSI-H statusom, zd\u00e1 sa, najviac profituje z anti-PD-1\/PD-L1 terapie. Z\u00e1rove\u0148 je vhodn\u00e9 roz\u0161\u00edri\u0165 s\u00fabor definovan\u00fdch premenn\u00fdch v r\u00e1mci stratifik\u00e1cie pacientov (vek pacientov, klinick\u00e9 \u0161t\u00e1dium, RAS status, MSS vs MSI-H status, imunosk\u00f3re). Je d\u00f4le\u017eit\u00e9 ur\u010di\u0165, \u010di bude prebieha\u0165 testovanie expresie iba na n\u00e1dorov\u00fdch bunk\u00e1ch alebo bude hodnoten\u00e1 aj expresia na TIL, pri\u010dom sa vych\u00e1dza z faktu, \u017ee \u00farove\u0148 expresie PD-1 koreluje s \u00farov\u0148ou expresie PD-L1. \u010eal\u0161\u00ed v\u00fdskum uk\u00e1\u017ee, ak\u00e9 bude postavenie imunoterapie v mana\u017emente CRC, j., \u010di p\u00f4jde o kombin\u00e1ciu s chemoterapeutikami alebo externou r\u00e1dioterapiou, alebo bude nasaden\u00e1 ako druhol\u00edniov\u00e1 lie\u010debn\u00e1 modalita.<\/p>\n

     <\/p>\n

    Po\u010fakovanie: <\/em><\/strong>Pr\u00e1ca vznikla s podporou grantu APVV-14-0318.<\/em><\/p>\n

     <\/p>\n

    LITERAT\u00daRA<\/strong><\/p>\n

      \n
    1. Markman JL, Shiao Impact of the immune system and immunotherapy in colorectal cancer. Journal of Gastrointestinal Oncology 2015; 6(2): 208-223. doi:10.3978\/j.issn.2078-6891.2014.077.<\/li>\n
    2. Zatloukalov\u00e1 P, Pjechov\u00e1 M, Bab\u010danov\u00e1 S, a The Role of PD-1\/ PD-L1 Signaling Pathway in Antitumor Immune Response. Klinicka onkologie 2016; 29(Suppl 4): 4S72-4S77. doi:10.14735\/amko20164S72.<\/li>\n
    3. Zak KM, Kitel R, Przetocka S, et Structure of the Complex of Human Programmed Death 1, PD-1, and Its Ligand PD-L1. Structure (London, England: 1993) 2015; 23(12): 2341-2348. doi:10.1016\/j.str. 2015. 09. 010.<\/li>\n
    4. Wang Z, Zhang C, Liu X, et Molecular and clinical characterization of PD-L1 expression at transcriptional level via 976 samples of brain glioma. Oncoimmunology 2016; 5(11). doi:10.1080\/2162402X.2016.1196310.<\/li>\n
    5. Udall M, Rizzo M, Kenny J, et PD-L1 diagnostic tests: a systematic literature review of scoring algorithms and test-validationmetrics: a systematic literature review of scoring algorithms and test-validation metrics. DiagnosticPathology 2018; 13. doi:10.1186\/s13000-018-0689-9.<\/li>\n
    6. Overman MJ, McDermott R, Leach JL, et Nivolumab in patients with metastatic DNA mismatch repair deficient\/microsatellite instability \u2013 highc olorectal cancer (CheckMate 142): results of anopen-label, multicentre, phase 2 study: results of anopen-label, multicentre, phase 2 study. The Lancet Oncology 2017; 18(9): 1182-1191. doi:10.1016\/S1470-2045(17)30422-9.<\/li>\n
    7. Bendell JC, Bang Y-J, Chee CE, et A phase Ib study of safety and clinical activity of atezolizumab (A) and cobimetinib (C) in patients (pts) with metastatic colorectal cancer (mCRC). Journal of Clinical Oncology 2018; 36(Suppl 4): 560-560. doi:10.1200\/JCO.2018.36.4_suppl.560.<\/li>\n
    8. Toh JWT, de Souza P, Lim SH, et al. The Potential Value of Immunotherapy in Colorectal Cancers: Review of the Evidence for Programmed Death-1 Inhibitor Therapy: Review of the Evidence for Programmed Death-1 Inhibitor Clinical Colorectal Cancer 2016; 15(4): 285-291. doi:10.1016\/j. clcc.2016.07.007.<\/li>\n
    9. Koganemaru S, Inoshita N, Miura Y, et al. Prognostic value of programmed death\u2010ligand 1 expression in patients with stage III colorectal Cancer Science 2017; 108(5): 853-858. doi:10.1111\/cas.13229.<\/li>\n
    10. Diaz LA, Marabelle A, Delord J-P, et Pembrolizumab therapy for microsatellite instability high (MSI-H) colorecta lcancer (CRC) and non-CRC. Journal of Clinical Oncology 2017; 35(Suppl 15): 3071-3071. doi:10.1200\/ JCO.2017.35.15_suppl.3071.<\/li>\n
    11. Marginean EC, Melosky Is There a Role for Programmed Death Ligand-1 Testing and Immunotherapy in Colorectal Cancer With Microsatellite Instability? Part II-The Challenge of Programmed Death Ligand-1 Testing and Its Role in Microsatellite Instability-High Colorectal Cancer. Archives of Pathology & Laboratory Medicine 2018; 142(1): 26-34. doi:10.5858\/arpa.2017-0041-RA.<\/li>\n
    12. Buder-Bakhaya K, Hassel Biomarkers for Clinical Benefit of Immune Checkpoint Inhibitor Treatment – A Review From the Melanoma Perspective and Beyond. Frontiers in Immunology 2018; 9. doi:10.3389\/fimmu.2018.01474<\/li>\n
    13. Herrera Wheredoes PD-1 blockade fit in HL therapy? Hematology. American Society of Hematology. Education Program. 2018\/11\/30; 2018(1): 213-220. doi:10.1182\/asheducation-2018.1.213.<\/li>\n
    14. Chovanec M, Cierna Z, Miskovska V, et al. Prognostic role of programmed-death ligand 1 (PD-L1) expressing tumor infiltrating lymphocytes in testicular germ cell Oncotarget 2017; 28; 8(13): 21794-21805.<\/li>\n
    15. Chovanec M, Albany C, Mego M, et Emerging Prognostic Biomarkers in Testicular Germ Cell Tumors: Looking Beyond Established Practice: Looking Beyond Established Practice. Frontiers in Oncology 2018; 8. doi:10.3389\/fonc.2018.00571.<\/li>\n
    16. Lukas RV, Rodon J, Becker K, et Clinical activity and safety of atezolizumab in patients with recurrent glioblastoma. Journal of Neuro-Oncology 2018; 140(2): 317-328. doi:10.1007\/s11060-018-2955-9.<\/li>\n
    17. Tang B, Yan X, Sheng X, et Safety and clinical activity with an anti-PD-1 antibody JS001 in advanced melanoma or urologic cancer patients. Journal of Hematology & Oncology 2019; 12(1): 7. doi:10.1186\/s13045-018-0693-2.<\/li>\n
    18. Guan J, Lim KS, Mekhail T, et Programmed Death Ligand-1 (PD-L1) Expression in the Programmed Death Receptor-1 (PD-1)\/PD-L1 Blockade. A Key Player Against Various Cancers. Archives of Pathology & Laboratory Medicine 2017; 141(6): 851-861. doi: 10.5858\/arpa.2016-0361-RA.<\/li>\n<\/ol>\n

       <\/p>\n

       <\/p>\n","protected":false},"excerpt":{"rendered":"

      *All tables, charts, graphs and pictures that are featured in this article can be found in the .pdf attachment at the end of the paper.   \u00davod Kolorekt\u00e1lny karcin\u00f3m (CRC) predstavuje v s\u00fa\u010dasnosti z\u00e1va\u017en\u00fd epidemiologick\u00fd probl\u00e9m z h\u013eadiska morbidity a mortality tohto onkologick\u00e9ho ochorenia v slovenskej popul\u00e1cii. Na t\u00fato skuto\u010dnos\u0165 reaguje aj implementovan\u00fd N\u00e1rodn\u00fd onkologick\u00fd<\/p>\n","protected":false},"author":7,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_mi_skip_tracking":false,"footnotes":""},"categories":[297],"tags":[1069,1291,1290,1288,1292],"class_list":["post-1806","post","type-post","status-publish","format-standard","hentry","category-pathology","tag-colorectal-cancer","tag-immune-checkpoint","tag-immunotherapy","tag-pd-1-pd-l1-en","tag-prognosis","typ_clanku-review-article"],"acf":{"abstrakt":"

      Application of immunotherapy in one of the most frequent oncological diseases, colorectal cancer (CRC), has not been defined up today. The review reflects the status of immunohistochemical determination of the expression of immune response checkpoint PD-1\/PD-L1 (programmed cell death-1\/programmed cell death-ligand-1) and its significance for the prognosis of this disease. The available data on CRC immunotherapy are compared with the current results regarding immunotherapy in non-small cell lung cancer (NSCLC) and other types of sol- id tumours. Several studies imply that for the effectivity of assessment of PD-1\/PD-L1 expression determination and immunotherapy standardization, additional predictive factors for the therapeutic response of CRC immunotherapy should be included. Monitoring the effectivity of CRC immunotherapy in clinical studies with large sets of patients and the inclusion of defined variables is required. More specific stratification of patient sets is important in support for the substantiation of immunotherapy approval of particular immunotherapeutic agents.<\/p>\n

      Keywords: <\/strong>colorectal cancer, immunotherapy, PD-1\/PD-L1, immune checkpoint, prognosis<\/p>\n","casopis":[{"ID":1883,"post_author":"7","post_date":"2019-10-28 13:35:57","post_date_gmt":"2019-10-28 12:35:57","post_content":"

        \r\n \t
      • Detection and validation of subchromosomal aberrations detected as additional findings in routine noninvasive prenatal testing for common trisomies<\/li>\r\n \t
      • Finding of a marker chromosome in a child with Cat-eye syndrome (case study)<\/li>\r\n \t
      • Experimental therapy with stem cells is promissing in the treatment of chronic diabetic ulcer \u2013 a case study<\/li>\r\n \t
      • Colonic mucosal Schwann cell hamartoma with tactile corpuscle-like bodies: a case report<\/li>\r\n \t
      • Accidental capture of the toxic strain Corynebacterium diphteriae<\/li>\r\n<\/ul>","post_title":"newsLab","post_excerpt":"","post_status":"publish","comment_status":"closed","ping_status":"closed","post_password":"","post_name":"newslab-004","to_ping":"","pinged":"","post_modified":"2019-11-04 13:53:35","post_modified_gmt":"2019-11-04 12:53:35","post_content_filtered":"","post_parent":0,"guid":"https:\/\/www.newslab.sk\/casopis\/newslab-4\/","menu_order":0,"post_type":"casopis","post_mime_type":"","comment_count":"0","filter":"raw"}],"strana":"90-93","upload_clanok":{"ID":1804,"id":1804,"title":"NEWSLAB_2-2019_Kocan","filename":"NEWSLAB_2-2019_Kocan.pdf","filesize":158320,"url":"https:\/\/www.newslab.sk\/wp-content\/uploads\/2019\/10\/NEWSLAB_2-2019_Kocan.pdf","link":"https:\/\/www.newslab.sk\/en\/uloha-imunitnej-odpovede-v-prognoze-kolorektalneho-karcinomu\/newslab_2-2019_kocan-2\/","alt":"","author":"7","description":"","caption":"","name":"newslab_2-2019_kocan-2","status":"inherit","uploaded_to":1806,"date":"2019-10-29 06:48:58","modified":"2019-10-29 06:48:58","menu_order":0,"mime_type":"application\/pdf","type":"application","subtype":"pdf","icon":"https:\/\/www.newslab.sk\/wp-includes\/images\/media\/document.png"}},"_links":{"self":[{"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/posts\/1806","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/users\/7"}],"replies":[{"embeddable":true,"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/comments?post=1806"}],"version-history":[{"count":0,"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/posts\/1806\/revisions"}],"wp:attachment":[{"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/media?parent=1806"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/categories?post=1806"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/tags?post=1806"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}