20.500.12556/RUL-118632 Uporaba gensko spremenjenih celic T pri imunoterapiji čvrstih tumorjev Immunotherapy of solid tumours with genetically modified T cells Med sistemskimi zdravljenji v zadnjem času velik pomen pridobivajo imunske terapije, ki namesto neposrednega zdravljenja tumorjev izrabljajo potencial človeškega imunskega sistema, da se bolj uspešno bojuje proti raku. Ena izmed obetavnih terapij je CAR T celična imunoterapija, ki temelji na genskem spreminjanju bolnikovih celic T, ki so pomembni del imunskega sistema. CAR T celična terapija je uspešna terapija za zdravljenje hematoloških malignomov. Uspeh te terapije pri zdravljenju čvrstih tumorjev pa preprečuje vrsta ovir. Za razliko od hematoloških malignomov morajo CAR T celice pri čvrstih tumorjih uspešno pripotovati iz krvi do mesta tumorja in se nato preko vaskularnih endotelnih celic prebiti v mikrookolje čvrstih tumorjev. V tumorskem mikrookolju delovanje številnih imunosupresorskih celic, kot so z rakom povezani fibroblasti, supresorske celice mieloidnega izvora, regulatorne celice T, s tumorjem povezani makrofagi in nevtrofilci ter dendritične celice ovirajo vezavo CAR T celic na tumorske antigene. Za tumorsko mikrookolje je značilen oksidativni stres, hipoksija, pomanjkanje hranil in nizek pH, kar dodatno omejuje delovanje CAR T celic. Ena od glavnih omejitev je prav tako heterogenost in pomanjkanje specifičnih tarčnih antigenov na celicah čvrstih tumorjev, kar lahko vodi v neučinkovitost terapije in do toksičnosti na zdravih tkivih. Razvijajo se številni novi pristopi za izboljšanje specifičnosti in delovanja CAR T celic z namenom premagovanja teh ovir. Immunotherapy of cancer is a type of therapy that targets the human immune system by boosting patient's natural defenses to fight cancer, rather than targeting tumour cells directly. Chimeric antigen receptor (CAR) T-cell therapy is a promising new type of immunotherapy, where patient’s T cells are collected and genetically engineered to express a receptor that recognizes a specific antigen. The adoptive transfer of CAR T cells has demonstrated remarkable success in treating hematologic cancers. However, solid tumours have barriers that are absent in hematologic malignancies. Firstly, CAR T cells must successfully traffic from the blood into solid tumour sites. There, they must successfully infiltrate the stromal elements of solid tumours in order to elicit tumour-specific cytotoxicity. Suppressive immune cells, namely regulatory T cells, myeloid-derived suppressor cells, tumour-associated macrophages and neutrophils in tumour microenvironment hinder CAR T cell binding on targeted tumour antigens. CAR T cells can rapidly become dysfunctional also due to a hostile tumour microenvironment characterized by oxidative stress, hypoxia, nutritional depletion, and acidic pH. One of the major obstacles is also the lack of specific tumour antigens that are highly and uniformly expressed on tumour cells, which can result in ineffective therapy or in on-target off-tumour effects. Many new approaches are currently being investigated to overcome these hurdles. biotehnologija CAR T celice imunoterapija čvrsti tumorji zdravljenje rak imunosupresorske celice biotechnology CAR T cells immunotherapy solid tumours treatment cancer immunosuppressive cells true false false [N. Pajk] Slovenski jezik Angleški jezik Diplomsko delo/naloga 2020-08-29 07:16:01 2020-08-29 07:16:06 2022-08-30 04:04:53 0000-00-00 00:00:00 2020 0 0 0000-00-00 NiDoloceno NiDoloceno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 606:616-006.6:602.68(043.2) 178601 27660547 10573.pdf 10573.pdf 1 59EAF7C8A5FB95050A97456FBF1DFBF1 db764219d85fb940bd71f69489fdcec89138b46841c8124758bc69f05316e983 8b591369-a1b9-11eb-a523-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=133011 Biotehniška fakulteta 0 0 0