Title Biological context of CAR therapy in cancer treatment Title (croatian) Biološki kontekst za CAR terapiju u liječenju raka Author Yaniv Izhaki Kotchinsky Mentor Ana Katušić Bojanac (mentor)Committee member Ana Katušić Bojanac (predsjednik povjerenstva)Committee member Floriana Jakuš (član povjerenstva)Committee member Ljiljana Šerman (član povjerenstva)Granter University of Zagreb Defense date and country 2021-07-16, Croatia Scientific / art field, BIOMEDICINE AND HEALTHCARE Abstract Malignant diseases have been prevalent in people since recorded history. The etiologies are numerous but usually cancer is driven by the transformation of normal cell into a pre-cancerous state due to mutations. It is known that these cells emerge every day due to errors in DNA replication, however most of them are eliminated either through apoptosis or via the immune system during immune surveillance. The issue arises how a pre-cancerous cell manages to proliferate while evading those mechanisms and consequently gives rise to cancer. Various therapies exist to treat malignancies, from classical chemotherapy and radiation therapy to more novel therapies, including “biologicals” where monoclonal antibodies directed at a specific antigen on the surface of malignant cells are used. New advances in genetics have allowed the advent of the adoptive cellular therapies combined with gene editing in genes of immune cells in order to alter the protein structure of their receptors and by that the molecular conditions required for their activation. One such therapy is the chimeric antigen receptor (CAR) T-cell therapy. This therapy utilizes a viral vector for gene editing of both CD4+ and CD8+ T cell receptor (TCR) to change intracellular signalling components thus enabling T cells to operate without a supporting environment, one which is usually lacking around malignant cells. CAR-T cell therapy was first developed in the 1980’s and since then massive strides have been achieved in transformation of this experimental tool to a recognized and FDA approved therapy, and as a third line/ treatment for refractory haematological malignancies since 2017. Since then, in several years it has led to a significant increase in remission rates with a substantial adverse effect profile and less successful lasting of remission. The treatment is performed in specialized centres and is currently only available in some countries due to the difficulty of therapy preparation as well as high costs. The goal of this review is to collate the various sources, trials, reviews, and meta-analysis and form a coherent review of the CAR-T cellular therapy. The principle behind its conception, the various generations and FDA approval process to the current therapy, its indications and - adverse effects have been presented and even as well as the conceptualization of the future of the therapy. CAR-T cells are CD4+ and/or CD8+ T cells that have been genetically engineered to produce chimeric (artificial) antigen receptors (CAR) on their surface.
Abstract (croatian) Maligne bolesti u ljudi dokazane su još u dalekoj prošlosti. Mogu biti brojnih etiologija no obično je kancerogeneza pokrenuta transformacijom normalne stanice u pretkancerogeno stanje, najčešće zbog mutacija. Zna se da takve stanice nastaju svakodnevno zbog pogrešaka u replikaciji DNA, međutim većina ih se eliminira ili apoptozom ili putem imunološkog sustava tijekom imunološkog nadzora. Pitanje koje se postavlja jest kako se pretkancerogena stanica uspijeva dijeliti izbjegavajući navedene mehanizme i posljedično tome vodi do razvoja maligne bolesti. Postoje različite terapije za liječenje malignih bolesti, od klasične kemoterapije, terapije zračenjem do novijih terapija, uključujući "biološke" – gdje se koriste monoklonska protutijela usmjerena na specifični antigen na površini malignih stanica. No napredak u genetici omogućio je pojavu adaptivnih staničnih terapija u kombinaciji s uređivanjem gena (engl. gene-editing) imunosnih stanica kako bi se mogla izmijeniti proteinska struktura njihovih receptora a time i molekularni uvjeti potrebni za njihovo usmjerenje ka uništavanju tumorskih stanica. Jedna od takvih terapija je terapija putem kimernog antigenskog receptora T-stanicama (CAR). Ova terapija koristi virusni vektor za uređivanje gena za receptor na T stanicama (TCR), radi promjene njegovih unutarstaničnih signalnih komponenti, kako bi omogućila T stanicama da rade bez suportivne okoline, one koje obično nedostaje oko malignih stanica. Terapija CAR-T stanicama prvi je put razvijena 1980-ih godina prošlog stoljeća i od tada je postignut veliki napredak u transformaciji eksperimentalnog alata u priznatu i odobrenu FDA terapiju kao treću liniju / tretman za refraktorne hematološke maligne bolesti od 2017. Odtad je u nekoliko godina pokazala značajan porast u postotku remisije no i sa bitnim štetnim učincima i manje uspješnom trajanju remisije. Liječenje se provodi u specijaliziranim centrima i trenutno je dostupno samo u nekim zemljama zbog poteškoća u pripremi terapije, kao i visokih troškova. Cilj ovog pregleda je iz različitih izvora, kliničkih ispitivanja, preglednih članaka, te meta-analize izložiti koherentan pregled CAR-T stanične terapije. Prikazan je princip koji stoji iza njegova koncepta, različitih generacija CAR receptora i postupka odobrenja FDA, do trenutne terapije, njezinih indikacija, štetnih učinaka, kao i konceptualizacija budućnosti terapije.
Keywords
CAR therapy
cancer
cytopaenia
cardiotoxicity
cytokine release syndrome
Keywords (croatian)
CAR terapija
rak
citopenija
kardiotoksičnost
sindrom otpuštanja citokina
Language english URN:NBN urn:nbn:hr:105:402109 Study programme Title: Medicine (in English language) Type of resource Text File origin Born digital Access conditions Open access Terms of use Public note Pohranitelj objekta unio ključne riječi. Created on 2021-12-22 11:46:28
