Oncolytic adenoviruses expressing transgenes targeting the tumor stroma to enhance the antitumor efficacy

[eng] Oncolytic virus (OV)-based therapies have an emerging role in the treatment of solid tumors, involving both direct cell lysis and immunogenic cell death. Nonetheless, tumor- associated stroma limits the efficacy of oncolytic viruses by forming a barrier that block efficient viral penetration a...

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Detalles Bibliográficos
Autor: Sostoa, Jana de
Tipo de recurso: tesis doctoral
Estado:Versión publicada
Fecha de publicación:2019
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/134699
Acceso en línea:https://hdl.handle.net/2445/134699
http://hdl.handle.net/10803/667027
Access Level:acceso abierto
Palabra clave:Oncologia
Transformació cel·lular
Immunotoxicologia
Oncology
Cell transformation
Immunotoxicology
id ES_03c3df9d66d44560e5a3b5bbd3d3e95f
oai_identifier_str oai:diposit.ub.edu:2445/134699
network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv Oncolytic adenoviruses expressing transgenes targeting the tumor stroma to enhance the antitumor efficacy
title Oncolytic adenoviruses expressing transgenes targeting the tumor stroma to enhance the antitumor efficacy
spellingShingle Oncolytic adenoviruses expressing transgenes targeting the tumor stroma to enhance the antitumor efficacy
Sostoa, Jana de
Oncologia
Transformació cel·lular
Immunotoxicologia
Oncology
Cell transformation
Immunotoxicology
title_short Oncolytic adenoviruses expressing transgenes targeting the tumor stroma to enhance the antitumor efficacy
title_full Oncolytic adenoviruses expressing transgenes targeting the tumor stroma to enhance the antitumor efficacy
title_fullStr Oncolytic adenoviruses expressing transgenes targeting the tumor stroma to enhance the antitumor efficacy
title_full_unstemmed Oncolytic adenoviruses expressing transgenes targeting the tumor stroma to enhance the antitumor efficacy
title_sort Oncolytic adenoviruses expressing transgenes targeting the tumor stroma to enhance the antitumor efficacy
dc.creator.none.fl_str_mv Sostoa, Jana de
author Sostoa, Jana de
author_facet Sostoa, Jana de
author_role author
dc.contributor.none.fl_str_mv Alemany Bonastre, Ramon
Universitat de Barcelona. Facultat de Farmàcia i Ciències de l'Alimentació
dc.subject.none.fl_str_mv Oncologia
Transformació cel·lular
Immunotoxicologia
Oncology
Cell transformation
Immunotoxicology
topic Oncologia
Transformació cel·lular
Immunotoxicologia
Oncology
Cell transformation
Immunotoxicology
description [eng] Oncolytic virus (OV)-based therapies have an emerging role in the treatment of solid tumors, involving both direct cell lysis and immunogenic cell death. Nonetheless, tumor- associated stroma limits the efficacy of oncolytic viruses by forming a barrier that block efficient viral penetration and spread. Another important hurdle for the efficacy of OVs is the antiviral immune responses, where virus-specific infiltrating T cells clear adenovirus-infected cells without compromising tumor burden. In this thesis, these hurdles have been addressed in separate chapters. We first hypothesized that arming an oncolytic adenovirus with a FAP-targeting bispecific T cell engager (FBiTE) could retarget infiltrated lymphocytes towards cancer-associated fibroblasts (CAFs), enhancing viral spread and favoring antitumor rather than anti-viral immune responses. The engineered ICO15K-expressing FBiTE virus showed similar infectivity and replication potency than the non-armed virus. FBiTE-mediated binding of CD3+ effector T cells and FAP+ target cells led to T-cell activation, proliferation, and cytotoxicity against FAP-positive cells in vitro. In vivo, FBiTE expression increased intratumoral accumulation of T cells and decreased the level of FAP, a marker of CAFs, in tumors. Finally, the antitumor activity of the FBiTE-armed adenovirus was superior to the parental virus. The data presented in this thesis strongly supports that the combination of viral oncolysis of cancer cells and FBiTE-mediated cytotoxicity of FAP- expressing CAFs might be an effective strategy to overcome a key limitation of oncolytic virotherapy, encouraging its further clinical development. Aiming to induce stroma disruption, we secondly generated a panel of oncolytic adenoviruses expressing FAP-targeting immunotoxins and a nitroreductase (NfrA)- activatable prodrug. During the development of these projects, we successfully rescued and characterized all the viruses. However, although immunotoxins molecules were properly expressed and secreted from modified-virus infected cells, no promising results were obtained. In contrast, NfrA-armed virus showed replication-dependent enzymatic activity on target cells, leading to increased oncolytic potency in vitro. These preliminary results indicate that this last strategy could be considered to foster viral spread in stroma-abundant tumors, encouraging its validation in an in vivo setting.
publishDate 2019
dc.date.none.fl_str_mv 2019
dc.type.none.fl_str_mv info:eu-repo/semantics/doctoralThesis
info:eu-repo/semantics/publishedVersion
format doctoralThesis
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/134699
http://hdl.handle.net/10803/667027
url https://hdl.handle.net/2445/134699
http://hdl.handle.net/10803/667027
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv (c) Sostoa, 2019
info:eu-repo/semantics/openAccess
rights_invalid_str_mv (c) Sostoa, 2019
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Universitat de Barcelona
publisher.none.fl_str_mv Universitat de Barcelona
dc.source.none.fl_str_mv Tesis Doctorals - Facultat - Farmàcia i Ciències de l'Alimentació
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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spelling Oncolytic adenoviruses expressing transgenes targeting the tumor stroma to enhance the antitumor efficacySostoa, Jana deOncologiaTransformació cel·lularImmunotoxicologiaOncologyCell transformationImmunotoxicology[eng] Oncolytic virus (OV)-based therapies have an emerging role in the treatment of solid tumors, involving both direct cell lysis and immunogenic cell death. Nonetheless, tumor- associated stroma limits the efficacy of oncolytic viruses by forming a barrier that block efficient viral penetration and spread. Another important hurdle for the efficacy of OVs is the antiviral immune responses, where virus-specific infiltrating T cells clear adenovirus-infected cells without compromising tumor burden. In this thesis, these hurdles have been addressed in separate chapters. We first hypothesized that arming an oncolytic adenovirus with a FAP-targeting bispecific T cell engager (FBiTE) could retarget infiltrated lymphocytes towards cancer-associated fibroblasts (CAFs), enhancing viral spread and favoring antitumor rather than anti-viral immune responses. The engineered ICO15K-expressing FBiTE virus showed similar infectivity and replication potency than the non-armed virus. FBiTE-mediated binding of CD3+ effector T cells and FAP+ target cells led to T-cell activation, proliferation, and cytotoxicity against FAP-positive cells in vitro. In vivo, FBiTE expression increased intratumoral accumulation of T cells and decreased the level of FAP, a marker of CAFs, in tumors. Finally, the antitumor activity of the FBiTE-armed adenovirus was superior to the parental virus. The data presented in this thesis strongly supports that the combination of viral oncolysis of cancer cells and FBiTE-mediated cytotoxicity of FAP- expressing CAFs might be an effective strategy to overcome a key limitation of oncolytic virotherapy, encouraging its further clinical development. Aiming to induce stroma disruption, we secondly generated a panel of oncolytic adenoviruses expressing FAP-targeting immunotoxins and a nitroreductase (NfrA)- activatable prodrug. During the development of these projects, we successfully rescued and characterized all the viruses. However, although immunotoxins molecules were properly expressed and secreted from modified-virus infected cells, no promising results were obtained. In contrast, NfrA-armed virus showed replication-dependent enzymatic activity on target cells, leading to increased oncolytic potency in vitro. These preliminary results indicate that this last strategy could be considered to foster viral spread in stroma-abundant tumors, encouraging its validation in an in vivo setting.[cat] Les teràpies basades en virus oncolítics pel tractament de tumors sòlids es consideren molt prometedores degut a la seva capacitat de combinar la lisi directa de cèl·lules canceroses i la mort cel·lular per l’activació del sistema immune. No obstant, l’estroma associat al càncer forma una barrera que bloqueja la penetració i distribució del virus en el tumor, limitant l’eficàcia dels virus oncolítics. Una altra limitació important és la resposta immune contra el virus. Les cèl·lules T citotòxiques específiques contra el virus que infiltren el tumor eliminen, normalment, les cèl·lules infectades per l’adenovirus sense comprometre la massa tumoral. En aquesta tesi, aquestes limitacions han estat abordades en capítols separats. Primer vam hipotetitzar que un adenovirus oncolític armat amb un bispecific T cell engager (BiTE) contra FAP (FBiTE) podria redirigir els limfòcits infiltrats contra els fibroblasts associats al càncer (CAFs), millorant la distribució viral i afavorint la resposta antitumoral vers l’antiviral. El virus ICO15K que expressa el FBiTE va mostrar un patró d’infectivitat i de replicació similars al virus no armat. La unió de les cèl·lules T efectores CD3+ i les cèl·lules diana FAP+ mitjançada pel FBiTE va provocar l’activació, la proliferació i la citotoxicitat de les cèl·lules T contra la cèl·lules FAP positives in vitro. In vivo, l’expressió de FBiTE va induir l’acumulació intratumoral de les cèl·lules T i la disminució dels nivells de FAP, un marcador de CAFs, en els tumors. Finalment, l’activitat antitumoral dels adenovirus armats amb el FBiTE va ser superior que la del virus parental. Els resultats presentats en aquesta tesi aporten fortes evidències que la combinació de l’oncolisi viral de les cèl·lules canceroses i la citotoxicitat dels CAFs FAP+ mitjançada pel FBiTE pot ser una estratègia efectiva per superar les limitacions claus de la viroteràpia. Aquests resultats incentiven el desenvolupament d’aquesta estratègia pel seu ús en la clínica. Amb l’objectiu de destruir l’estroma, vam generar un panell d’adenovirus oncolítics que expressaven diferents immunotoxines específiques contra FAP i una nitroreducatasa (NfrA) activadora de prodroga. Durant el desenvolupament d’aquests projectes, vam obtenir i caracteritzar tots els virus. No obstant, encara que les diferents immunotoxines van ser adequadament expressades i secretades per les cèl·lules infectades pels virus, no vam obtenir capresultat prometedor. El virus armat amb la NfrA, en canvi, va mostrar una activació enzimàtica depenent de la replicació del virus en les cèl·lules diana, incrementant la potència oncolítica del virus in vitro. Aquests resultats preliminars indiquen que aquesta última estratègia podria fomentar la distribució viral en tumors rics en estroma i incentiven la seva validació en models animals.Universitat de BarcelonaAlemany Bonastre, RamonUniversitat de Barcelona. Facultat de Farmàcia i Ciències de l'Alimentació2019info:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/134699http://hdl.handle.net/10803/667027Tesis Doctorals - Facultat - Farmàcia i Ciències de l'Alimentacióreponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglés(c) Sostoa, 2019info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1346992026-05-27T06:46:51Z
score 15,300719

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