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dc.creatorMartín-Otal, C. (Celia)-
dc.creatorLasarte-Cia, A. (Aritz)-
dc.creatorSerrano-Tejero, D. (Diego)-
dc.creatorCasares, N. (Noelia)-
dc.creatorConde-Gallastegi, E. (Enrique)-
dc.creatorNavarro-Negredo, F.C. (Flor Cecilia)-
dc.creatorSánchez-Moreno, I. (Inés)-
dc.creatorGorraiz, M. (Marta)-
dc.creatorSarrión, P. (Patricia)-
dc.creatorCalvo-González, A. (Alfonso)-
dc.creatorAndrea, C.E. (Carlos Eduardo) de-
dc.creatorEcheveste, J.I. (José I.)-
dc.creatorVilas, A. (Amaia)-
dc.creatorRodriguez-Madoz, J.R. (Juan Roberto)-
dc.creatorSan-Miguel, J.F. (Jesús F.)-
dc.creatorProsper-Cardoso, F. (Felipe)-
dc.creatorHervas-Stubbs, S. (Sandra)-
dc.creatorLasarte, J.J. (Juan José)-
dc.creatorLozano-Moreda, T. (Teresa)-
dc.date.accessioned2022-12-07T10:18:51Z-
dc.date.available2022-12-07T10:18:51Z-
dc.date.issued2022-
dc.identifier.citationMartín-Otal, C. (Celia); Lasarte-Cía, A.; Serrano-Tejero, D. (Diego); et al. "Targeting the extra domain A of fibronectin for cancer therapy with CAR-T cells". Journal for Immunotherapu of Cancer. 10 (8), 2022, e004479es
dc.identifier.issn2051-1426-
dc.identifier.urihttps://hdl.handle.net/10171/64805-
dc.description.abstractBackground One of the main difficulties of adoptive cell therapies with chimeric antigen receptor (CAR)-T cells in solid tumors is the identification of specific target antigens. The tumor microenvironment can present suitable antigens for CAR design, even though they are not expressed by the tumor cells. We have generated a CAR specific for the splice variant extra domain A (EDA) of fibronectin, which is highly expressed in the tumor stroma of many types of tumors but not in healthy tissues. Methods EDA expression was explored in RNA-seq data from different human tumor types and by immunohistochemistry in paraffin-embedded tumor biopsies. Murine and human anti-EDA CAR-T cells were prepared using recombinant retro/lentiviruses, respectively. The functionality of EDA CAR-T cells was measured in vitro in response to antigen stimulation. The antitumor activity of EDA CAR-T cells was measured in vivo in C57BL/6 mice challenged with PM299L-EDA hepatocarcinoma cell line, in 129Sv mice-bearing F9 teratocarcinoma and in NSG mice injected with the human hepatocarcinoma cell line PLC. Results EDA CAR-T cells recognized and killed EDA-expressing tumor cell lines in vitro and rejected EDA-expressing tumors in immunocompetent mice. Notably, EDA CAR-T cells showed an antitumor effect in mice injected with EDA-negative tumor cells lines when the tumor stroma or the basement membrane of tumor endothelial cells express EDA. Thus, EDA CAR-T administration delayed tumor growth in immunocompetent 129Sv mice challenged with teratocarcinoma cell line F9. EDA CAR-T treatment exerted an antiangiogenic effect and significantly reduced gene signatures associated with epithelial-mesenchymal transition, collagen synthesis, extracellular matrix organization as well as IL-6-STAT5 and KRAS pathways. Importantly, the human version of EDA CAR, that includes the human 41BB and CD3 zeta endodomains, exerted strong antitumor activity in NSG mice challenged with the human hepatocarcinoma cell line PLC, which expresses EDA in the tumor stroma and the endothelial vasculature. EDA CAR-T cells exhibited a tropism for EDA-expressing tumor tissue and no toxicity was observed in tumor bearing or in healthy mice. Conclusions These results suggest that targeting the tumor-specific fibronectin splice variant EDA with CAR-T cells is feasible and offers a therapeutic option that is applicable to different types of cancer.-
dc.description.sponsorshipThe study was supported by grants from Ministerio de Ciencia e Innovación (PID2019-108989RB-I00 financed by MCIN/ AEI /10.13039/501100011033; PID2021-128283OA-I00 MCIN/ AEI /10.13039/501100011033; PLEC2021-008094 MCIN/ AEI/10.13039/501100011033, AUTOCART, RTC- 2017- 6585- 1), Gobierno de Navarra Industria (0011-1411-2019-000079; Proyecto DESCARTHeS and 0011-1411- 2022-000088; Proyecto SOCRATHeS), the European Union (T2EVOLVE, IMI H2020- JTI- IMI2- 2019-18 Contract 945393 and CARAMBA, SC1-PM- 08-2017. Contract 754658), Fundación Bancaria La Caixa-Hepacare Project, ISCiii Retic Tercel RD16/011/0005 funded by ISCiii + Fondos FEDER, Red de Terapias Avanzadas TERAV (RD21/0017/0009) funded by ISCiii + Unión Europea – NextGenerationEU Plan de Recuperación Transformación y Resiliencia and from Paula & Rodger Riney Foundation. TL is a recipient of a Juan de la Cierva grant (IJCI-2017-34204).-
dc.language.isoen-
dc.relationinfo:eu-repo/grantAgreement/EC/H2020/945393/EU-
dc.relationinfo:eu-repo/grantAgreement/EC/H2020/754658/EU-
dc.rightsinfo:eu-repo/semantics/openAccess-
dc.subjectTumor microenvironment-
dc.subjectCell engineering-
dc.subjectImmunotherapy-
dc.subjectAdoptive-
dc.subjectReceptors-
dc.subjectChimeric antigen-
dc.subjectTumor biomarkers-
dc.titleTargeting the extra domain A of fibronectin for cancer therapy with CAR-T cells-
dc.typeinfo:eu-repo/semantics/article-
dc.description.noteThis is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license-
dc.identifier.doi10.1136/jitc-2021-004479-
dadun.citation.number8-
dadun.citation.publicationNameJournal for Immunotherapy of Cancer-
dadun.citation.startingPagee004479-
dadun.citation.volume10-

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