Targeting the extra domain A of fibronectin for cancer therapy with CAR-T cells.

Autor:	Martín-Otal C; Programa de Inmunología e Inmunoterapia, Centro de Investigación Médica Aplicada, Pamplona, Spain., Lasarte-Cia A; Programa de Inmunología e Inmunoterapia, Centro de Investigación Médica Aplicada, Pamplona, Spain., Serrano D; Programa de Tumores sólidos, Centro de Investigación Médica Aplicada, Pamplona, Spain., Casares N; Programa de Inmunología e Inmunoterapia, Centro de Investigación Médica Aplicada, Pamplona, Spain., Conde E; Programa de Inmunología e Inmunoterapia, Centro de Investigación Médica Aplicada, Pamplona, Spain., Navarro F; Programa de Inmunología e Inmunoterapia, Centro de Investigación Médica Aplicada, Pamplona, Spain., Sánchez-Moreno I; Programa de Inmunología e Inmunoterapia, Centro de Investigación Médica Aplicada, Pamplona, Spain., Gorraiz M; Programa de Inmunología e Inmunoterapia, Centro de Investigación Médica Aplicada, Pamplona, Spain., Sarrión P; Programa de Inmunología e Inmunoterapia, Centro de Investigación Médica Aplicada, Pamplona, Spain., Calvo A; Programa de Tumores sólidos, Centro de Investigación Médica Aplicada, Pamplona, Spain., De Andrea CE; Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain.; Departamento de Patología, Clinica Universidad de Navarra, Pamplona, Navarra, Spain., Echeveste J; Departamento de Patología, Clinica Universidad de Navarra, Pamplona, Navarra, Spain., Vilas A; Programa de Hemato-Oncología, Centro de Investigación Médica Aplicada, CIMA, Pamplona, Spain., Rodriguez-Madoz JR; Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain.; Centro de Investigacion Biomedica en Red de Cancer (CIBERONC), Madrid, Spain; Cancer Center Universidad de Navarra (CCUN), Universidad de Navarra, Pamplona, Spain, San Miguel J; Centro de Investigacion Biomedica en Red de Cancer (CIBERONC), Madrid, Spain; Cancer Center Universidad de Navarra (CCUN), Universidad de Navarra, Pamplona, Spain, Prosper F; Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain.; Programa de Hemato-Oncología, Centro de Investigación Médica Aplicada, CIMA, Pamplona, Spain.; Centro de Investigacion Biomedica en Red de Cancer (CIBERONC), Madrid, Spain; Cancer Center Universidad de Navarra (CCUN), Universidad de Navarra, Pamplona, Spain, Hervas-Stubbs S; Programa de Inmunología e Inmunoterapia, Centro de Investigación Médica Aplicada, Pamplona, Spain.; Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain., Lasarte JJ; Departamento de Hematología, Clínica Universidad de Navarra, Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain., Lozano T; Departamento de Hematología, Clínica Universidad de Navarra, Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain.
Jazyk:	angličtina
Zdroj:	Journal for immunotherapy of cancer [J Immunother Cancer] 2022 Aug; Vol. 10 (8).
DOI:	10.1136/jitc-2021-004479
Abstrakt:	Background: 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 CD3ζ 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. Competing Interests: Competing interests: None declared. (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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