Natural Flt3Lg-Based Chimeric Antigen Receptor (Flt3-CAR) T Cells Successfully Target Flt3 on AML Cell Lines

Relapsed/refractory acute myeloid leukemia (AML) cannot be cured with chemotherapy alone, as the blasts survive the treatment. Chimeric antigen receptor (CAR) approaches for AML are being actively developed. CARs promote immune reactions through recognition of the target molecular epitopes at the su...

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Autores principales:	Varvara Maiorova, Murad D. Mollaev, Polina Vikhreva, Elena Kulakovskaya, Dmitry Pershin, Dmitriy M. Chudakov, Alexey Kibardin, Michael A. Maschan, Sergey Larin
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	ligand-based targeting CAR T cell therapy acute myeloid leukemia Medicine R
Acceso en línea:	https://doaj.org/article/0af6a223b7c04eecb2755b3406e7a266
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id	oai:doaj.org-article:0af6a223b7c04eecb2755b3406e7a266
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spelling	oai:doaj.org-article:0af6a223b7c04eecb2755b3406e7a2662021-11-25T19:10:23ZNatural Flt3Lg-Based Chimeric Antigen Receptor (Flt3-CAR) T Cells Successfully Target Flt3 on AML Cell Lines10.3390/vaccines91112382076-393Xhttps://doaj.org/article/0af6a223b7c04eecb2755b3406e7a2662021-10-01T00:00:00Zhttps://www.mdpi.com/2076-393X/9/11/1238https://doaj.org/toc/2076-393XRelapsed/refractory acute myeloid leukemia (AML) cannot be cured with chemotherapy alone, as the blasts survive the treatment. Chimeric antigen receptor (CAR) approaches for AML are being actively developed. CARs promote immune reactions through recognition of the target molecular epitopes at the surface of cancer cells. The recognition involves the extracellular portion of the CAR protein, which corresponds to either the antibody or the physiological binding partner of the targeted antigen. Here, we design a chimeric receptor with a full-length natural Flt3-ligand recognition module that targets Flt3 tyrosine kinase, known as an adverse marker in AML. We demonstrate specific killing of Flt3-positive THP-1 cells by Flt3-CAR T cells and the lack of cytotoxicity towards Flt3-negative U937 cells. We prove that the inherent cytolytic capacity of T cells is essential for the killing. Finally, we confirm the authenticity of targeting by its competitive dose-dependent inhibition with a soluble Flt3-ligand. The developed system can be viewed as a non-immunogenic functional equivalent of scFv-mediated targeting. The robust in vitro antitumor effects of Flt3-CAR T cells, combined with their low off-target cytotoxicity, hold promise for AML treatment.Varvara MaiorovaMurad D. MollaevPolina VikhrevaElena KulakovskayaDmitry PershinDmitriy M. ChudakovAlexey KibardinMichael A. MaschanSergey LarinMDPI AGarticleligand-based targetingCAR T cell therapyacute myeloid leukemiaMedicineRENVaccines, Vol 9, Iss 1238, p 1238 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	ligand-based targeting CAR T cell therapy acute myeloid leukemia Medicine R
spellingShingle	ligand-based targeting CAR T cell therapy acute myeloid leukemia Medicine R Varvara Maiorova Murad D. Mollaev Polina Vikhreva Elena Kulakovskaya Dmitry Pershin Dmitriy M. Chudakov Alexey Kibardin Michael A. Maschan Sergey Larin Natural Flt3Lg-Based Chimeric Antigen Receptor (Flt3-CAR) T Cells Successfully Target Flt3 on AML Cell Lines
description	Relapsed/refractory acute myeloid leukemia (AML) cannot be cured with chemotherapy alone, as the blasts survive the treatment. Chimeric antigen receptor (CAR) approaches for AML are being actively developed. CARs promote immune reactions through recognition of the target molecular epitopes at the surface of cancer cells. The recognition involves the extracellular portion of the CAR protein, which corresponds to either the antibody or the physiological binding partner of the targeted antigen. Here, we design a chimeric receptor with a full-length natural Flt3-ligand recognition module that targets Flt3 tyrosine kinase, known as an adverse marker in AML. We demonstrate specific killing of Flt3-positive THP-1 cells by Flt3-CAR T cells and the lack of cytotoxicity towards Flt3-negative U937 cells. We prove that the inherent cytolytic capacity of T cells is essential for the killing. Finally, we confirm the authenticity of targeting by its competitive dose-dependent inhibition with a soluble Flt3-ligand. The developed system can be viewed as a non-immunogenic functional equivalent of scFv-mediated targeting. The robust in vitro antitumor effects of Flt3-CAR T cells, combined with their low off-target cytotoxicity, hold promise for AML treatment.
format	article
author	Varvara Maiorova Murad D. Mollaev Polina Vikhreva Elena Kulakovskaya Dmitry Pershin Dmitriy M. Chudakov Alexey Kibardin Michael A. Maschan Sergey Larin
author_facet	Varvara Maiorova Murad D. Mollaev Polina Vikhreva Elena Kulakovskaya Dmitry Pershin Dmitriy M. Chudakov Alexey Kibardin Michael A. Maschan Sergey Larin
author_sort	Varvara Maiorova
title	Natural Flt3Lg-Based Chimeric Antigen Receptor (Flt3-CAR) T Cells Successfully Target Flt3 on AML Cell Lines
title_short	Natural Flt3Lg-Based Chimeric Antigen Receptor (Flt3-CAR) T Cells Successfully Target Flt3 on AML Cell Lines
title_full	Natural Flt3Lg-Based Chimeric Antigen Receptor (Flt3-CAR) T Cells Successfully Target Flt3 on AML Cell Lines
title_fullStr	Natural Flt3Lg-Based Chimeric Antigen Receptor (Flt3-CAR) T Cells Successfully Target Flt3 on AML Cell Lines
title_full_unstemmed	Natural Flt3Lg-Based Chimeric Antigen Receptor (Flt3-CAR) T Cells Successfully Target Flt3 on AML Cell Lines
title_sort	natural flt3lg-based chimeric antigen receptor (flt3-car) t cells successfully target flt3 on aml cell lines
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/0af6a223b7c04eecb2755b3406e7a266
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Natural Flt3Lg-Based Chimeric Antigen Receptor (Flt3-CAR) T Cells Successfully Target Flt3 on AML Cell Lines

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