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Design and Production An Effective Bispecific Tandem Chimeric Antigen Receptor on T Cells against CD123 and Folate Receptor ß towards B-Acute Myeloid Leukaemia Blasts
OBJECTIVE: The clinical studies of acute myeloid leukaemia (AML) revealed that antigen escaping variants cause cancer recurrence even after treatment with chimeric antigen receptor (CAR)-T cells that target a single tumour antigen. Due to the heterogeneous expression of antigens on leukaemia blasts,...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Royan Institute
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8665988/ https://www.ncbi.nlm.nih.gov/pubmed/34939758 http://dx.doi.org/10.22074/cellj.2021.7314 |
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author | Ghamari, Ali Pakzad, Parviz Majd, Ahmad Ebrahimi, Marzieh Hamidieh, Amir Ali |
author_facet | Ghamari, Ali Pakzad, Parviz Majd, Ahmad Ebrahimi, Marzieh Hamidieh, Amir Ali |
author_sort | Ghamari, Ali |
collection | PubMed |
description | OBJECTIVE: The clinical studies of acute myeloid leukaemia (AML) revealed that antigen escaping variants cause cancer recurrence even after treatment with chimeric antigen receptor (CAR)-T cells that target a single tumour antigen. Due to the heterogeneous expression of antigens on leukaemia blasts, we hypothesized that a novel bispecific CAR, directed to the folate receptor beta (FRβ)-binding single-chain variable fragment (scFv) and an IL3α-binding receptor (CD123) that has more expression in AML blasts, can decrease CAR-T cell exhaustion and increase the efficacy of CAR-T cells to prevent antigen escaping and consequent recurrence of AML. MATERIALS AND METHODS: In this experimental study, the survival, proliferation, and cytolysis of CAR-T cells remains suboptimal even with a costimulatory endodomain. Hence, we designed and constructed a tandem CAR that joins an FRβ and CD123 in the second generation retroviral vector to generate a bispecific tandem CAR (TanCAR-T cell). RESULTS: TanCAR FRβ-CD123 T cells showed distinct binding to FRβ or CD123 expressing cells. They could lyse the leukaemia cell lines (66.1 ± 11%) comparable to the single CAR-T cells against these determinants. TanCAR FRβ- CD123 T cells simultaneously engaged FRβ and CD123, which promoted T cell activation in targeting and lysis of the examined leukaemia cell lines. TanCAR-T cell significantly induced interferon gamma (IFNγ) and interleukin 2 (IL-2) production more than single CAR-T cells, which produced a synergistic enhancement of TanCAR FRβ-CD123 T cell function when dual antigens faced simultaneously. CONCLUSION: Dual-specific TanCAR FRβ-CD123 T cells showed therapeutic potential to improve AML control by co- engaging FRβ and CD123 molecules in a robust, divalent immune system. This strategy may be a useful therapeutic approach in patients with relapsed B-cell malignancies. |
format | Online Article Text |
id | pubmed-8665988 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Royan Institute |
record_format | MEDLINE/PubMed |
spelling | pubmed-86659882021-12-15 Design and Production An Effective Bispecific Tandem Chimeric Antigen Receptor on T Cells against CD123 and Folate Receptor ß towards B-Acute Myeloid Leukaemia Blasts Ghamari, Ali Pakzad, Parviz Majd, Ahmad Ebrahimi, Marzieh Hamidieh, Amir Ali Cell J Original Article OBJECTIVE: The clinical studies of acute myeloid leukaemia (AML) revealed that antigen escaping variants cause cancer recurrence even after treatment with chimeric antigen receptor (CAR)-T cells that target a single tumour antigen. Due to the heterogeneous expression of antigens on leukaemia blasts, we hypothesized that a novel bispecific CAR, directed to the folate receptor beta (FRβ)-binding single-chain variable fragment (scFv) and an IL3α-binding receptor (CD123) that has more expression in AML blasts, can decrease CAR-T cell exhaustion and increase the efficacy of CAR-T cells to prevent antigen escaping and consequent recurrence of AML. MATERIALS AND METHODS: In this experimental study, the survival, proliferation, and cytolysis of CAR-T cells remains suboptimal even with a costimulatory endodomain. Hence, we designed and constructed a tandem CAR that joins an FRβ and CD123 in the second generation retroviral vector to generate a bispecific tandem CAR (TanCAR-T cell). RESULTS: TanCAR FRβ-CD123 T cells showed distinct binding to FRβ or CD123 expressing cells. They could lyse the leukaemia cell lines (66.1 ± 11%) comparable to the single CAR-T cells against these determinants. TanCAR FRβ- CD123 T cells simultaneously engaged FRβ and CD123, which promoted T cell activation in targeting and lysis of the examined leukaemia cell lines. TanCAR-T cell significantly induced interferon gamma (IFNγ) and interleukin 2 (IL-2) production more than single CAR-T cells, which produced a synergistic enhancement of TanCAR FRβ-CD123 T cell function when dual antigens faced simultaneously. CONCLUSION: Dual-specific TanCAR FRβ-CD123 T cells showed therapeutic potential to improve AML control by co- engaging FRβ and CD123 molecules in a robust, divalent immune system. This strategy may be a useful therapeutic approach in patients with relapsed B-cell malignancies. Royan Institute 2021-11 2021-11-23 /pmc/articles/PMC8665988/ /pubmed/34939758 http://dx.doi.org/10.22074/cellj.2021.7314 Text en The Cell Journal (Yakhteh) is an open access journal which means the articles are freely available online for any individual author to download and use the providing address. https://creativecommons.org/licenses/by-nc/3.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Article Ghamari, Ali Pakzad, Parviz Majd, Ahmad Ebrahimi, Marzieh Hamidieh, Amir Ali Design and Production An Effective Bispecific Tandem Chimeric Antigen Receptor on T Cells against CD123 and Folate Receptor ß towards B-Acute Myeloid Leukaemia Blasts |
title | Design and Production An Effective Bispecific Tandem Chimeric
Antigen Receptor on T Cells against CD123 and Folate
Receptor ß towards B-Acute Myeloid Leukaemia Blasts |
title_full | Design and Production An Effective Bispecific Tandem Chimeric
Antigen Receptor on T Cells against CD123 and Folate
Receptor ß towards B-Acute Myeloid Leukaemia Blasts |
title_fullStr | Design and Production An Effective Bispecific Tandem Chimeric
Antigen Receptor on T Cells against CD123 and Folate
Receptor ß towards B-Acute Myeloid Leukaemia Blasts |
title_full_unstemmed | Design and Production An Effective Bispecific Tandem Chimeric
Antigen Receptor on T Cells against CD123 and Folate
Receptor ß towards B-Acute Myeloid Leukaemia Blasts |
title_short | Design and Production An Effective Bispecific Tandem Chimeric
Antigen Receptor on T Cells against CD123 and Folate
Receptor ß towards B-Acute Myeloid Leukaemia Blasts |
title_sort | design and production an effective bispecific tandem chimeric
antigen receptor on t cells against cd123 and folate
receptor ß towards b-acute myeloid leukaemia blasts |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8665988/ https://www.ncbi.nlm.nih.gov/pubmed/34939758 http://dx.doi.org/10.22074/cellj.2021.7314 |
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