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Development of A Chimeric Antigen Receptor Targeting C-Type Lectin-Like Molecule-1 for Human Acute Myeloid Leukemia

The treatment of patients with acute myeloid leukemia (AML) with targeted immunotherapy is challenged by the heterogeneity of the disease and a lack of tumor-exclusive antigens. Conventional immunotherapy targets for AML such as CD33 and CD123 have been proposed as targets for chimeric antigen recep...

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Autores principales: Laborda, Eduardo, Mazagova, Magdalena, Shao, Sida, Wang, Xinxin, Quirino, Herlinda, Woods, Ashley K., Hampton, Eric N., Rodgers, David T., Kim, Chan Hyuk, Schultz, Peter G., Young, Travis S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5713229/
https://www.ncbi.nlm.nih.gov/pubmed/29077054
http://dx.doi.org/10.3390/ijms18112259
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author Laborda, Eduardo
Mazagova, Magdalena
Shao, Sida
Wang, Xinxin
Quirino, Herlinda
Woods, Ashley K.
Hampton, Eric N.
Rodgers, David T.
Kim, Chan Hyuk
Schultz, Peter G.
Young, Travis S.
author_facet Laborda, Eduardo
Mazagova, Magdalena
Shao, Sida
Wang, Xinxin
Quirino, Herlinda
Woods, Ashley K.
Hampton, Eric N.
Rodgers, David T.
Kim, Chan Hyuk
Schultz, Peter G.
Young, Travis S.
author_sort Laborda, Eduardo
collection PubMed
description The treatment of patients with acute myeloid leukemia (AML) with targeted immunotherapy is challenged by the heterogeneity of the disease and a lack of tumor-exclusive antigens. Conventional immunotherapy targets for AML such as CD33 and CD123 have been proposed as targets for chimeric antigen receptor (CAR)-engineered T-cells (CAR-T-cells), a therapy that has been highly successful in the treatment of B-cell leukemia and lymphoma. However, CD33 and CD123 are present on hematopoietic stem cells, and targeting with CAR-T-cells has the potential to elicit long-term myelosuppression. C-type lectin-like molecule-1 (CLL1 or CLEC12A) is a myeloid lineage antigen that is expressed by malignant cells in more than 90% of AML patients. CLL1 is not expressed by healthy Hematopoietic Stem Cells (HSCs), and is therefore a promising target for CAR-T-cell therapy. Here, we describe the development and optimization of an anti-CLL1 CAR-T-cell with potent activity on both AML cell lines and primary patient-derived AML blasts in vitro while sparing healthy HSCs. Furthermore, in a disseminated mouse xenograft model using the CLL1-positive HL60 cell line, these CAR-T-cells completely eradicated tumor, thus supporting CLL1 as a promising target for CAR-T-cells to treat AML while limiting myelosuppressive toxicity.
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spelling pubmed-57132292017-12-07 Development of A Chimeric Antigen Receptor Targeting C-Type Lectin-Like Molecule-1 for Human Acute Myeloid Leukemia Laborda, Eduardo Mazagova, Magdalena Shao, Sida Wang, Xinxin Quirino, Herlinda Woods, Ashley K. Hampton, Eric N. Rodgers, David T. Kim, Chan Hyuk Schultz, Peter G. Young, Travis S. Int J Mol Sci Communication The treatment of patients with acute myeloid leukemia (AML) with targeted immunotherapy is challenged by the heterogeneity of the disease and a lack of tumor-exclusive antigens. Conventional immunotherapy targets for AML such as CD33 and CD123 have been proposed as targets for chimeric antigen receptor (CAR)-engineered T-cells (CAR-T-cells), a therapy that has been highly successful in the treatment of B-cell leukemia and lymphoma. However, CD33 and CD123 are present on hematopoietic stem cells, and targeting with CAR-T-cells has the potential to elicit long-term myelosuppression. C-type lectin-like molecule-1 (CLL1 or CLEC12A) is a myeloid lineage antigen that is expressed by malignant cells in more than 90% of AML patients. CLL1 is not expressed by healthy Hematopoietic Stem Cells (HSCs), and is therefore a promising target for CAR-T-cell therapy. Here, we describe the development and optimization of an anti-CLL1 CAR-T-cell with potent activity on both AML cell lines and primary patient-derived AML blasts in vitro while sparing healthy HSCs. Furthermore, in a disseminated mouse xenograft model using the CLL1-positive HL60 cell line, these CAR-T-cells completely eradicated tumor, thus supporting CLL1 as a promising target for CAR-T-cells to treat AML while limiting myelosuppressive toxicity. MDPI 2017-10-27 /pmc/articles/PMC5713229/ /pubmed/29077054 http://dx.doi.org/10.3390/ijms18112259 Text en © 2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Communication
Laborda, Eduardo
Mazagova, Magdalena
Shao, Sida
Wang, Xinxin
Quirino, Herlinda
Woods, Ashley K.
Hampton, Eric N.
Rodgers, David T.
Kim, Chan Hyuk
Schultz, Peter G.
Young, Travis S.
Development of A Chimeric Antigen Receptor Targeting C-Type Lectin-Like Molecule-1 for Human Acute Myeloid Leukemia
title Development of A Chimeric Antigen Receptor Targeting C-Type Lectin-Like Molecule-1 for Human Acute Myeloid Leukemia
title_full Development of A Chimeric Antigen Receptor Targeting C-Type Lectin-Like Molecule-1 for Human Acute Myeloid Leukemia
title_fullStr Development of A Chimeric Antigen Receptor Targeting C-Type Lectin-Like Molecule-1 for Human Acute Myeloid Leukemia
title_full_unstemmed Development of A Chimeric Antigen Receptor Targeting C-Type Lectin-Like Molecule-1 for Human Acute Myeloid Leukemia
title_short Development of A Chimeric Antigen Receptor Targeting C-Type Lectin-Like Molecule-1 for Human Acute Myeloid Leukemia
title_sort development of a chimeric antigen receptor targeting c-type lectin-like molecule-1 for human acute myeloid leukemia
topic Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5713229/
https://www.ncbi.nlm.nih.gov/pubmed/29077054
http://dx.doi.org/10.3390/ijms18112259
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