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ALPL-1 is a target for chimeric antigen receptor therapy in osteosarcoma

Osteosarcoma (OS) remains a dismal malignancy in children and young adults, with poor outcome for metastatic and recurrent disease. Immunotherapies in OS are not as promising as in some other cancer types due to intra-tumor heterogeneity and considerable off-target expression of the potentially targ...

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Autores principales: Mensali, Nadia, Köksal, Hakan, Joaquina, Sandy, Wernhoff, Patrik, Casey, Nicholas P., Romecin, Paola, Panisello, Carla, Rodriguez, René, Vimeux, Lene, Juzeniene, Asta, Myhre, Marit R., Fåne, Anne, Ramírez, Carolina Castilla, Maggadottir, Solrun Melkorka, Duru, Adil Doganay, Georgoudaki, Anna-Maria, Grad, Iwona, Maturana, Andrés Daniel, Gaudernack, Gustav, Kvalheim, Gunnar, Carcaboso, Angel M., de Alava, Enrique, Donnadieu, Emmanuel, Bruland, Øyvind S., Menendez, Pablo, Inderberg, Else Marit, Wälchli, Sébastien
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10250459/
https://www.ncbi.nlm.nih.gov/pubmed/37291203
http://dx.doi.org/10.1038/s41467-023-39097-x
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author Mensali, Nadia
Köksal, Hakan
Joaquina, Sandy
Wernhoff, Patrik
Casey, Nicholas P.
Romecin, Paola
Panisello, Carla
Rodriguez, René
Vimeux, Lene
Juzeniene, Asta
Myhre, Marit R.
Fåne, Anne
Ramírez, Carolina Castilla
Maggadottir, Solrun Melkorka
Duru, Adil Doganay
Georgoudaki, Anna-Maria
Grad, Iwona
Maturana, Andrés Daniel
Gaudernack, Gustav
Kvalheim, Gunnar
Carcaboso, Angel M.
de Alava, Enrique
Donnadieu, Emmanuel
Bruland, Øyvind S.
Menendez, Pablo
Inderberg, Else Marit
Wälchli, Sébastien
author_facet Mensali, Nadia
Köksal, Hakan
Joaquina, Sandy
Wernhoff, Patrik
Casey, Nicholas P.
Romecin, Paola
Panisello, Carla
Rodriguez, René
Vimeux, Lene
Juzeniene, Asta
Myhre, Marit R.
Fåne, Anne
Ramírez, Carolina Castilla
Maggadottir, Solrun Melkorka
Duru, Adil Doganay
Georgoudaki, Anna-Maria
Grad, Iwona
Maturana, Andrés Daniel
Gaudernack, Gustav
Kvalheim, Gunnar
Carcaboso, Angel M.
de Alava, Enrique
Donnadieu, Emmanuel
Bruland, Øyvind S.
Menendez, Pablo
Inderberg, Else Marit
Wälchli, Sébastien
author_sort Mensali, Nadia
collection PubMed
description Osteosarcoma (OS) remains a dismal malignancy in children and young adults, with poor outcome for metastatic and recurrent disease. Immunotherapies in OS are not as promising as in some other cancer types due to intra-tumor heterogeneity and considerable off-target expression of the potentially targetable proteins. Here we show that chimeric antigen receptor (CAR) T cells could successfully target an isoform of alkaline phosphatase, ALPL-1, which is highly and specifically expressed in primary and metastatic OS. The target recognition element of the second-generation CAR construct is based on two antibodies, previously shown to react against OS. T cells transduced with these CAR constructs mediate efficient and effective cytotoxicity against ALPL-positive cells in in vitro settings and in state-of-the-art in vivo orthotopic models of primary and metastatic OS, without unexpected toxicities against hematopoietic stem cells or healthy tissues. In summary, CAR-T cells targeting ALPL-1 show efficiency and specificity in treating OS in preclinical models, paving the path for clinical translation.
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spelling pubmed-102504592023-06-10 ALPL-1 is a target for chimeric antigen receptor therapy in osteosarcoma Mensali, Nadia Köksal, Hakan Joaquina, Sandy Wernhoff, Patrik Casey, Nicholas P. Romecin, Paola Panisello, Carla Rodriguez, René Vimeux, Lene Juzeniene, Asta Myhre, Marit R. Fåne, Anne Ramírez, Carolina Castilla Maggadottir, Solrun Melkorka Duru, Adil Doganay Georgoudaki, Anna-Maria Grad, Iwona Maturana, Andrés Daniel Gaudernack, Gustav Kvalheim, Gunnar Carcaboso, Angel M. de Alava, Enrique Donnadieu, Emmanuel Bruland, Øyvind S. Menendez, Pablo Inderberg, Else Marit Wälchli, Sébastien Nat Commun Article Osteosarcoma (OS) remains a dismal malignancy in children and young adults, with poor outcome for metastatic and recurrent disease. Immunotherapies in OS are not as promising as in some other cancer types due to intra-tumor heterogeneity and considerable off-target expression of the potentially targetable proteins. Here we show that chimeric antigen receptor (CAR) T cells could successfully target an isoform of alkaline phosphatase, ALPL-1, which is highly and specifically expressed in primary and metastatic OS. The target recognition element of the second-generation CAR construct is based on two antibodies, previously shown to react against OS. T cells transduced with these CAR constructs mediate efficient and effective cytotoxicity against ALPL-positive cells in in vitro settings and in state-of-the-art in vivo orthotopic models of primary and metastatic OS, without unexpected toxicities against hematopoietic stem cells or healthy tissues. In summary, CAR-T cells targeting ALPL-1 show efficiency and specificity in treating OS in preclinical models, paving the path for clinical translation. Nature Publishing Group UK 2023-06-08 /pmc/articles/PMC10250459/ /pubmed/37291203 http://dx.doi.org/10.1038/s41467-023-39097-x Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Mensali, Nadia
Köksal, Hakan
Joaquina, Sandy
Wernhoff, Patrik
Casey, Nicholas P.
Romecin, Paola
Panisello, Carla
Rodriguez, René
Vimeux, Lene
Juzeniene, Asta
Myhre, Marit R.
Fåne, Anne
Ramírez, Carolina Castilla
Maggadottir, Solrun Melkorka
Duru, Adil Doganay
Georgoudaki, Anna-Maria
Grad, Iwona
Maturana, Andrés Daniel
Gaudernack, Gustav
Kvalheim, Gunnar
Carcaboso, Angel M.
de Alava, Enrique
Donnadieu, Emmanuel
Bruland, Øyvind S.
Menendez, Pablo
Inderberg, Else Marit
Wälchli, Sébastien
ALPL-1 is a target for chimeric antigen receptor therapy in osteosarcoma
title ALPL-1 is a target for chimeric antigen receptor therapy in osteosarcoma
title_full ALPL-1 is a target for chimeric antigen receptor therapy in osteosarcoma
title_fullStr ALPL-1 is a target for chimeric antigen receptor therapy in osteosarcoma
title_full_unstemmed ALPL-1 is a target for chimeric antigen receptor therapy in osteosarcoma
title_short ALPL-1 is a target for chimeric antigen receptor therapy in osteosarcoma
title_sort alpl-1 is a target for chimeric antigen receptor therapy in osteosarcoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10250459/
https://www.ncbi.nlm.nih.gov/pubmed/37291203
http://dx.doi.org/10.1038/s41467-023-39097-x
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