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

Authors :
Nadia Mensali
Hakan Köksal
Sandy Joaquina
Patrik Wernhoff
Nicholas P. Casey
Paola Romecin
Carla Panisello
René Rodriguez
Lene Vimeux
Asta Juzeniene
Marit R. Myhre
Anne Fåne
Carolina Castilla Ramírez
Solrun Melkorka Maggadottir
Adil Doganay Duru
Anna-Maria Georgoudaki
Iwona Grad
Andrés Daniel Maturana
Gustav Gaudernack
Gunnar Kvalheim
Angel M. Carcaboso
Enrique de Alava
Emmanuel Donnadieu
Øyvind S. Bruland
Pablo Menendez
Else Marit Inderberg
Sébastien Wälchli
Source :
Nature Communications, Vol 14, Iss 1, Pp 1-15 (2023)
Publication Year :
2023
Publisher :
Nature Portfolio, 2023.

Abstract

Abstract 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.

Subjects

Subjects :
Science

Details

Language :
English
ISSN :
20411723
Volume :
14
Issue :
1
Database :
Directory of Open Access Journals
Journal :
Nature Communications
Publication Type :
Academic Journal
Accession number :
edsdoj.b35d7698f54300a9d32846913690b0
Document Type :
article
Full Text :
https://doi.org/10.1038/s41467-023-39097-x