Document Type
Article
Publication Date
6-8-2023
Publication Title
Nature Communications
ISSN
2041-1723
Volume
14
Issue/No.
3375
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.
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
NSUWorks Citation
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; and Wälchli, Sébastien, "ALPL-1 is a target for chimeric antigen receptor therapy in osteosarcoma." (2023). HPD Articles. 495.
https://nsuworks.nova.edu/hpd_facarticles/495
ORCID ID
DOI
10.1038/s41467-023-39097-x
Copyright
© The Author(s) 2023
Comments
Competing interests: S.W., E.M.I., and Ø.B. are inventors of the patent WO2020127734. A.M.G. and A.D.D. were not employees of Glycostem Therapeutics B.V. when their contribution for this study was performed. I.G. was not employee of Thermo Fisher Scientific when is contribution for this study was performed. P.M. is cofounder on OneChain Immunotherapeutics, a Josep Carreras Leukemia Research Institute spinoff company. The remaining authors declare no competing interests.