Nadia Mensali, Oslo University Hospital
Hakan Köksal, Oslo University Hospital
Sandy Joaquina, Oslo University Hospital
Patrik Wernhoff, Oslo University Hospital
Nicholas P. Casey, Oslo University Hospital
Paola Romecin, Josep Carreras Leukemia Research Institute; Instituto de Salud Carlos III (ISCIII)
Carla Panisello, Josep Carreras Leukemia Research Institute; Instituto de Salud Carlos III (ISCIII)
René Rodriguez, Hospital Universitario Central de Asturias; Instituto Universitario de Oncología del Principado de Asturias; Instituto de Salud Carlos III
Lene Vimeux, Université de Paris
Asta Juzeniene, Oslo University Hospital
Marit R. Myhre, Oslo University Hospital
Anne Fåne, Oslo University Hospital
Carolina Castilla Ramírez, University of Sevilla
Solrun Melkorka Maggadottir, Oslo University Hospital
Adil Doganay Duru, Nova Southeastern University
Anna-Maria Georgoudaki, Nova Southeastern University; Karolinska Institutet
Iwona Grad, Oslo University Hospital
Andrés Daniel Maturana, Nagoya University
Gustav Gaudernack, Oslo University Hospital
Gunnar Kvalheim, Oslo University Hospital
Angel M. Carcaboso, Institut de Recerca Sant Joan de Deu
Enrique de Alava, University of Seville
Emmanuel Donnadieu, Université de Paris
Øyvind S. Bruland, University of Oslo
Pablo Menendez, Josep Carreras Leukemia Research Institute; Instituto de Salud Carlos III (ISCIII); Institució Catalana de Recerca i Estudis Avançats (ICREA); University of Barcelona
Else Marit Inderberg, Oslo University Hospital
Sébastien Wälchli, Oslo University Hospital

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Nature Communications








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.


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.

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Creative Commons Attribution 4.0 International License
This work is licensed under a Creative Commons Attribution 4.0 International License.



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