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

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 Alava, Emmanuel Donnadieu, Øyvind S. Bruland, Pablo Menendez, Else Marit Inderberg () and Sébastien Wälchli ()
Additional contact information
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
Carla Panisello: Josep Carreras Leukemia Research Institute
René Rodriguez: Hospital Universitario Central de Asturias
Lene Vimeux: Université de Paris, Institut Cochin, INSERM, CNRS, Equipe labellisée Ligue Contre le Cancer
Asta Juzeniene: Oslo University Hospital
Marit R. Myhre: Oslo University Hospital
Anne Fåne: Oslo University Hospital
Carolina Castilla Ramírez: Virgen del Rocio University Hospital, CSIC, University of Sevilla, CIBER-ONC
Solrun Melkorka Maggadottir: Oslo University Hospital
Adil Doganay Duru: Nova Southeastern University
Anna-Maria Georgoudaki: Nova Southeastern University
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 Alava: Virgen del Rocio University Hospital, CSIC, University of Sevilla, CIBER-ONC
Emmanuel Donnadieu: Université de Paris, Institut Cochin, INSERM, CNRS, Equipe labellisée Ligue Contre le Cancer
Øyvind S. Bruland: Oslo University Hospital and Institute of Clinical Medicine, University of Oslo
Pablo Menendez: Josep Carreras Leukemia Research Institute
Else Marit Inderberg: Oslo University Hospital
Sébastien Wälchli: Oslo University Hospital

Nature Communications, 2023, vol. 14, issue 1, 1-15

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.

Date: 2023
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DOI: 10.1038/s41467-023-39097-x

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