ALPL-1 is a target for chimeric antigen receptor therapy in osteosarcoma
Mensali, Nadia (Department of Cellular Therapy. Oslo University Hospital)
Köksal, Hakan (Oslo University Hospital)
Joaquina, Sandy (Oslo University Hospital)
Wernhoff, Patrick (Oslo University Hospital)
Casey, Nicholas P. (Oslo University Hospital)
Romecín, Paola Alejandra (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Panisello, Carla (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Rodríguez, René (Instituto de Salud Carlos III)
Vimeux, Lene (Université de Paris)
Juzeniene, Asta (Oslo University Hospital)
Myhre, Marit R. (Oslo University Hospital)
Fåne, Anne (Oslo University Hospital)
Castilla-Ramirez, Carolina (Hospital Universitario Virgen del Rocío (Sevilla, Andalusia))
Maggadottir, Solrun Melkork (Oslo University Hospital)
Duru, Adil Doganay (Nova Southeastern University)
Georgoudaki, Anna-Maria (Department of Oncology-Pathology. Karolinska Institutet)
Grad, Iwona (Oslo University Hospital)
Maturana, Andrés Daniel (Nagoya University)
Gaudernack, Gustav (Department of Cancer Immunology. Oslo University Hospital)
Kvalheim, Gunnar (Department of Cellular Therapy. Oslo University Hospital)
Carcaboso, Angel M. (Institut de Recerca Sant Joan de Déu)
De Álava, Enrique (Universidad de Sevilla)
Donnadieu, Emma (Université de Paris)
Bruland, Øyvind S (University of Oslo)
Menendez, Pablo (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Inderberg, Else Marit (Oslo University Hospital)
Wälchli, Sébastien (Oslo University Hospital)

Data:	2023
Resum:	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.
Ajuts:	Instituto de Salud Carlos III FI21/00161 "la Caixa" Foundation CI21-00189
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Alkaline Phosphatase ; Bone Neoplasms ; Cell Line, Tumor ; Child ; Humans ; Immunotherapy ; Immunotherapy, Adoptive ; Osteosarcoma ; T-Lymphocytes
Publicat a:	Nature communications, Vol. 14 Núm. 1 (december 2023) , p. 3375, ISSN 2041-1723

DOI: 10.1038/s41467-023-39097-x
PMID: 37291203

15 p, 2.7 MB

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