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ALPL-1 is a target for chimeric antigen receptor therapy in osteosarcoma
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| Titill: | ALPL-1 is a target for chimeric antigen receptor therapy in osteosarcoma |
| Höfundur: |
... 17 fleiri höfundar Sýna alla höfunda |
| Útgáfa: | 2023-06-08 |
| Tungumál: | Enska |
| Umfang: | 2830905 |
| Deild: | Faculty of Medicine |
| Birtist í: | Nature Communications; 14(1) |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-023-39097-x |
| Efnisorð: | Child; Humans; Immunotherapy, Adoptive; T-Lymphocytes; Immunotherapy; Osteosarcoma/therapy; Bone Neoplasms/therapy; Cell Line, Tumor; Alkaline Phosphatase; General Physics and Astronomy; General Chemistry; General Biochemistry,Genetics and Molecular Biology |
| URI: | https://hdl.handle.net/20.500.11815/4388 |
Tilvitnun:Mensali , N , Köksal , H , Joaquina , S , Wernhoff , P , Casey , N P , Romecin , P , Panisello , C , Rodriguez , R , Vimeux , L , Juzeniene , A , Myhre , M R , Fåne , A , Ramírez , C C , Maggadottir , S M , Duru , A D , Georgoudaki , A M , Grad , I , Maturana , A D , Gaudernack , G , Kvalheim , G , Carcaboso , A M , de Alava , E , Donnadieu , E , Bruland , Ø S , Menendez , P , Inderberg , E M & Wälchli , S 2023 , ' ALPL-1 is a target for chimeric antigen receptor therapy in osteosarcoma ' , Nature Communications , vol. 14 , no. 1 , 3375 , pp. 3375 . https://doi.org/10.1038/s41467-023-39097-x
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Útdráttur: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.
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Athugasemdir:Funding Information: The authors would like to thank our colleagues from the Translational Research Unit and the Flow cytometry Core facility of OUS for providing technical assistance. We are grateful to Gibco and Life Technologies AS for supplying CTS™ Dynabeads™ CD3/CD28 and Drs. Mengyu Wang and Hanne B. Scholz (Oslo University Hospital) for providing the mesenchymal stem cells. We thank Prof. Michael Nishimura (Loyola University Chicago Stritch School of Medicine, USA) for sharing the truncated CD34 sequence. This study was supported by the Norwegian Research Council (Grant numbers: 284983 and 316407 to S.W. and 326811 to E.M.I), the Norwegian Health Region South East (Grant numbers: 2020601, 2018579, 2016006 and 2019062 to S.W. and 2019004 to E.M.I.) and S.J. is supported by the Norwegian Research Council under the frame of the Era-Net EURONANOMED-3 European Research project “NAN-4-TUM”. We thank Nova Southeastern University Center for Collaborative Research Core Facilities personnel Dr. Robin Krueger, Solly-Ann Barton-Case and Dr. Bojie Dai for their support in generation of RNAseq data. A.-M.G. was supported by the Swedish Society for Medical Research (SSMF). Research in P.M.’s Laboratory was funded by “la Caixa” Foundation Validate Program, ISCIII-RICORS within the Next Generation EU program (plan de recuperación, transformación y resilencia), and core support from CERCA/Generalitat de Catalunya and Fundació Josep Carreras-Obra Social la Caixa, the CaixaImpulse Grant CI21-00189, which has received funding from the European Institute of Innovation and Technology (EIT). This body of the European Union receives support from the European Union’s Horizon 2021 research and innovation program. C.P. is supported by a PFIS fellowship from Instituto de Salud Carlos III (ISCIII) (FI21/00161). Figures 3 a, 3 e, 4a , ad Supplementary Fig. 4a were prepared using BioRender.com. Funding Information: The authors would like to thank our colleagues from the Translational Research Unit and the Flow cytometry Core facility of OUS for providing technical assistance. We are grateful to Gibco and Life Technologies AS for supplying CTS™ Dynabeads™ CD3/CD28 and Drs. Mengyu Wang and Hanne B. Scholz (Oslo University Hospital) for providing the mesenchymal stem cells. We thank Prof. Michael Nishimura (Loyola University Chicago Stritch School of Medicine, USA) for sharing the truncated CD34 sequence. This study was supported by the Norwegian Research Council (Grant numbers: 284983 and 316407 to S.W. and 326811 to E.M.I), the Norwegian Health Region South East (Grant numbers: 2020601, 2018579, 2016006 and 2019062 to S.W. and 2019004 to E.M.I.) and S.J. is supported by the Norwegian Research Council under the frame of the Era-Net EURONANOMED-3 European Research project “NAN-4-TUM”. We thank Nova Southeastern University Center for Collaborative Research Core Facilities personnel Dr. Robin Krueger, Solly-Ann Barton-Case and Dr. Bojie Dai for their support in generation of RNAseq data. A.-M.G. was supported by the Swedish Society for Medical Research (SSMF). Research in P.M.’s Laboratory was funded by “la Caixa” Foundation Validate Program, ISCIII-RICORS within the Next Generation EU program (plan de recuperación, transformación y resilencia), and core support from CERCA/Generalitat de Catalunya and Fundació Josep Carreras-Obra Social la Caixa, the CaixaImpulse Grant CI21-00189, which has received funding from the European Institute of Innovation and Technology (EIT). This body of the European Union receives support from the European Union’s Horizon 2021 research and innovation program. C.P. is supported by a PFIS fellowship from Instituto de Salud Carlos III (ISCIII) (FI21/00161). Figures a, e, , ad Supplementary Fig. were prepared using BioRender.com. Publisher Copyright: © 2023, The Author(s).
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