ALPL-1 is a target for chimeric antigen receptor therapy in osteosarcoma.
Por:
Mensali, N, Köksal, H, Joaquina, S, Wernhoff, P, Casey, NP, Romecin, P, Panisello, C, Rodriguez, R, Vimeux, L, Juzeniene, A, Myhre, MR, Fåne, A, Ramírez, CC, Maggadottir, SM, Duru, AD, Georgoudaki, AM, Grad, I, Maturana, AD, Gaudernack, G, Kvalheim, G, Carcaboso AM, de Alava, E, Donnadieu, E, Bruland, OS, Menendez, P, Inderberg, EM and Wälchli, S
Publicada:
8 jun 2023
Ahead of Print:
8 jun 2023
Resumen:
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.
Filiaciones:
Mensali, N:
Oslo Univ Hosp, Dept Cellular Therapy, Translat Res Unit, Oslo, Norway
Köksal, H:
Oslo Univ Hosp, Dept Cellular Therapy, Translat Res Unit, Oslo, Norway
Joaquina, S:
Oslo Univ Hosp, Dept Cellular Therapy, Translat Res Unit, Oslo, Norway
Wernhoff, P:
Oslo Univ Hosp, Dept Cellular Therapy, Translat Res Unit, Oslo, Norway
Casey, NP:
Oslo Univ Hosp, Dept Cellular Therapy, Translat Res Unit, Oslo, Norway
Romecin, P:
Josep Carreras Leukemia Res Inst, Barcelona, Spain
Inst Salud Carlos III ISCIII, Red Espanola Terapias Avanzadas TERAV, RICORS, RD21 0017 0029, Madrid, Spain
Panisello, C:
Josep Carreras Leukemia Res Inst, Barcelona, Spain
Inst Salud Carlos III ISCIII, Red Espanola Terapias Avanzadas TERAV, RICORS, RD21 0017 0029, Madrid, Spain
Rodriguez, R:
Hosp Univ Cent Asturias, Inst Invest Sanitaria Principado Asturias ISPA, Oviedo, Spain
Inst Univ Oncol Principado Asturias, Oviedo, Spain
Inst Salud Carlos III, Ctr Invest Biomed Red Oncol CIBER ONC, Madrid, Spain
Vimeux, L:
Univ Paris, CNRS, Inst Cochin, INSERM,Equipe Labellisee Ligue Canc, F-75014 Paris, France
Juzeniene, A:
Oslo Univ Hosp, Inst Canc Res, Dept Radiat Biol, Oslo, Norway
Myhre, MR:
Oslo Univ Hosp, Dept Cellular Therapy, Translat Res Unit, Oslo, Norway
Fåne, A:
Oslo Univ Hosp, Dept Cellular Therapy, Translat Res Unit, Oslo, Norway
Ramírez, CC:
Univ Seville, Virgen del Rocio Univ Hosp, Inst Biomed Sevilla IBiS, CSIC,CIBER ONC, Seville 41013, Spain
Maggadottir, SM:
Oslo Univ Hosp, Dept Cellular Therapy, Translat Res Unit, Oslo, Norway
Duru, AD:
Nova Southeastern Univ, NSU Cell Therapy Inst, Dr Kiran C Patel Coll Allopath Med, Ft Lauderdale, FL 33314 USA
Georgoudaki, AM:
Nova Southeastern Univ, NSU Cell Therapy Inst, Dr Kiran C Patel Coll Allopath Med, Ft Lauderdale, FL 33314 USA
Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden
Grad, I:
Oslo Univ Hosp, Inst Canc Res, Dept Radiat Biol, Oslo, Norway
Maturana, AD:
Nagoya Univ, Grad Sch Bioagr Sci, Lab Anim Cell Physiol, Nagoya, Aichi, Japan
Gaudernack, G:
Oslo Univ Hosp, Dept Canc Immunol, Oslo, Norway
Kvalheim, G:
Oslo Univ Hosp, Dept Cellular Therapy, Translat Res Unit, Oslo, Norway
Carcaboso AM:
Inst Recerca St Joan de Deu, SJD Pediat Canc Ctr Barcelona, Barcelona 08950, Spain
de Alava, E:
Univ Seville, Virgen del Rocio Univ Hosp, Inst Biomed Sevilla IBiS, CSIC,CIBER ONC, Seville 41013, Spain
Univ Seville, Sch Med, Dept Normal & Pathol Cytol & Histol, Seville 41009, Spain
Donnadieu, E:
Univ Paris, CNRS, Inst Cochin, INSERM,Equipe Labellisee Ligue Canc, F-75014 Paris, France
Bruland, OS:
Oslo Univ Hosp, Dept Oncol, Oslo, Norway
Univ Oslo, Inst Clin Med, Oslo, Norway
Menendez, P:
Josep Carreras Leukemia Res Inst, Barcelona, Spain
Inst Salud Carlos III ISCIII, Red Espanola Terapias Avanzadas TERAV, RICORS, RD21 0017 0029, Madrid, Spain
ISCIII, CIBER ONC, Barcelona, Spain
ICREA, Barcelona, Spain
Univ Barcelona, Sch Med, Dept Biomed, Barcelona, Spain
Inderberg, EM:
Oslo Univ Hosp, Dept Cellular Therapy, Translat Res Unit, Oslo, Norway
Wälchli, S:
Oslo Univ Hosp, Dept Cellular Therapy, Translat Res Unit, Oslo, Norway
Green Submitted, gold
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