Publicaciones científicas
Soluble CD137 as a dynamic biomarker to monitor agonist CD137 immunotherapies
Javier Glez-Vaz # 1 2 , Arantza Azpilikueta # 1 2 , Irene Olivera 1 2 , Assunta Cirella 1 2 3 , Alvaro Teijeira 1 2 4 , Maria C Ochoa 1 2 3 4 , Maite Alvarez 1 2 3 4 , Iñaki Eguren-Santamaria 1 2 , Carlos Luri-Rey 1 2 , Maria E Rodriguez-Ruiz 1 2 3 4 , Xinxin Nie 5 , Lieping Chen 5 6 , Sonia Guedan 7 , Miguel F Sanamed 1 2 3 4 , Jose Luis Perez Gracia 1 2 3 4 , Ignacio Melero 8 2 3 4
Abstract
Background: On the basis of efficacy in mouse tumor models, multiple CD137 (4-1BB) agonist agents are being preclinically and clinically developed. The costimulatory molecule CD137 is inducibly expressed as a transmembrane or as a soluble protein (sCD137). Moreover, the CD137 cytoplasmic signaling domain is a key part in approved chimeric antigen receptors (CARs). Reliable pharmacodynamic biomarkers for CD137 ligation and costimulation of T cells will facilitate clinical development of CD137 agonists in the clinic.
Methods: We used human and mouse CD8 T cells undergoing activation to measure CD137 transcription and protein expression levels determining both the membrane-bound and soluble forms. In tumor-bearing mice plasma sCD137 concentrations were monitored on treatment with agonist anti-CD137 monoclonal antibodies (mAbs). Human CD137 knock-in mice were treated with clinical-grade agonist anti-human CD137 mAb (Urelumab).
Sequential plasma samples were collected from the first patients intratumorally treated with Urelumab in the INTRUST clinical trial. Anti-mesothelin CD137-encompassing CAR-transduced T cells were stimulated with mesothelin coated microbeads. sCD137 was measured by sandwich ELISA and Luminex. Flow cytometry was used to monitor CD137 surface expression.
Results: CD137 costimulation upregulates transcription and protein expression of CD137 itself including sCD137 in human and mouse CD8 T cells. Immunotherapy with anti-CD137 agonist mAb resulted in increased plasma sCD137 in mice bearing syngeneic tumors. sCD137 induction is also observed in human CD137 knock-in mice treated with Urelumab and in mice transiently humanized with T cells undergoing CD137 costimulation inside subcutaneously implanted Matrigel plugs.
The CD137 signaling domain-containing CAR T cells readily released sCD137 and acquired CD137 surface expression on antigen recognition. Patients treated intratumorally with low dose Urelumab showed increased plasma concentrations of sCD137.
Conclusion: sCD137 in plasma and CD137 surface expression can be used as quantitative parameters dynamically reflecting therapeutic costimulatory activity elicited by agonist CD137-targeted agents.
CITA DEL ARTÍCULO J Immunother Cancer. 2022 Mar;10(3):e003532. doi: 10.1136/jitc-2021-003532
![](/.resources/ModuloCUN/resources/img/publicaciones/icono-destacado-investigadores.png)
Nuestros autores
![Silueta investigadores. Cima Universidad de Navarra](/.imaging/mte/cima/profesional_carrusel-80x80/dam/cima/imagenes/profesionales/silueta-cima/jcr:content/silueta-cima.png)
![Arantza Azpilicueta. Programa Inmunología e Inmunoterapia. Cima](/.imaging/mte/cima/profesional_carrusel-80x80/dam/cima/imagenes/profesionales/programas-transversales/inmunologia-inmunoterapia/arantza-azpilicueta-lusarreta/jcr:content/arantza-azpilicueta-lusarreta.jpg)
![Irene Olivera. Programa Inmunología e Inmunoterapia. Cima](/.imaging/mte/cima/profesional_carrusel-80x80/dam/cima/imagenes/profesionales/programas-transversales/inmunologia-inmunoterapia/irene-olivera-valle/jcr:content/irene-olivera-valle.jpg)
![Assunta Cirella. Programa Inmunología e Inmunoterapia. Cima](/.imaging/mte/cima/profesional_carrusel-80x80/dam/cima/imagenes/profesionales/programas-transversales/inmunologia-inmunoterapia/assunta-cirella/jcr:content/assunta-cirella.jpg)
![Carmen Ochoa. Inmunología e Inmunoterapia. Cima Colaboradora de investigación del Programa de Inmunología e Inmunoterapia del Cima Universidad de Navarra](/.imaging/mte/cima/profesional_carrusel-80x80/dam/cima/imagenes/profesionales/programas-transversales/inmunologia-inmunoterapia/carmen-ochoa-nieto/jcr:content/carmen-ochoa-nieto.jpg)
![Carlos Luri. Programa de Inmunología e Inmunoterapia. Cima Universidad de Navarra](/.imaging/mte/cima/profesional_carrusel-80x80/dam/cima/imagenes/profesionales/programas-transversales/inmunologia-inmunoterapia/carlos-luri/jcr:content/carlos-luri.jpg)