Publicaciones científicas

Soluble CD137 as a dynamic biomarker to monitor agonist CD137 immunotherapies

01-mar-2022 | Revista: Journal for Immunotherapy of Cancer

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


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