Soluble CD137 as a dynamic biomarker to monitor agonist CD137 immunotherapies

Abstract

BackgroundOn 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.MethodsWe 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.ResultsCD137 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.ConclusionsCD137 in plasma and CD137 surface expression can be used as quantitative parameters dynamically reflecting therapeutic costimulatory activity elicited by agonist CD137-targeted agents.

CD137 (4-1BB) requires physically associated cIAPs for signal transduction and antitumor effects

“…eCFP/NF-κB reporter Jurkat cells were transduced with lentivirus encoding for an anti-mesothelin BBz CAR, provided by S. Guedán (Hospital Clinic, Barcelona, Spain) and C. June (University of Pennsylvania, Philadelphia, PA, USA) ( 81 ). After 6 hours, CAR expression was confirmed by flow cytometry.…”

Soluble CD137: A Potential Prognostic Biomarker in Critically Ill Patients

“…Notably, lymphocyte activation correlates with an increase in sCD137 levels approximately 3 days afterward, hinting at the potential role of sCD137 in dampening T cell activation and CD137-dependent costimulatory signaling pathways [14]. Given that plasma sCD137 signifies prior CD137 activation [34], its elevated levels in SIRS/sepsis patients implies an early activation of CD137 signaling during severe illness.…”

Detection of sFas, sCD137, and IL-27 Cytokines as Potential Biomarkers for Hepatocellular Carcinoma Diagnosis

“… 32 In a different context, Glez-Vaz et al reported that anti-CD137 agonists led to an sCD137 increase in mice bearing syngeneic tumors. 33 Taken together, serum levels of IL-27 and sCD137 could be synergistically elevated by activating the CD137 signaling pathway to trigger an inflammatory response in liver cancer. This mechanism may be the reason why IL-27 and sCD137 had a positive correlation in our study.…”