Department of Medicine, Division of Oncology, Stanford University, Stanford, CA
Cariad Chester , Serena Chang , John F. Kurland , Idit Sagiv-Barfi , Debra Czerwinski , Amanda Rajapaksa , Erin Waller , Mohith Sadaram , Lori Richards , Lewis J. Cohen , Christoph Matthias Ahlers , Maria Jure-Kunkel , Holden Maecker , Ronald Levy , Holbrook Edwin Kohrt
Background: Anti-CD137 antibody was shown in both murine cancer models and in a first-in-human, phase I trial (Sznol et al., 2008) to increase peripheral activated CD8 T cells and IFN-inducible genes, thereby facilitating a cytolytic, antitumor, Th1 response. A multiparametric immune pharmacodynamic assessment of the effects of anti-CD137 therapy has not been previously performed. Methods: We employed the novel technology of mass cytometry time of flight (CyTOF) to investigate the patient’s global immune status prior to and during a phase 1 study (NCT01471210) of Urelumab, a fully human anti-CD137 antibody, administered once per 3-week cycle in patients with solid tumors and B-cell non-Hodgkin’s lymphoma. Peripheral blood was obtained at 4 time points throughout treatment (baseline, 24-hrs after 1st dose of cycle 1, immediately before cycle 2, and post cycle 3 at response evaluation, C3R). PBMCs were isolated and stimulated for 4 hours with PMA/ionomycin. Immune cell characterization and function were analyzed in FlowJo and SPADE from mass cytometry results. Results: Preliminary findings from 4 patients show an increase in CD8 T cells up to 40.6% (SEM+/-13%) and NK cells up to 61.7% (SEM+/-20%) with a decrease in CD4 T cells up to 23.2% (SEM+/-6.5%) and regulatory CD4 T cells up to 17.8% (SEM+/-15%) comparing C3R to baseline. CyTOF cytokine analysis, revealed increases in GMCSF and IFN-gamma by C3R. CyTOF cytokine analysis, revealed increases in GMCSF and IFN-gamma by C3R. Conclusions: These preliminary data are consistent with anti-CD137 agonism and generate hypotheses of putative biomarkers of clinical activity now being investigated and to be reported from the ongoing clinical trial. Clinical trial information: NCT01471210.
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