Immune modulation with weekly dosing of an agonist CD40 antibody in a phase I study of patients with advanced solid tumors
Volume 10, Issue 10
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November 15, 2010
Pages 983 - 993http://dx.doi.org/10.4161/cbt.10.10.13251
Authors: Jens Rüter, Scott J. Antonia, Howard A. Burris, Richard D. Huhn and Robert H. Vonderheide View affiliations
Background: Single-dose infusion of the agonistic anti-CD40 monoclonal antibody (mAb) CP-870,893 accomplishes immune activation and clinical responses in patients with advanced cancers, but repeat dosing of this agent has not been reported.
Patients and methods: Patients with advanced solid tumor malignancies received weekly intravenous infusions of CP-870,893 in four dose level cohorts. Safety and immune pharmacodynamics were assessed.
Results: Twenty-seven patients were enrolled. The most common adverse event was transient, infusion-related cytokine release syndrome (CRS). Dose-limiting toxicities included grade 3 CRS and grade 3 urticaria; the maximum tolerated dose (MTD) was estimated to be 0.2 mg/kg. Seven patients (26%) had stable disease as the best clinical response; no partial or complete responses were observed. At the MTD, patient B lymphocytes exhibited persistently increased expression of costimulatory and adhesion molecules without resetting to baseline between doses. In 4 of 8 patients (50%) evaluated at the MTD, there were marked declines in total CD3+ T lymphocytes, as well as CD4+ and CD8+ subsets.
Conclusions: Weekly infusions of the agonist CD40 antibody CP-870,893 were well-tolerated, but there was little clinical activity in advanced cancer patients. Correlative studies demonstrate chronic B cell activation and in some patients, T cell depletion. Longer dosing intervals may be desirable for optimal immune pharmacodynamics.