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Clinical Trial
. 2010 Nov 15;10(10):983-93.
doi: 10.4161/cbt.10.10.13251. Epub 2010 Nov 15.

Immune modulation with weekly dosing of an agonist CD40 antibody in a phase I study of patients with advanced solid tumors

Jens Rüter  1 , Scott J Antonia, Howard A Burris, Richard D Huhn, Robert H Vonderheide
Affiliations
Clinical Trial

Immune modulation with weekly dosing of an agonist CD40 antibody in a phase I study of patients with advanced solid tumors

Jens Rüter et al. Cancer Biol Ther. .

Abstract

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.

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.

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.

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.

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Figures

Figure 1
Figure 1
Change relative to baseline in hematologic and serum chemistry parameters after first, second and fourth infusion of CP-870,893 in patients at MTD or higher. ALC, absolute lymphocyte count; AMC, absolute monocyte count; Plts, platelets; Ddi, D-dimer; INR, international ratio; Hgb, hemoglobin; AST, asparate aminotransferase; ALT, alanine aminotransferase; Bili, total bilirubin. Arrows indicate treatment days (day 1, 8, 15, 22). Values expressed as mean ± SEM, n = 8–18.
Figure 2
Figure 2
Pharmacodynamics of CP-870,893 after first, second and fourth infusion of CP-870,893. Parameters are shown relative to baseline. CD19 (%+) = percentage of CD19+ cells among lymphocytes, CD19 (abs) = absolute number of CD19+ cells, CD54 (%+) = CD54+ cells among CD19+ cells, CD86 (%+) CD86+ cells among CD19+ cells. Arrows indicate treatment days (day 1, 8, 15, 22). Values expressed as mean ± SEM, n = 8–18.
Figure 3
Figure 3
Modulation in T-cell subsets following treatment with CP-870,893. (A and B) Baseline parameters of eight patients treated at the MTD or higher study expressed in absolute numbers for each patient (unique patient number noted on x-axis) for (A) CD4+ and (B) CD8+ T cell subsets. Naïve = CD45RA+CCR7+CD27+CD28+, CM = Central Memory = CD45RA-CCR7+CD27+CD28+, EM = Effector Memory = CD45RA−CCR7−CD27+/−CD28+/−, Effector = CD45RA+CCR7−CD27−CD28−. SD denotes patients who had stable disease as best clinical response. Change in (C) absolute CD3 counts, (D) absolute CD4 counts and (E) absolute CD8 counts, comparing end of study to baseline. Change relative to baseline in the percentages of four T-cell subsets, defined above, for (F) CD4 and (G) CD8 subsets in response to treatment, shown as mean ± SEM.
Figure 4
Figure 4
Baseline parameters and treatment-related changes of IFNγ and perforin expression and regulatory T cells. Fraction of IFNγ among CD8+ (A) and CD4+ (C), fraction of perforin among CD8+ (E), fraction of FoxP3+ among CD4+ (G) and absolute Foxp3+ CD4+ cells per ul blood (I) at baseline. Relative changes comparing end of study to baseline in IFNγ among CD8+ (B) and CD4+ (D), fraction of perforin among CD8+ (F), fraction of FoxP3+ among CD4+ (H) and absolute count of Foxp3+ CD4+ cells (J).
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