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

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.

• Authors: Jens Rüter, Scott J Antonia, Howard A Burris, Richard D Huhn, Robert H Vonderheide
• Journal: Cancer biology & therapy (Cancer Biol Ther) Vol. 10 Issue 10 Pg. 983-93 (Nov 15 2010) ISSN: 1555-8576 [Electronic] United States
• PMID: 20855968 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents
• CD40 Antigens
• Cytokines
• selicrelumab

Topics

• Aged
• Aged, 80 and over
• Antibodies, Monoclonal (pharmacokinetics, therapeutic use)
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents (pharmacokinetics, therapeutic use)
• CD40 Antigens (agonists)
• Cytokines (metabolism)
• Female
• Flow Cytometry
• Humans
• Infusions, Intravenous
• Male
• Maximum Tolerated Dose
• Middle Aged
• Neoplasms (drug therapy, immunology)
• Remission Induction
• T-Lymphocyte Subsets (immunology)
• Tissue Distribution