This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Vonderheide, R. H. Articles by Antonia, S. J. Search for Related Content PubMed PubMed Citation Articles by Vonderheide, R. H. Articles by Antonia, S. J.

Clinical Activity and Immune Modulation in Cancer Patients Treated With CP-870,893, a Novel CD40 Agonist Monoclonal Antibody

Robert H. Vonderheide, Keith T. Flaherty, Magi Khalil, Molly S. Stumacher, David L. Bajor, Natalie A. Hutnick, Patricia Sullivan, J. Joseph Mahany, Maryann Gallagher, Amy Kramer, Stephanie J. Green, Peter J. O'Dwyer, Kelli L. Running, Richard D. Huhn, Scott J. Antonia

From the Abramson Family Cancer Research Institute, Abramson Cancer Center, Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA; Thoracic Oncology Program, Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida College of Medicine, Tampa, FL; and Pfizer Inc, New London, CT

Address reprint requests to Robert H. Vonderheide, MD, PhD, Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, 551 BRB II/III, 421 Curie Blvd, Philadelphia, PA 19104; e-mail: rhv{at}mail.med.upenn.edu

Purpose: The cell-surface molecule CD40 activates antigen-presenting cells and enhances immune responses. CD40 is also expressed by solid tumors, but its engagement results in apoptosis. CP-870,893, a fully human and selective CD40 agonist monoclonal antibody (mAb), was tested for safety in a phase I dose-escalation study.

Patients and Methods: Patients with advanced solid tumors received single doses of CP-870,893 intravenously. The primary objective was to determine safety and the maximum-tolerated dose (MTD). Secondary objectives included assessment of immune modulation and tumor response.

Results: Twenty-nine patients received CP-870,893 in doses from 0.01 to 0.3 mg/kg. Dose-limiting toxicity was observed in two of seven patients at the 0.3 mg/kg dose level (venous thromboembolism and grade 3 headache). MTD was estimated as 0.2 mg/kg. The most common adverse event was cytokine release syndrome (grade 1 to 2) which included chills, rigors, and fever. Transient laboratory abnormalities affecting lymphocytes, monocytes, platelets, D-dimer and liver function tests were observed 24 to 48 hours after infusion. Four patients with melanoma (14% of all patients and 27% of melanoma patients) had objective partial responses at restaging (day 43). CP-870,893 infusion resulted in transient depletion of CD19+ B cells in blood (93% depletion at the MTD for < 1 week). Among B cells remaining in blood, we found a dose-related upregulation of costimulatory molecules after treatment.

Conclusion: The CD40 agonist mAb CP-870,893 was well tolerated and biologically active, and was associated with antitumor activity. Further studies of repeated doses of CP-870,893 alone and in combination with other antineoplastic agents are warranted.

Supported by Pfizer Inc, New London, CT, and by National Cancer Institute Grant No. P50 CA093372 (R.H.V.).

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

This article has been cited by other articles:

				A. Moschonas, M. Kouraki, P. G. Knox, E. Thymiakou, D. Kardassis, and A. G. Eliopoulos CD40 Induces Antigen Transporter and Immunoproteasome Gene Expression in Carcinomas via the Coordinated Action of NF-{kappa}B and of NF-{kappa}B-Mediated De Novo Synthesis of IRF-1 Mol. Cell. Biol., October 15, 2008; 28(20): 6208 - 6222. [Abstract] [Full Text] [PDF]

				C. Jackaman, A. M. Lew, Y. Zhan, J. E. Allan, B. Koloska, P. T. Graham, B. W. S. Robinson, and D. J. Nelson Deliberately provoking local inflammation drives tumors to become their own protective vaccine site Int. Immunol., September 29, 2008; (2008) dxn104v1. [Abstract] [Full Text] [PDF]

				R. Puliaev, I. Puliaeva, L. A. Welniak, A. E. Ryan, M. Haas, W. J. Murphy, and C. S. Via CTL-Promoting Effects of CD40 Stimulation Outweigh B Cell-Stimulatory Effects Resulting in B Cell Elimination and Disease Improvement in a Murine Model of Lupus J. Immunol., July 1, 2008; 181(1): 47 - 61. [Abstract] [Full Text] [PDF]

				C. L. Ahonen, A. Wasiuk, S. Fuse, M. J. Turk, M. S. Ernstoff, A. A. Suriawinata, J. D. Gorham, R. M. Kedl, E. J. Usherwood, and R. J. Noelle Enhanced efficacy and reduced toxicity of multifactorial adjuvants compared with unitary adjuvants as cancer vaccines Blood, March 15, 2008; 111(6): 3116 - 3125. [Abstract] [Full Text] [PDF]

				C. M. Paulos, A. Kaiser, C. Wrzesinski, C. S. Hinrichs, L. Cassard, A. Boni, P. Muranski, L. Sanchez-Perez, D. C. Palmer, Z. Yu, et al. Toll-like Receptors in Tumor Immunotherapy Clin. Cancer Res., September 15, 2007; 13(18): 5280 - 5289. [Abstract] [Full Text] [PDF]