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Journal of Clinical Oncology, Vol 25, No 7 (March 1), 2007: pp. 876-883 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.08.3311 Clinical Activity and Immune Modulation in Cancer Patients Treated With CP-870,893, a Novel CD40 Agonist Monoclonal Antibody
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.
The cell-surface molecule CD40, a member of the tumor necrosis factor (TNF) receptor superfamily, broadly regulates immune activation, mediates tumor apoptosis, and has been studied as a target for novel cancer therapy.1-3 CD40 is expressed by dendritic cells, B lymphocytes, monocytes, and other benign cells. Considerable data demonstrate that signaling via CD40 activates antigen-presenting cells (APCs)1-5 including dendritic cells and B cells. The natural ligand for CD40 is CD154, which is expressed primarily on the surface of activated T lymphocytes6 and provides a major component of T-cell "help" for immune responses.7-9 Agonistic CD40 antibodies substitute for the function of CD4+ lymphocytes in murine models of T cell–mediated immunity.7-9 In tumor-bearing hosts, CD40 agonists trigger effective immune responses against tumor-associated antigens.10-13 CD40 is also expressed on many tumor cells and mediates a direct cytotoxic effect.2 CD40 expression has been reported on 30% to 70% of primary samples of human solid tumors, including melanoma and carcinomas. Engagement of CD40 on tumor cells results in apoptosis in vitro and impaired tumor growth in vivo.14-18 CP-870,893 is a fully human and selective CD40 agonist monoclonal antibody (mAb) and has both direct (non–immune-mediated) and indirect (immune-mediated) effects on tumor cell death. CP-870,893 activates human APCs in vitro and inhibits growth of human tumors in both immune-deficient and immune-reconstituted SCID-beige mice.19,20 Binding of CP-870,893 does not compete with CD154. Here, we report results of the first human clinical trial of the agonistic CD40 mAb CP-870,893. This study was designed to determine the safety and maximum-tolerated dose (MTD) of a single intravenous infusion of CP-870,893 and to assess immune modulation and clinical activity in patients.
Patients Twenty-nine patients with advanced solid malignancies were enrolled between April 2004 and September 2005 at the Abramson Cancer Center, University of Pennsylvania (Philadelphia, PA), and the H. Lee Moffitt Cancer Center, University of South Florida (Tampa, FL). This was the first human, open label, phase I dose-escalation study of a single intravenous infusion of CP-870,893. The protocol and informed consent forms were approved by the local institutional review boards. The primary objective was to determine the safety, tolerability, and MTD of a single dose of CP-870,893. Secondary objectives were to characterize pharmacokinetics, pharmacodynamics, immune modulation, and antitumor activity. Patients had to be at least 18 years old with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 and adequate end organ function. Signed informed consent was required. Patients with autoimmune disorders, coagulopathies, or major illness and those who were pregnant or lactating were excluded. Concurrent treatment with anticancer drugs was not allowed.
Study Design
Study Procedures
Tumor Response
Pharmacokinetics of CP-870,893
Pharmacodynamics of CP-870,893
Statistical Analysis
Patient Characteristics, Toxicity, and Determination of MTD Twenty-nine patients with advanced solid tumors were evaluated (Table 1). Six dose levels were explored, with the majority of patients treated with 0.2 mg/kg (n = 9) or 0.3 mg/kg (n = 7) of CP-870,893. Infusion was well tolerated, and adverse events and abnormal laboratory values are summarized in Tables A1 and A2 (online only). Three DLT events were observed: venous thromboembolism (one patient at 0.3 mg/kg), grade 3 headache (one patient at 0.3 mg/kg), and grade 3 transient elevations in serum transaminases (one patient at 0.2 mg/kg). Because two patients in the 0.3 mg/kg cohort had DLT, the MTD was estimated as 0.2 mg/kg per the clinical protocol.
Cytokine Release Syndrome The most common adverse event was dose-related cytokine release syndrome (CRS; grade 1 to 2). This syndrome was clinically evident within minutes to hours after infusion, manifested by varying combinations of chills, rigors, fever, rash, nausea, vomiting, muscle aches, and back pain. The syndrome was most pronounced in patients receiving 0.2 mg/kg or 0.3 mg/kg, and was associated in these patients with elevations in serum TNF-  and IL-6 (Fig 1). Serum tryptase levels were not elevated, indicating that the syndrome was not an anaphylactic or allergic reaction. Rigors were readily treated with meperidine, and the syndrome fully resolved within 24 hours in all but one patient, who experienced an ongoing and severe headache for 8 days after infusion (classified as a DLT). Prophylactic use of acetaminophen and antihistamines was instituted after the first two patients at 0.2 mg/kg dose level were noted to have grade 2 CRS, but this did not prevent grade 2 CRS in subsequent patients.
Hematologic Toxicity and Laboratory Abnormalities Infusion of CP-870,893 was associated with dose-related and transient decreases peripheral lymphocytes, monocytes, and platelets (Figs 2A to 2C). The nadir was observed 24 to 48 hours after infusion. Recovery of counts was prompt and complete in most patients by day 8. This effect manifests as grade 3 lymphopenia in 11 patients and grade 4 lymphopenia in 2 patients. Three patients, each at the 0.3 mg/kg dose level, developed grade 2 thrombocytopenia. None of these abnormalities was considered a DLT.
Modest, transient elevations in serum D-dimer were observed in most patients treated at the two highest dose levels (Fig 2D). Similarly, there was an elevation in thrombin–antithrombin 3 complex formation on day 3 in most patients at the two highest dose levels (data not shown). Other standard coagulation parameters were not affected by CP-870,893 infusion. There were no signs of disseminated intravascular coagulation. A patient with mesothelioma treated at 0.3 mg/kg developed dyspnea and hypoxia 1 hour after CP-870,893 was infused via a central venous catheter. The patient was found to have a thrombus in the superior vena cava associated with the catheter and was diagnosed with a pulmonary embolism (grade 4 thrombosis). He was treated with systemic anticoagulation. This patient had a history of a lower extremity deep venous thrombosis and had completed a course of coumadin before enrollment. The event was considered a DLT because attribution to study drug could not be ruled out.
Hepatic Toxicity
Other Toxicities
Antitumor Activity
Redosing With CP-870,893
Pharmacokinetics Serum concentrations of CP-870,893 were measurable (> 0.38 µg/mL) only in patients treated with 0.1 mg/kg or more of CP-870,893 (Fig 4). At the highest dose level, CP-870,893 concentrations were measurable for only 8 hours after dosing. The half-life of CP-870,893 was not estimated at any dose level as it was felt to be extremely unlikely that the terminal disposition phase for a monoclonal antibody, such as CP-870,893, would be present as early as 8 hours after dosing.
Pharmacodynamics To assess pharmacodynamic actions of CP-870,893, flow cytometry analysis was performed to evaluate CD19+ B cells in blood before and after treatment. We found that CP-870,893 infusion resulted in a marked, rapid, and dose-dependent decrease in the percentage of CD19+ B cells among peripheral-blood lymphocytes, with an effect evident within 1 hour of infusion and sustained for at least 2 days (Fig 5A). The peripheral-blood concentration of CD19+ B cells (ie, percentage of CD19+ B cells multiplied by the absolute lymphocyte count) also rapidly decreased, with a maximum effect observed at 24 hours for each dose level (Fig 5B). On average, for all patients, the concentration of CD19+ B cells decreased from 173 cells/mm3 (standard deviation, 176 cells/mm3) before treatment to 16 cells/mm3 (standard deviation, 19 cells/mm3) on day 2 (paired t test P < .0001).
We then evaluated the expression of the costimulatory molecule CD86 on patient B cells before and after treatment as a potential pharmacodynamic effect of CP-870,893. Exposure of B cells to CP-870,893 in vitro upregulates CD86 without inducing apoptosis (Table A4, online only). In patients in vivo, we found a marked, rapid, and dose-related upregulation of the costimulatory molecule CD86 after infusion of CP-870,893. Both the percentage of CD86+ cells among CD19+ B cells and the MESF for CD86 among CD86+, CD19+ B cells increased after infusion (Fig 5C to 5D). At the highest dose levels, there was an eight- to 10-fold increase in the percentage of CD86+ cells and a 1.5- to 2.5-fold increase in the MESF of CD86. Results of repeat-measure analysis of variance demonstrated that changes from baseline differed significantly over time for percentage of CD19+ B cells, percentage of CD86+, CD19+ B cells, and the MESF of CD86 on CD86+, CD19+ B cells (P < .01 for each). Changes from baseline at 1 hour, 8 hours, 2 days, and 3 days after infusion were significantly different from zero, whereas days 15 and 43 were not. There was also a linear association of log dose with change in percentage of CD19+ B cells and change in percentage of CD86+, CD19+ B cells, meaning that differences from baseline were larger for higher doses. Dose-time interactions were also significant, indicating that the dose relationships differed across time.
The purpose of this investigation was to evaluate the safety and biologic impact of treating cancer patients with a single intravenous infusion of CP-870,893, a fully human agonist mAb against the cell-surface molecule CD40. Treatment with a single infusion of CP-870,893 was well tolerated and was associated with objective tumor responses, including four patients with PR, of which one is sustained at 14 months and associated with complete resolution of abnormal tracer activity on fluorodeoxyglucose positron emission tomography. Clinical and pharmacodynamic evaluations demonstrate broad physiologic activation via CD40 after infusion.
The most common adverse event was transient grade 1 to 2 CRS, occurring in 55% of patients and associated with acute elevations in serum TNF- CP-870,893 binds to a wide variety of benign cells that express CD40, including lymphocytes, monocytes, platelets, endothelial cells, and hepatocytes. As a likely reflection of these interactions in vivo, a pattern of transient hematologic and metabolic laboratory abnormalities was observed after infusion, including decreased lymphocytes, monocytes, and platelets; elevated D-dimer; and elevated AST, ALT, and total bilirubin. For some parameters, the changes may reflect toxicity at the end organ. CD40+ hepatocytes, for example, undergo apoptosis after CD40 activation.22 For lymphocytes, monocytes, and platelets, CP-870,893 most likely triggers alteration in circulation and extravasation, rather than apoptosis, given the rapidity of recovery. CD40 ligation on endothelium has complex effects, involving adhesion molecules, cytokines, chemokines, and coagulation factors.23-27 D-dimer elevations in our patients may reflect low-grade activation of coagulation. In contrast to the 3-week half-life for other IgG2 mAbs,21 the serum half-life of CP-870,893 is short, with the drug measurable in serum for less than 24 hours, a finding most likely related to binding of the antibody to a widely distributed target. We observed objective PR in four patients with metastatic melanoma. The mechanism of tumor regression may involve an indirect effect of immune activation, a direct cytotoxic against CD40+ tumors cells, or both. Evaluation of tumor CD40 expression was not an eligibility criterion in this study. CD40 activation in tumor-bearing animals induces tumor-specific cytotoxic T lymphocytes, primarily through activation of APCs and cross presentation of tumor antigens10-13 and even for tumors that are CD40 negative.10,13 Direct cytotoxicity of tumor cells, including melanoma, after CD40 ligation has also been described.2,17 Although CD40 is expressed in primary melanoma lesions in vivo, CD40 expression in metastatic lesions of melanoma is weak.17 A lack of CD40 expression on metastatic melanoma would make a direct cytotoxic effect of CP-870,893 unlikely. In a trial using human CD40-ligand (rhCD40L) as a CD40 agonist in cancer patients,28 objective responses were also observed in the first human study but unlike in our experience with CP-870,893, CRS was not reported, and the MTD of rhCD40L was defined on the basis of transient elevations in serum transaminases. CP-870,893 is a potent activator of CD40-expressing APCs in vitro.1,5 To determine the pharmacodynamics of CP-870,893, we utilized flow cytometry to evaluate peripheral-blood CD19+ B cells, which uniformly express CD40. The in vitro effects of CD40 activation of human B cells, including upregulation of costimulatory molecules, are well described.29,30 CP-870,893 infusion resulted in a rapid but transient decline in both the percentage and absolute count of CD19+ B cells in peripheral blood. B cells remaining in blood after treatment demonstrated a dose-related upregulation of CD86, but a difficulty with this assay is that the maximal effect of CD86 upregulation occurs at the time of maximal B-cell depletion. Activation of B cells no longer in circulation is unknown. Nevertheless, we hypothesize that CP-870,893 infusion globally activates (rather than destroys) peripheral-blood B cells, as evidenced by the rapid return of B cells into the circulation coincident with the decline of CP-870,893 plasma levels at 24 to 48 hours. A similar effect may occur for peripheral-blood monocytes and dendritic cells after CP-870,893 infusion. Whether CP-870,893 infusion is associated with enhanced tumor-antigen presentation and induction of cellular tumor-specific immunity remains to be explored in future studies.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: Stephanie J. Green, Pfizer; Kelli L. Running, Pfizer; Richard D. Huhn, Pfizer Leadership: N/A Consultant: N/A Stock: Stephanie J. Green, Pfizer; Kelli L. Running, Pfizer; Richard D. Huhn, Pfizer Honoraria: Scott J. Antonia, Pfizer Research Funds: Robert H. Vonderheide, Pfizer; Peter J. O'Dwyer, Pfizer; Scott J. Antonia, Pfizer Testimony: N/A Other: N/A
Conception and design: Robert H. Vonderheide, Keith T. Flaherty, Peter J. O'Dwyer, Kelli L. Running, Richard D. Huhn, Scott J. Antonia Financial support: Robert H. Vonderheide, Peter J. O'Dwyer Administrative support: Robert H. Vonderheide, Amy Kramer, Peter J. O'Dwyer, Kelli L. Running, Scott J. Antonia Provision of study materials or patients: Robert H. Vonderheide, Keith T. Flaherty, Peter J. O'Dwyer, Scott J. Antonia Collection and assembly of data: 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, Peter J. O'Dwyer, Kelli L. Running, Richard D. Huhn, Scott J. Antonia Data analysis and interpretation: Robert H. Vonderheide, Keith T. Flaherty, Magi Khalil, Molly S. Stumacher, David L. Bajor, Natalie A. Hutnick, Maryann Gallagher, Amy Kramer, Stephanie J. Green, Peter J. O'Dwyer, Kelli L. Running, Richard D. Huhn, Scott J. Antonia Manuscript writing: Robert H. Vonderheide, Keith T. Flaherty, Stephanie J. Green, Richard D. Huhn, Scott J. Antonia Final approval of manuscript: 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
We thank DuPont Guerry, Lynn Schuchter, Charles Abrams, Colleen Redlinger, and Ambika Sohal (University of Pennsylvania), Patrick Stauffer, Sem Bastien, and Michael Langevin (Moffitt), and Vahe Bedian, Ronald Gladue, Antonio Gualberto, and Dennis Noe (Pfizer).
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.
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Nat Med 5:780-787, 1999[CrossRef][Medline] 13. van Mierlo GJ, den Boer AT, Medema JP, et al: CD40 stimulation leads to effective therapy of CD40(-) tumors through induction of strong systemic cytotoxic T lymphocyte immunity. Proc Natl Acad Sci U S A 99:5561-5566, 2002 14. Hess S, Engelmann H: A novel function of CD40: Induction of cell death in transformed cells. J Exp Med 183:159-167, 1996 15. Wingett DG, Vestal RE, Forcier K, et al: CD40 is functionally expressed on human breast carcinomas: Variable inducibility by cytokines and enhancement of Fas-mediated apoptosis. Breast Cancer Res Treat 50:27-36, 1998[CrossRef][Medline] 16. Hirano A, Longo DL, Taub DD, et al: Inhibition of human breast carcinoma growth by a soluble recombinant human CD40 ligand. Blood 93:2999-3007, 1999 17. von Leoprechting A, van der Bruggen P, Pahl HL, et al: Stimulation of CD40 on immunogenic human malignant melanomas augments their cytotoxic T lymphocyte-mediated lysis and induces apoptosis. Cancer Res 59:1287-1294, 1999 18. Eliopoulos AG, Davies C, Knox PG, et al: CD40 induces apoptosis in carcinoma cells through activation of cytotoxic ligands of the tumor necrosis factor superfamily. Mol Cell Biol 20:5503-5515, 2000 19. Bedian V, Donovan C, Garder J, et al: In vitro characterization and pre-clinical pharmacokinetics of CP-870,893, a human anti-CD40 agonist antibody. J Clin Oncol 24:109s, 2006 (suppl; abstr 2539) 20. Gladue R, Cole S, Donovan C, et al: In vivo efficacy of the CD40 agonist antibody CP-870,893 against a broad range of tumor types: Impact of tumor CD40 expression, dendritic cells, and chemotherapy. J Clin Oncol 24:103s, 2006 (suppl; abstr 2514) 21. Ribas A, Camacho LH, Lopez-Berestein G, et al: Antitumor activity in melanoma and anti-self responses in a phase I trial with the anti-cytotoxic T lymphocyte-associated antigen 4 monoclonal antibody CP-675,206. J Clin Oncol 23:8968-8977, 2005 22. Afford SC, Randhawa S, Eliopoulos AG, et al: CD40 activation induces apoptosis in cultured human hepatocytes via induction of cell surface fas ligand expression and amplifies fas-mediated hepatocyte death during allograft rejection. J Exp Med 189:441-446, 1999 23. Karmann K, Hughes CC, Schechner J, et al: CD40 on human endothelial cells: Inducibility by cytokines and functional regulation of adhesion molecule expression. Proc Natl Acad Sci U S A 92:4342-4346, 1995 24. Dechanet J, Grosset C, Taupin JL, et al: CD40 ligand stimulates proinflammatory cytokine production by human endothelial cells. J Immunol 159:5640-5647, 1997[Abstract] 25. Zhou L, Stordeur P, de Lavareille A, et al: CD40 engagement on endothelial cells promotes tissue factor-dependent procoagulant activity. Thromb Haemost 79:1025-1028, 1998[Medline] 26. Miller DL, Yaron R, Yellin MJ: CD40L-CD40 interactions regulate endothelial cell surface tissue factor and thrombomodulin expression. J Leukoc Biol 63:373-379, 1998[Abstract] 27. Thienel U, Loike J, Yellin MJ: CD154 (CD40L) induces human endothelial cell chemokine production and migration of leukocyte subsets. Cell Immunol 198:87-95, 1999[CrossRef][Medline] 28. Vonderheide RH, Dutcher JP, Anderson JE, et al: Phase I study of recombinant human CD40 ligand in cancer patients. J Clin Oncol 19:3280-3287, 2001 29. Schultze JL, Michalak S, Seamon MJ, et al: CD40 activated human B cells: An alternative source of highly efficient antigen presenting cells to generate autologous antigen-specific T cells for adoptive immunotherapy. J Clin Invest 100:2757-2765, 1997[Medline] 30. Coughlin CM, Vance BA, Grupp SA, et al: RNA-transfected CD40-activated B cells induce functional T-cell responses against viral and tumor antigen targets: Implications for pediatric immunotherapy. Blood 103:2046-2054, 2004 Submitted July 19, 2006; accepted December 4, 2006. This article has been cited by other articles:
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
