Of the patients with SD, two patients had melanoma, two had renal cell carcinoma, two had mesothelioma and one had a uterine cancer. tumor malignancies received weekly intravenous infusions of CP-870,893 in four dose level cohorts. Security and immune pharmacodynamics were assessed. Conclusions Weekly infusions of the agonist CD40 antibody CP-870,893 were well-tolerated, but there was little medical activity in advanced malignancy patients. Correlative studies demonstrate chronic B-cell activation and in some individuals, T-cell depletion. Longer dosing intervals may be desired for ideal immune pharmacodynamics. strong class=”kwd-title” Key phrases: CD40, immunotherapy, antibody, T cell, B cell Intro The cell-surface molecule CD40 is a member of the tumor necrosis element (TNF) receptor superfamily and regulates immune activation by virtue of its manifestation on antigen-presenting cells (APC) including B cells, monocytes and dendritic cells.1 Considerable in vivo and in vitro data demonstrate that signaling via CD40 activates APCs by binding CD154, the natural ligand for CD40 on activated T cells.1 Data from mouse models suggest that agonistic CD40 antibodies RYBP substitute for the function of CD4+ T cells in models of T-cell-mediated immunity2C4 and result in effective immune reactions against tumor antigens.5C8 Additionally, CD40 is often indicated by solid tumor cells and upon ligation, mediates tumor cell apoptosis and growth impairment.1 Consequently, CD40 agonists are becoming explored as potential novel therapy for malignancy. CP-870,893 is definitely a fully human being agonistic CD40 monoclonal antibody (mAb) that has been shown to activate human being APC in vitro, including dendritic cells and B cells.9,10 In addition, CP-870,893-activated APC induce T-cell proliferation and secretion of effector cytokines including IFN Cysteamine HCl and IL-2.10 CP-870,893 has been shown to inhibit growth of human being tumors in both immune-deficient and immune-reconstituted SCID-beige mice.11,12 In the first-in-human clinical study of CP-870,893,13 a single infusion was given to individuals with advanced malignancy at doses ranging from 0.01 mg/kg to 0.3 mg/kg with the most common adverse event becoming transient grade 1 to 2 2 cytokine launch syndrome (CRS). Four individuals with advanced melanoma experienced a partial response to a single infusion. All individuals eventually relapsed except for one individual whose remission Cysteamine HCl was managed while receiving repeat doses of CP-870,893 every 6C8 weeks.13 Pharmacodynamic studies shown a marked, rapid and dose-dependent decrease in the percentage of CD19+ B cells among peripheral blood lymphocytes and concomitant upregulation of CD86 on the remaining B cells. This effect was obvious within 1 hour of infusion and peaked between 2C3 days after infusion.13 Given the promising clinical results of this solitary dose phase I study, we performed a second phase I study investigating the effects of administering CP-870,893 on a weekly basis. The rationale for this routine was based on the observation that the majority of both the pharmacodynamic effect of CP-870,893 and changes in laboratory guidelines (such as liver function checks) peaked then resolved within one week of a single infusion. It was appreciated Cysteamine HCl from previously published mouse tumor models of anti-CD40 mAb therapy that Cysteamine HCl certain schedules of mAb administration, particularly daily dosing, could result in deleterious effects on T cells secondary to hyperstimulation.14,15 The goal of this study was to determine the safety and maximum tolerated dose (MTD) of weekly CP-870,893 infusion, and to compare safety data with clinical response and immune pharmacodynamics. Results Patient characteristics, toxicity and dedication of MTD. Twenty-seven individuals with advanced solid tumors were treated with this study (Table 1). Patients experienced a wide range of 13 unique tumor histologies, but 11 individuals (41%) experienced melanoma. Four weekly dose levels were explored, with the majority of patients becoming treated with 0.2 mg/kg (n = 13) or 0.25 mg/kg (n = 6) of CP-870,893. Infusion of the drug was well-tolerated, and adverse events are summarized in Table 2. Two dose limiting toxicities (DLT) were observed in the initial cohorts, both happening in the 0.25 mg/kg dose level (grade 3 CRS in one patient and grade 3 urticaria in another). No DLTs were observed among the first six individuals treated with 0.2 mg/kg of CP-870,893 and the MTD of weekly infusion of CP-870,893 was estimated as 0.2 mg/kg in accordance with the clinical protocol. This is the same MTD as was estimated for single-dose CP-870,893 administration in the first-in-human study.13 In an MTD growth cohort of seven additional individuals treated with 0.2 mg/kg weekly CP-870,893, two additional events of grade 3 infusion-related CRS were observed, with the overall rate of grade 3 CRS at this dose level becoming 15%. Table 1 Patient characteristics thead valign=”middle” CharacteristicNumber% /thead SexMale1867Female933Age, yearsMean61.6Range(45C80)Race/ethnicityWhite2489Asian27Black14ECOG PS019701830Tumor typesAnal malignancy14Bladder malignancy14Breast malignancy311Colon malignancy14Hepatocellular carcinoma14Melanoma1141Mesothelioma27Nasopharyngeal malignancy14Neuroendocrine tumor14Non-small cell lung malignancy14Ovarian malignancy14Renal cell carcinoma27Uterine malignancy14Prior treatmentChemotherapy2696Radiation1348Surgery27100Immunotherapy*415Treatment Group0.05 mg/kg5190.1 mg/kg3110.2 mg/kg13480.25 mg/kg622 Open in a separate window *includes interferon-alpha, IL-2,.
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