Phase I Clinical Trial of the Immunocytokine EMD 273063 in Melanoma Patients

Abstract

Purpose-To evaluate the safety, toxicity, in vivo immunologic activation, and maximum-tolerated dose (MTD) of EMD 273063 (hu14.18-IL-2) in patients with metastatic melanoma.Patients and Methods-Thirty-three patients were treated with EMD 273063, a humanized anti-GD2 monoclonal antibody (mAb) linked to interleukin-2 (IL-2). EMD 273063 was given as a 4-hour intravenous infusion on days 1, 2, and 3 of week 1. Patients with stabilization or regression of disease could receive a second course of treatment at week 5. Dose levels evaluated were 0.8, 1.6, 3.2, 4.8, 6.0, and 7.5 mg/m 2 /d.Results-Nineteen of 33 patients completed course 1 with stable disease and went on to receive course 2. Eight patients had stable disease on completion of course 2. Grade 3 adverse events included hypophosphatemia (11 patients), hyperglycemia (three patients), hypotension (two patients), thrombocytopenia (one patient), hypoxia (three patients), elevated hepatic transaminases (two patients), and hyperbilirubinemia (one patient). Opioids were required for treatment-associated arthralgias and/or myalgias during 17 of 52 treatment courses. No grade 4 adverse events were observed. Dose-limiting toxicities at the MTD included hypoxia, hypotension, and elevations in AST/ ALT. Grade 3 toxicities were anticipated based on prior studies of IL-2 or anti-GD2 mAbs, and all resolved. Immune activation was induced, as measured by lymphocytosis, increased peripheral-blood natural killer activity, and cell numbers, and increased serum levels of the soluble alpha chain of the IL-2 receptor complex. Authors' disclosures of potential conflicts of interest are found at the end of this article. Authors' Disclosures of Potential Conflicts of InterestThe following authors or their immediate family members have 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. Acted as a consultant within the last 2 years: Ralph Reisfeld, EMD. Served as an officer or member of the Board of a company: Stephen D. Gillies, EMD. Received more than $2,000 per year from a company for either of the last 2 years: Stephen D. Gillies, EMD.Supported by grant Nos. CA32685, CA14520, CA87025, CA81403, and RR03186 from the National Institutes of Health and a grant from the Midwest Athletes for Childhood Cancer Fund. Partial personnel support was provided by EMD for data management required by EMD for this study, which was beyond the clinical research and data monitoring required for this National Cancer Institute-supported study. NIH Public Access

Novel antibodies as anticancer agents

“…Anti-CD20mAb (Di-Leu-16) conjugated to IL-2 has demonstrated enhanced ADCC activity in comparison with the control anti-CD-20 (Rituximab) in SCID mice non-Hodgkin's lymphoma model (NHL) (Gillies et al, 2005). Phase I clinical trial of the immunocytokine EMD 273063, which is constructed of humanized anti-GD2 mAb linked to IL-2, in melanoma patients has been conducted with promising results (King et al, 2004). The immunocytokine induced immune activation, with reversible toxicity.…”

Intratumoral immunocytokine treatment results in enhanced antitumor effects

“…ICs are synthetic proteins that combine both of these strategies via a tumor antigen-specific mAb fused to an immune-stimulating cytokine. Members of this novel class of immunotherapy have been shown to have significant antitumor and antimetastatic effects in several murine tumor models and are currently being investigated for clinical safety and anticancer potential in human patients with neuroblastoma (NB), melanoma, ovarian and prostate cancers [8,[21][22]32]. Our laboratories have been involved in the preclinical and clinical development of two ICs [39]: huKS-IL2, which consists of the humanized mAb huKS1/4 that recognizes epithelial cell adhesion molecule (EpCAM) and is linked to IL2; and hu14.18-IL2, which is an anti-disialoganglioside GD 2 mAb also linked to IL2.…”

Induction of IgG antibodies against the GD2 carbohydrate tumor antigen by vaccination with peptide mimotopes

“…In the next step, ch14.18 was expressed as a fusion protein with IL-2, to target the cytokine directly to the tumor site [22]. This compound is already being tested in clinical trials [23].…”