Phase I Trial of Sequential Low-Dose 5-Aza-2′-Deoxycytidine Plus High-Dose Intravenous Bolus Interleukin-2 in Patients with Melanoma or Renal Cell Carcinoma

Abstract

Purpose: The silencing of gene expression through DNA methylation contributes to defects in antigen presentation and apoptosis in melanoma and renal cell cancer. To determine how a hypomethylating agent would modulate the toxicity and antitumor activity of immunotherapy, we initiated a phase I trial of 5-aza-2 ¶-deoxycytidine (decitabine) plus high-dose interleukin 2 (IL-2). Experimental Design: Patients received s.c. decitabine daily  5 days on weeks 1 and 2 of a 12-week cycle. High-dose IL-2, consisting of two cycles of IL-2 600,000 IU/kg i.v. q8 hours  14 doses separated by a 2-week break, was administered starting on week 3. Decitabine was escalated from 0.1 to 0.25 mg/kg. The hypomethylating activity of decitabine was assessed during cycle 1 by measuring hemoglobin F levels and changes in DNA methylation in peripheral blood mononuclear cells. Results: Twenty-one patients with melanoma or renal cell cancer were enrolled. Decitabine did not alter the tolerability of IL-2 but caused grade 4 neutropenia in most patients. Grade 4 neutropenia lasting more than 7 days was the only dose-limiting toxicity, with a trend toward a higher incidence with increasing decitabine doses. Infection occurred in only one patient despite the high incidence of neutropenia, and granulocyte colony-stimulating factor use in several patients expedited neutrophil recovery. Decitabine augmented hemoglobin F levels and altered DNA methylation and gene expression in peripheral blood mononuclear cells in a doseindependent manner that overlapped with the administration of IL-2. Objective responses occurred in 31% of melanoma patients. Conclusions: Decitabine can be safely administered with high-dose IL-2 and may enhance the activity of IL-2 in melanoma.

Methylation status of the SOCS3 gene in human malignant melanomas

“…Recently, a phase I trial of low-dose 5-Aza-dC plus interleukin-2 was performed in patients with malignant melanoma (50). Among 16 patients, the response rate was 31% (50). Although global methylation was evaluated using repetitive sequences in this study, the methylation status of specific genes affected by 5-Aza-dC treatment were not examined.…”

“…We expect that transcriptional silencing of the SOCS3 gene by aberrant methylation might contribute to resistance of malignant melanoma cells to IFN treatment. Recently, a phase I trial of low-dose 5-Aza-dC plus interleukin-2 was performed in patients with malignant melanoma (50). Among 16 patients, the response rate was 31% (50).…”

Genetic diversity and immunological characteristics of malignant melanoma: the therapeutic spectrum

“…A daganatokban ezen enzimek gátlásával (DNMT-inhibitor például a decitabin, HDAC-inhibitor például a valproát) visszafordítható a tumorszuppresszor gének aberráns hipermetilációja, ami géncsendesítést okozott, ezáltal expressziójuk növekedésével újra el tudják látni a sejtosztódást fékező funkciójukat. A jövőben melanomás betegek is profi tál-hatnak ezen kutatások eredményeiből [34,35]. Emellett a cutan melanomák 60%-ában patológiásan működő PI3K/AKT/mTOR szignáltranszdukciós útvonal nemcsak a tumorszuppresszor PTEN által gátolható, hanem célzottan, AKT-inhibitorokkal (például perifosin) és mTOR-gátlókkal (például temsirolimus, everolimus) is.…”

Pharmaco-epigenomics: discovering therapeutic approaches and biomarkers for cancer therapy

“…However, injection of decitabine in nude mice carrying melanoma xenografts led to resensitization to interferon treatment (Reu et al, 2006). A phase I clinical trial of decitabine together with interleukin-2 in melanoma patients further showed an objective response in 31% of the patients (Gollob et al, 2006). Likewise, preclinical data also suggests that epigenetic therapy can induce radiosensitization and enhance current conventional treatment regimens (Munshi et al, 2005).…”