Phase I/II study of GM-CSF DNA as an adjuvant for a multipeptide cancer vaccine in patients with advanced melanoma Journal Article
| Authors: | Perales, M. A.; Yuan, J.; Powel, S.; Gallardo, H. F.; Rasalan, T. S.; Gonzalez, C.; Manukian, G.; Wang, J.; Zhang, Y.; Chapman, P. B.; Krown, S. E.; Livingston, P. O.; Ejadi, S.; Panageas, K. S.; Engelhorn, M. E.; Terzulli, S. L.; Houghton, A. N.; Wolchok, J. D. |
| Article Title: | Phase I/II study of GM-CSF DNA as an adjuvant for a multipeptide cancer vaccine in patients with advanced melanoma |
| Abstract: | Granulocyte-macrophage colony-stimulating factor (GM-CSF) enhances immune responses by inducing proliferation, maturation, and migration of dendritic cells (DCs) as well as expansion and differentiation of B and T lymphocytes. The potency of DNA vaccines can be enhanced by the addition of DNA encoding cytokines, acting as molecular adjuvants. We conducted a phase I/II trial of human GM-CSF DNA in conjunction with a multipeptide vaccine (gp100 and tyrosinase) in stage III/IV melanoma patients. Nineteen human leukocyte antigen (HLA)-A*0201(+) patients were treated. Three dose levels were studied: 100, 400, and 800 μg DNA/injection, administered subcutaneously every month with 500 μg of each peptide. In the dose-ranging study, three patients were treated at each dose level. The remaining patients were then treated at the highest dose. Most toxicities were grade 1 injection-site reactions. Eight patients (42%) developed CD8+ T-cell responses, defined by a ≥3 SD increase in baseline reactivity to tyrosinase or gp100 peptide in tetramer or intracellular cytokine staining (ICS) assays. There was no relationship between dose and T-cell response. Responding T cells had an effector memory cell phenotype. Polyfunctional T cells were also demonstrated. At a median of 31 months follow-up, median survival has not been reached. Human GM-CSF DNA was found to be a safe adjuvant. |
| Keywords: | controlled study; clinical trial; interferon; cancer patient; cancer staging; drug megadose; follow up; neoplasm staging; cd8+ t lymphocyte; cell proliferation; lymphocyte proliferation; t lymphocyte; cd8-positive t-lymphocytes; phenotype; glycoprotein gp 100; melanoma; phase 2 clinical trial; cell maturation; dendritic cell; granulocyte macrophage colony stimulating factor; assay; b lymphocyte; injection site reaction; lymphocyte differentiation; cytokine; double stranded dna; cellular immunity; immune response; cancer vaccines; staining; peptides; gene therapy; cell migration; effector cell; dna vaccine; phase 1 clinical trial; monophenol monooxygenase; peptide vaccine; adjuvants, immunologic; hla a antigen; vaccines, dna; vaccines, subunit; adjuvant; granulocyte macrophage colony-stimulating factors, recombinant |
| Journal Title: | Molecular Therapy |
| Volume: | 16 |
| Issue: | 12 |
| ISSN: | 1525-0016 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2008-12-01 |
| Start Page: | 2022 |
| End Page: | 2029 |
| Language: | English |
| DOI: | 10.1038/mt.2008.196 |
| PUBMED: | 18797450 |
| PROVIDER: | scopus |
| PMCID: | PMC3909666 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 24" - "Export Date: 17 November 2011" - "CODEN: MTOHC" - "Source: Scopus" |
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