Safety and immunogenicity of tyrosinase DNA vaccines in patients with melanoma.

Abstract

Immunity to self antigens on cancer is constrained by tolerance/ignorance. DNA vaccines encoding xenogeneic differentiation antigens, such as tyrosinase (TYR), mediate tumor protection and regression in implantable mouse models, and dogs with spontaneous melanoma. We conducted a trial of mouse and human TYR DNA vaccines in stage III/IV melanoma patients. Eighteen human leukocyte antigen (HLA)-A*0201(+) melanoma patients were randomized as follows: one group received three mouse TYR DNA injections followed by three human TYR DNA injections; the other group received the same vaccines in opposite sequence. The study was conducted at three dose levels: 100, 500, and 1,500 microg DNA/injection, administered intramuscularly (IM) every 3 weeks. Most toxicities were grade 1 injection site reactions. Seven patients developed CD8(+) T-cell responses, defined by a >3 SD increase in baseline reactivity to TYR peptide in tetramer or intracellular cytokine staining (ICS) assays. There was found to be no relationship between dose, assigned schedule, and T-cell response. At a median of 42 months follow-up, median survival has not been reached. Mouse and human TYR DNA vaccines were found safe and induced CD8(+) T-cell responses in 7 of 18 patients. T cells recognizing a native TYR peptide had a phenotype consistent with that of effector memory cells.

• Authors: Jedd D Wolchok, Jianda Yuan, Alan N Houghton, Humilidad F Gallardo, Teresa S Rasalan, Jian Wang, Yan Zhang, Rajaram Ranganathan, Paul B Chapman, Susan E Krown, Philip O Livingston, Melanie Heywood, Isabelle Riviere, Katherine S Panageas, Stephanie L Terzulli, Miguel A Perales
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 15 Issue 11 Pg. 2044-50 (Nov 2007) ISSN: 1525-0016 [Print] United States
• PMID: 17726460 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies
• Vaccines, DNA
• Monophenol Monooxygenase

Topics

• Adult
• Aged
• Animals
• Antibodies (immunology)
• CD8-Positive T-Lymphocytes (enzymology, immunology)
• Drug-Related Side Effects and Adverse Reactions (immunology)
• Humans
• Immunogenetics
• Immunotherapy
• Melanoma (genetics, immunology, pathology, therapy)
• Mice
• Middle Aged
• Monophenol Monooxygenase (genetics, immunology, metabolism)
• Neoplasm Staging
• Phenotype
• Survival Rate
• Vaccines, DNA (administration & dosage, immunology)