Safety and immunogenicity of tyrosinase DNA vaccines in patients with melanoma.
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.
Wolchok
Jedd D
JD
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. wolchokj@mskcc.org
Yuan
Jianda
J
Houghton
Alan N
AN
Gallardo
Humilidad F
HF
Rasalan
Teresa S
TS
Wang
Jian
J
Zhang
Yan
Y
Ranganathan
Rajaram
R
Chapman
Paul B
PB
Krown
Susan E
SE
Livingston
Philip O
PO
Heywood
Melanie
M
Riviere
Isabelle
I
Panageas
Katherine S
KS
Terzulli
Stephanie L
SL
Perales
Miguel A
MA
D000328:Adult; D000368:Aged; D000818:Animals; D000906:Antibodies / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology; D064420:Drug-Related Side Effects and Adverse Reactions / Q000276:immunology*; D006801:Humans; D007125:Immunogenetics; D007167:Immunotherapy; D008545:Melanoma / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008875:Middle Aged; D014442:Monophenol Monooxygenase / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D009367:Neoplasm Staging; D010641:Phenotype; D015996:Survival Rate; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000276:immunology*
D000906:Antibodies; D019444:Vaccines, DNA; D014442:Monophenol Monooxygenase