Xenogeneic DNA immunization in melanoma models for minimal residual disease.
BACKGROUND
DNA immunization with xenogeneic genes encoding homologous antigens protects mice against tumor challenge with syngeneic melanoma in a lung metastasis model. The effect of xenogeneic human TRP-2 (hTRP2) DNA immunization on disease confined to an orthotopic site, the skin, and in a model of minimal residual disease that is relevant to a setting of adjuvant therapy for micrometastatic cancer is reported.


METHODS
Immunization and tumor challenge with B16F10LM3 melanoma were performed in C57BL/6 mice and in mice genetically deficient in MHC class I or II molecules. A melanoma variant of B16 with a predilection for lung metastasis was selected and used to challenge C57BL/6 mice. Tumor challenge in the footpad with the B16 variant was followed by local tumor growth and lung metastasis. The tumor-bearing distal extremities were surgically resected and mice were randomized to receive hTRP2 DNA immunization or no treatment. Approximately 3-5 weeks after surgical resection, lungs were harvested and metastases counted.


RESULTS
Xenogeneic DNA immunization with hTRP2 prevented tumor growth in the skin by a mechanism requiring CD4(+) and CD8(+) T cells but did not inhibit the growth of established tumors. Adjuvant immunization with hTRP2 DNA after resection significantly reduced lung metastases and decreased local recurrence rates after surgical resection.


CONCLUSIONS
Xenogeneic DNA immunization with hTRP2 was effective in protecting mice from intradermal tumor challenge. Immunization prevented local recurrence and the development of metastases in a mouse model of minimal residual disease, supporting a role for DNA immunization against melanosomal antigens as an adjuvant to surgery in high-risk primary melanomas.
Hawkins
William G
WG
Swim Across America Laboratory, Departments of Surgery & Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA.
Gold
Jason S
JS
Blachere
Nathalie E
NE
Bowne
Wilbur B
WB
Hoos
Axel
A
Lewis
Jonathan J
JJ
Houghton
Alan N
AN
D000818:Animals; D015478:Antigens, Heterophile / Q000494:pharmacology*; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000494:pharmacology*; D004273:DNA, Neoplasm / Q000276:immunology; D004195:Disease Models, Animal; D018572:Disease-Free Survival; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000276:immunology; D007114:Immunization / Q000379:methods; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000276:immunology; D008175:Lung Neoplasms / Q000276:immunology / Q000517:prevention & control / Q000556:secondary; D008545:Melanoma / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D018365:Neoplasm, Residual / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D012878:Skin Neoplasms / Q000276:immunology / Q000517:prevention & control* / Q000556:secondary
D015478:Antigens, Heterophile; D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D004273:DNA, Neoplasm; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase