Long-term survival of dogs with advanced malignant melanoma after DNA vaccination with xenogeneic human tyrosinase: a phase I trial.
OBJECTIVE
Canine malignant melanoma (CMM) is a spontaneous, aggressive, and metastatic neoplasm. Preclinical mouse studies have shown that xenogeneic DNA vaccination with genes encoding tyrosinase family members can induce antibody and cytotoxic T-cell responses, resulting in tumor rejection. These studies provided the rationale for a trial of xenogeneic DNA vaccination in CMM using the human tyrosinase gene.


METHODS
Three cohorts of three dogs each with advanced (WHO stage II, III, or IV) CMM received four biweekly i.m. injections (dose levels 100, 500, or 1500 micro g, respectively/vaccination) of human tyrosinase plasmid DNA i.m. via the Biojector2000 delivery device.


RESULTS
Mild local reactions at injection sites were the only toxicities observed, with no signs of autoimmunity. One dog with stage IV disease had a complete clinical response in multiple lung metastases for 329 days. Two dogs with stage IV disease had long-term survivals (421 and 588+ days) in the face of significant bulky metastatic disease, and two other dogs with locally controlled stage II/III disease had long-term survivals (501 and 496 days) with no evidence of melanoma on necropsy. Four other dogs were euthanized because of progression of the primary tumor. The Kaplan-Meier median survival time for all nine dogs was 389 days.


CONCLUSIONS
The results of this trial demonstrate that xenogeneic DNA vaccination of dogs with advanced malignant melanoma is a safe and potentially therapeutic modality. On the basis of these results, additional evaluation of this novel therapeutic is warranted in locally controlled CMM and advanced human melanoma.
Bergman
Philip J
PJ
Donaldson-Atwood Cancer Clinic and Flaherty Comparative Oncology Laboratory, The E&M Bobst Hospital of the Animal Medical Center, New York, New York 10021, USA. Philip.bergman@amcny.org
McKnight
Joanne
J
Novosad
Andrew
A
Charney
Sarah
S
Farrelly
John
J
Craft
Diane
D
Wulderk
Michelle
M
Jeffers
Yusuf
Y
Sadelain
Michel
M
Hohenhaus
Ann E
AE
Segal
Neil
N
Gregor
Polly
P
Engelhorn
Manuel
M
Riviere
Isabelle
I
Houghton
Alan N
AN
Wolchok
Jedd D
JD
D000818:Animals; D019496:Cancer Vaccines / Q000627:therapeutic use*; D015331:Cohort Studies; D018076:DNA, Complementary / Q000378:metabolism; D004285:Dogs; D005260:Female; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D008297:Male; D008545:Melanoma / Q000401:mortality / Q000628:therapy*; D014442:Monophenol Monooxygenase / Q000235:genetics; D010957:Plasmids / Q000378:metabolism; D013902:Radiography, Thoracic; D013997:Time Factors; D019444:Vaccines, DNA / Q000627:therapeutic use*
D019496:Cancer Vaccines; D018076:DNA, Complementary; D019444:Vaccines, DNA; D014442:Monophenol Monooxygenase