Long-term survival of dogs with advanced malignant melanoma after DNA vaccination with xenogeneic human tyrosinase: a phase I trial.

Abstract

PURPOSE: 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. EXPERIMENTAL DESIGN: 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.