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Long-Term Survival of Dogs with Advanced Malignant Melanoma after DNA Vaccination with Xenogeneic Human Tyrosinase

A Phase I Trial¹

Donaldson-Atwood Cancer Clinic and Flaherty Comparative Oncology Laboratory, The E&M Bobst Hospital of the Animal Medical Center, New York, New York 10021 [P. J. B., J. M., A. N., S. C., J. F., D. C., A. E. H.], and Memorial Sloan-Kettering Cancer Center, New York, New York 10021 [M. W., Y. J., M. S., N. S., P. G., M. E., I. R., A. N. H., J. D. W.]

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 induceantibody 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 µg, 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.

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