DEVELOPMENT OF A XENOGENEIC DNA VACCINE PROGRAM FOR SPONTANEOUS CANCER IN DOGS & CATS AT THE ANIMAL MEDICAL CENTER

Philip J. Bergman DVM, PhD, DACVIM-Onc

Head, Donaldson-Atwood Cancer Clinic & Flaherty Comparative Oncology Laboratory

The Animal Medical Center

Adjunct Associate Faculty Member, Memorial Sloan-Kettering Cancer Center

New York, NY 10021

212-329-8674 (office), 212-702-0971 (fax)

Philip.Bergman@amcny.org

Introduction: Canine malignant melanoma (CMM) is an aggressive neoplasm treated with surgery and/or fractionated RT; however, metastatic disease is common and chemoresistant. Preclinical and clinical studies by our laboratory and others have shown that xenogeneic DNA vaccination with tyrosinase family members can produce immune responses resulting in tumor rejection or protection and prolongation of survival. These studies provided the impetus for development of a xenogeneic DNA vaccine program in CMM.

Materials & Methods: Cohorts of three dogs each received increasing doses of xenogeneic plasmid DNA encoding either human tyrosinase (huTyr; 100/500/1500mcg), murine GP75 (muGP75; 100/500/1500mcg), murine tyrosinase (muTyr; 5 dogs each at 100/500mcg), muTyr + HuGM-CSF (9 dogs at 50mcg muTyr, 3 dogs each at 100/400/800mcg HuGM-CSF, or 3 dogs each at 50mcg muTyr with 100/400/800mcg HuGM-CSF), or 50 mcg MuTyr intramuscularly biweekly for a total of 4 vaccinations.

Results: The Kaplan-Meier median survival time (KM MST) for all stage II-IV dogs treated with huTyr, muGP75 and muTyr are 389, 153 and 224 days, respectively (HuTyr results published in Clin Cancer Res, 2003). Preliminarily, the KM MST for stage II-IV dogs treated with 50mcg MuTyr, 100/400/800mcg HuGM-CSF or combination MuTyr/HuGM-CSF are 242, 148 and >833 (median not reached) days, respectively. Thirty-three stage II-III dogs with loco-regionally controlled CMM across the xenogeneic vaccine studies have a KM MST of > 569 days (median not reached). Minimal to mild pain was noted on vaccination and one dog experienced vitiligo. We have recently investigated antibody responses in dogs vaccinated with HuTyr and found 2-5 fold increases in circulating antibodies to human Tyrosinase (manuscript in press, 2006).

Conclusions: The results of these trials demonstrate that xenogeneic DNA vaccination in CMM: 1) is safe, 2) leads to the development of anti-tyrosinase antibodies, 3) is potentially therapeutic, and 4) is an attractive candidate for further evaluation in an adjuvant, minimal residual disease Phase II setting for CMM (licensure trial Q2, 2006). A phase I trial of HuPSMA in dogs with advanced malignancies is ongoing and a phase I trial of MuCD20 in dogs and cats with B-cell non-Hodgkin’s lymphoma will launch in February, 2006.