Phase I & Ib Trials of Murine Tyrosinase ± Human GM‐CSF DNA Vaccination in Dogs with Advanced Malignant Melanoma

Abstract

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. The potency of DNA vaccines can be further enhanced by adding DNA encoding cytokine genes. We have shown in preclinical mouse models that GM‐CSF DNA enhances immune responses and tumor protection. These studies provided the impetus for murine tyrosinase (muTyr) ± human GM‐CSF (huGM‐CSF) DNA vaccination in CMM. Materials & Methods: Two groups of five dogs each with advanced (WHO stage II‐IV) CMM received four biweekly IM injections (100 ug or 500 ug, respectively/vaccination) of plasmid DNA encoding muTyr via the Biojector2000 jet delivery device. Subsequently, three groups of nine dogs each with advanced CMM received four biweekly IM injections of plasmid DNA encoding muTyr (50 ug), huGM‐CSF (3 dogs each at 100/400/800 ug) or both. Results: Minimal to mild pain was noted on vaccination and no toxicity or induction of autoimmunity was seen. The KM median survival time was 224 days (100/500 ug muTyr), 278 days (50 ug muTyr), 140 days (huGM‐CSF) and >265 days (muTyr & huGM‐CSF; 6 dogs still alive). Conclusions: The results of these trials demonstrate that xenogeneic DNA vaccination continues to be a safe and potentially therapeutic modality for CMM. These results also warrant further evaluation of this novel therapeutic in a Phase II setting.

Aetiology, clinical presentation and current treatment options of equine malignant melanoma – a review of the literature

“…Treatment with both interleukins resulted in a halt of tumour growth and even a size reduction to 80 % of the baseline volume in the horses treated with interleukin-12 after 64 days (Müller et al 2011). The differentiation antigens glycoprotein 100 (gp100) and tyrosinase proved to be therapeutic as melanoma vaccines in mice, dogs and men (Bergman et al 2001, Gyorffy et al 2005, Wolchok et al 2007. To further improve the rather adjuvant interleukin therapy, a combination of DNA coding for interleukin-12 and -18 and DNA coding for human gp100 or tyrosinase was evaluated in 27 grey horses bearing melanomas.…”

Efeitos antineoplásicos do dicloroacetato de sódio (DCA) e omeprazol em linhagens de melanoma oral canino: estudo dos mecanismos de ação

“…Sua incidência consiste em 3-7% de todas as neoplasias nos cães, além de cerca de 9-20% de todos os tumores cutâneos desta espécie (9,12). De todas as neoplasias de cavidade oral, o melanoma oral canino (MOC) tem se destacado em sua incidência com números exorbitantes em literatura cientifica ao redor do mundo (9,12,13). Em diversos estudos, o melanoma oral canino foi relatado como a malignidade oral mais comum na espécie, seguida de carcinoma de células escamosas e fibrossarcoma (9,12,14,15).…”