1. Background

Melanoma is a common neoplasm affecting companion animals, particularly dogs. Arising from melanocytes derived from the neural crest [1], it can manifest anywhere in the body. In the dog it is most commonly found as an oral tumor, tumor of the digit, or tumor of the skin. Melanoma in humans primarily presents as a dermal neoplasia and is considered malignant. While local therapy such as surgery and/or radiation therapy is used as the primary therapy to target regional disease, systemic metastases for non-dermal locations represents a therapeutic challenge as multiple studies have demonstrated relative resistance to systemic chemotherapy with reported response rates of 8–28% and no evidence of improvement in survival [5,6,7].

While systemic chemotherapy has failed to improve outcomes, immunotherapy has shown promise in both humans and companion animals [4,8,9]. Among the first indications that melanoma represented an immune responsive disease were anecdotal reports of spontaneous remission in multiple species [10,11].Techniques to non-specifically induce the innate immune response in dogs have included use of Corynebacterium parvum [12], liposome-encapsulated muramyl tripeptide phosphatidylethanolamine (L-MTP-PE) with or without granulocyte macrophage colony stimulating factor (GM CSF) [13], and PEGylated tumor necrosis factor (TNFα) [14], amongst others [4,9]. Techniques to target the adaptive immune system have included injection of autologous dendritic cells expanded ex vivo via transduction with human gp100, a melanoma antigen, as an adjuvant to radiation therapy [15], as well as allogeneic whole-cell tumor vaccines expressing various melanoma antigens [16]. Adoptive cell transfer, utilizing transfusion of tumor specific T lymphocytes to cancer patients, has shown success treating human melanoma but has not yet been largely evaluated in canine melanoma patients [17].

2. Development of Oncept

A novel approach was taken with the advent of the Oncept melanoma vaccine. This vaccine uses xenogeneic DNA to elicit an immune response in dogs; specifically human DNA encoding tyrosinase.Human DNA encoding tyrosinase is placed into a bacterial plasmid and injected into the canine patient [21].This study evaluated 18 patients and determined that the vaccine was safe and effectively induced immunity based upon T cell responses. The resultant human tyrosinase protein is at least 85% homologous (with some reports up to 92% homologous) to canine tyrosinase, therefore both different enough to elicit an immune response, and similar enough to provide an appropriate target in the canine melanoma cells [23]. Initial studies also evaluated murine tyrosinase with or without human granulocyte colony stimulating factor (GM-CSF), as well as murine GP75, a tumor associated antigen located within the membrane of melanosomes; based upon these studies, the most robust immune response and correlating improvement in survival was associated with use of human tyrosinase [24].The vaccine is delivered via Biojector 2000 or Vet Jet carbon dioxide powered jet needleless transdermal delivery devices that are FDA approved for intramuscular injections. The plasmid is then collected by dendritic cells to begin the immune response. Humoral response post vaccine has been documented and antibodies were documented to persist for three to nine months [25].

The first clinical study evaluating efficacy of Oncept in canine patients evaluated 58 patients with WHO stage II or III, histologically confirmed oral melanoma [23]. To evaluate survival, the 58 Oncept treated dogs were compared to a historical control population of 53 dogs who achieved locoregional disease control via surgery. These control patients were derived from a single academic institution, and had participated in previous clinical trials either receiving a placebo or another treatment that was determined to not have significant anti-tumor activity after surgery. Control patients were matched to prospectively enrolled patients in terms of signalment and staging criteria as closely as possible. When comparing these groups, median survival time based upon Kaplan–Meier analysis was not reached for the Oncept treated group and 324 days for the historical controls. When the 25th percentiles of MSTs for the treatment group was calculated it was 464 days compared to 156 days for historical controls. In fact, only 15 dogs died due to melanoma disease and were therefore included in the Kaplan–Meier analysis. Other published criticisms [26,27] of this study have included the use of the historical, non-contemporaneous control group which may not accurately account for advances in local therapy, or in pathologic advances in the interpretation and assessment of melanoma.

3. Retrospective Studies

A study by Ottnod et al. retrospectively evaluated 45 dogs with locoregional control of oral melanoma achieved by surgery, combined with radiation therapy if necessary for incomplete margins [27]. Dogs with stage IV disease, macroscopic disease, or dogs receiving other systemic therapies were excluded. Twenty-two of the 45 dogs received Oncept as an adjuvant after locoregional treatment. Disease and patient characteristics were similar between patients that did and did not receive the vaccine. The PFS, DFI, and MST were not statistically significant between vaccinated (199 days, 171 days, 485 days respectively) and unvaccinated dogs (247 days, 258 days, 585 days respectively). The study also separately evaluated dogs with stage II or III disease, to better compare to the original Grosenbaugh study. The results of this sub-analysis still did not show a statistically significant difference in PFS or MST between patients receiving Oncept vs. those that did not receive further therapy (PFS: 179.5 days vs. 247.5 days, MST: 477 days vs. 491 days respectively). However, the DFI was significantly longer for patients not receiving the vaccine (331 days vs. 140 days (p = 0.02)). In this study, histopathology characteristics suggestive of less aggressive biological activity, such as mitotic index less than 4, nuclear atypia less than 30, and Ki67 less than 19.5, were suggestive of improved patient outcomes.

McLean and Lobetti documented the South African experience with Oncept after surgical excision in dogs with melanomas arising in various locations, including oral (n = 25), digital (n = 6), or infiltrative cutaneous (n = 7) melanomas [34]. At the end of the study period 6 dogs with oral melanoma were still alive at a median of 26 months, while the 16 dogs that had died of progressive disease had a median survival of 11.5 months (with 3 dogs dying due to unrelated disease). However, results are severely limited by small case numbers, lack of case details, and heterogeneous disease locations. 

This entry is adapted from the peer-reviewed paper 10.3390/vetsci9110597