Use of Oncept Melanoma Vaccine in Veterinary Patients: Comparison
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The Oncept melanoma vaccine is xenogeneic DNA vaccine targeting tyrosinase. It is USDA approved for treatment of stage II to III canine oral melanoma and is also used off-label for melanomas arising in other locations and in other species. While the vaccine appears safe, the published data is mixed as to whether it provides a survival benefit, and the use of the vaccine is somewhat controversial in the veterinary oncology community.While the vaccine appears to be safe, there does not appear to be evidence that it improves outcome when used. Further studies to better evaluate its use in patients, and exploration of other treatment options for melanoma, need to be performed.

  • melanoma
  • DNA vaccine
  • veterinary oncology

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 [2][3][4].

While systemic chemotherapy has failed to improve outcomes, immunotherapy has shown promise in both humans and companion animals [5][6][7]. Among the first indications that melanoma represented an immune responsive disease were anecdotal reports of spontaneous remission in multiple species [8][9].Techniques to non-specifically induce the innate immune response in dogs have included use of Corynebacterium parvum [10], liposome-encapsulated muramyl tripeptide phosphatidylethanolamine (L-MTP-PE) with or without granulocyte macrophage colony stimulating factor (GM CSF) [11], and PEGylated tumor necrosis factor (TNFα) [12], amongst others [5][7]. 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 [13], as well as allogeneic whole-cell tumor vaccines expressing various melanoma antigens [14]. 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 [15].

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 [16].The 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 [17]. 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 [18].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 [19].

The first clinical study evaluating efficacy of Oncept in canine patients evaluated 58 patients with WHO stage II or III, histologically confirmed oral melanoma [17]. 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 [20][21] 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 [21]. 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 progression free survival (PFS), disease-free interval (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 the 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 the 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 [22]. 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. 

4. Use in Other Species

Twenty-four cats received 114 doses of Oncept in a 2015 study evaluating safety [23]. Thirteen grade 1 or 2 adverse events were reported, which included pain at injection site, hyperpigmentation, muscle fasciculations, and mildly decreased appetite for 1–2 days after administration. The melanoma vaccine has also been used in an off-label basis in horses and has again been demonstrated to be safe [24]. Case reports for use of Oncept in zoo species also exist. Examples include use in a wild mountain Gorilla (Gorilla beringei beringei) [25] with melanoma arising from the left lip commissure and metastases to multiple lymph nodes, an African lion (Panthera leo) [26] with melanoma of the lip, and an African penguin (Spheniscus demersus) [27] with melanoma arising inside the nares

5. Conclusions and Future Studies

Summarizing the currently available published data, there unfortunately fails to be definitive proof that the Oncept melanoma vaccine improves disease free intervals or survival in veterinary patients. It is unfortunate that the majority of currently available studies are retrospective in nature, given the inherent limitations that retrospective studies present including heterogeneous patient staging and treatment protocols, lack of randomization and control groups, and limitations to documenting patient outcomes [20][28].Despite these limitations, there are documented cases of dogs with diffuse metastatic disease or macroscopic tumors disappearing after treatment with Oncept [16][18][24][29][30]. A persistent question is if Oncept is expected to be effective against amelanotic melanomas, in which melanin pigment is not being produced by the cancer cells due to de-differentiation [31].As an additional concern, it has been well documented that monitoring for immune therapies, such as Oncept, should not follow the same criteria as those used for more traditional cytotoxic therapy [32]. Treatment responses may be delayed in comparison to more traditional therapy, and a phenomenon called pseudo-progression can occur when the immune system, incited by the immunotherapy, reacts to the malignant cells, which leads to an inflammatory response. This can lead to the appearance of increased tumor size on imaging studies, which will ultimately be followed by lesion regression afterwards. Relying on RECIST criteria [33] in these situations may not be appropriate and could lead to abandonment of therapy when it is actually effective.

One conclusion that can undeniably be made is that Oncept is safe. Across all studies and in multiple species only low-grade local toxicity in a small number of patients has been reported

[16][17][18][21][22][23][24][29][30][34][35][36][37][38][39][40][41][42]

.Beyond this, there continues to be a dire need for additional research evaluating therapeutic strategies to combat canine melanoma, such as further investigation of other immunotherapy directed strategies including checkpoint inhibitors which are now widely used in human patients with advanced melanoma

[32].

.

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