Abstract
Objectives
A xenogeneic human tyrosinase DNA vaccine was developed for treatment of dogs with oral malignant melanoma (Oncept; Merial). No studies have evaluated the safety or efficacy of this vaccine in cats. The purpose of this study was to evaluate the safety of the canine melanoma vaccine in cats diagnosed with melanoma.
Methods
Medical records were reviewed from cats diagnosed with malignant melanoma and treated with the canine melanoma DNA vaccine (Oncept). Data regarding signalment, melanoma location, treatments received, vaccine adverse effects and cause of death were collected.
Results
A total of 114 melanoma vaccines were administered to 24 cats. Seven cats (11.4%) had clinical adverse effects from a total of 13 vaccines classified as grade 1 or 2 based on the Veterinary Cooperative Oncology Group’s common terminology criteria for adverse events v1.1. These included pain on vaccine administration, brief muscle fasciculation, transient inappetence, depression, nausea and mild increase in pigmentation at the injection site. Nineteen cats were deceased at study close. The most common cause of death was melanoma (14 cats). Hematological and biochemical changes were observed in six cats, five of which had concurrent disease or treatments that likely caused or greatly contributed to the laboratory abnormalities found. Therefore, these adverse events were considered unlikely to be caused by the melanoma vaccine. One cat had transient grade 1 hypoalbuminemia, which was possibly caused by the vaccination but not thoroughly evaluated.
Conclusions and relevance
The canine melanoma DNA vaccine can be safely administered to cats, with minimal risk of adverse effects.
Introduction
Melanocytic tumors are relatively rare in cats. The primary sites affected most commonly are intraocular, periocular and dermal sites,1–28 although other primary locations involving oral, nares, digit and orbital lesions have been described.8,10,20,21,29–31 Malignant melanoma appears to have an aggressive local behavior and a high risk for dissemination in cats, regardless of the primary site of origin.7,10,13,15,18,21,26,27,32 Surgery and radiation therapy have been the primary modalities used for treatment of malignant melanoma in this species.17,21,29,29,33–38 Therapies to address the metastatic potential of these tumors in cats have not been reported to date.
A xenogeneic human tyrosinase DNA vaccine has been developed and licensed for treatment of dogs diagnosed with oral malignant melanoma (Oncept; Merial).39–42 The use of this vaccine in cases where the primary tumor is controlled through surgery or radiation appears to improve survival by inducing tumor-specific antibodies, cytotoxic T cells and antitumor responses.41,43 When tested in normal dogs, antigen-specific T cells were observed against the vaccine’s human tyrosinase antigen in 100% of cases. 43 The vaccine is well tolerated by dogs, with minimal adverse effects reported.39,42,44,45 As Oncept is based on human tyrosinase DNA, it should always be xenogeneic for other species than humans and therefore should be capable of eliciting an immune response. A small study showed that the canine vaccine is well tolerated when given to horses and elicits a significant humoral response to the protein encoded by the DNA plasmid vector. 46 No studies have been performed to date to evaluate the safety or efficacy of the canine melanoma vaccine in cats. The purpose of this study was to evaluate the safety of the canine melanoma vaccine when administered to cats diagnosed with melanoma.
Materials and methods
Patient selection
Records of cats diagnosed with malignant melanoma and treated with the canine melanoma DNA vaccine (Oncept; Merial) were solicited from several veterinary oncology practices in North America in 2011. In order to be included in this study, cats had to have a diagnosis of melanoma based on histopathology and have received at least one melanoma vaccine. Patients that received previous or concurrent treatments, whether surgical, medical or radiation therapy, or any combination of these, were eligible for study participation. Updated medical records were requested for all cases up to November 2012, when the study was closed.
Records review
Medical records were reviewed to obtain data regarding breed, gender, age at time of diagnosis, concurrent conditions, date of melanoma diagnosis, primary location of the melanoma, staging procedures and any previous or concurrent cancer treatments. The dates of melanoma vaccine administration, the anatomic location of vaccine administration, and information regarding clinical adverse effects detected by the veterinarian or reported by the owners after the administration of the melanoma vaccine were identified. Laboratory results obtained prior to and after vaccine administration were analyzed when available. The Veterinary Cooperative Oncology Group’s common terminology criteria for adverse events (VCOG-CTCAE) v1.1 was applied to grade the severity of adverse effects. 47 Updated records were obtained for all cases until death, loss to follow-up, or the closing of this study in November 2012.
Results
Study population
A total of 24 medical records were obtained that satisfied the inclusion criteria. The records were obtained from 16 veterinary oncology practices by December 2011, when accrual of new cases ended. Cases were obtained from the following institutions: Michigan State University Veterinary Teaching Hospital (East Lansing, MI); Veterinary Oncology and Referral Clinic (Milford, OH); Veterinary Medical Care (Mount Pleasant, SC); Gulf Coast Veterinary Diagnostic Imaging and Oncology (Houston, TX); Veterinary Medical Specialists of Pittsburgh (Pittsburgh, PA); Animal Cancer Specialists (Seattle, WA); VCA Veterinary Specialty Center of Seattle (Seattle, WA); Animal Specialty Center (Yonkers, NY); Veterinary Oncology and Hematology Center (Norwalk, CT); Southeast Veterinary Oncology (Orange Park, FL); University of Georgia Veterinary Teaching Hospital (Athens, GA); VCA San Francisco Veterinary Specialists and Emergency Service (San Francisco, CA); SAGE Centers for Veterinary Specialty and Emergency Care (Campbell, CA); Veterinary Oncology Center (Renton, WA); BluePearl Veterinary Partners – Queens (New York, NY); and Katonah Bedford Veterinary Center (Bedford Hills, NY). All cats received at least one melanoma vaccine between January 2008 and December 2011. The cases were followed until November 2012.
Most cats were older, with a median age of 12.9 years (mean 12.0 years; range 3.4–17.1 years). Breeds included 13 domestic shorthair cats (54.1%), three domestic mediumhair (12.5%), five domestic longhair cats (20.8%), one Manx (4.2%), one Persian mix (4.2%) and one Maine Coon (4.2%). There were 14 spayed females (58.3%) and 10 neutered males (41.7%). Concurrent conditions were present at the time of melanoma diagnosis in nine cats: heart disease and a basal cell tumor (n = 1), thymic cyst (n = 1), hyperthyroidism previously treated with radioiodine (n = 2), untreated hyperthyroidism (n = 1), hyperthyroidism treated with methimazole (n = 1), dermatophytosis (n = 2), brain tumor (n = 1), and splenic mast cell tumor (n = 1). One cat developed fibrosarcoma over the sternal area a year after starting the melanoma vaccine series.
Nineteen cats were deceased at the time the study was closed. The cause of death was reported by the attending veterinarian to be melanoma progression (n = 14), renal failure (n = 1), congestive heart failure (n = 1), methimazole toxicity (n = 1) or unknown (n = 2). Two patients were lost to follow-up, while three patients were alive, without evidence of cancer at the time this study was finalized, as reported by their veterinarian at the last recheck.
Tumor distribution and prior or concurrent cancer treatments
All cats were diagnosed as having tumors described as melanoma (n = 4), malignant melanoma (n = 13), epitheloid melanoma (n = 1), or amelanotic melanoma (n = 6), as established by histopathology. The primary tumors were classified as oral (eight cats; 33.3%), ocular/periorbital (four cats; 16.7%), dermal (seven cats; 29.2%), mucocutaneous (nare [two cats], lip [two cats]; 16.7%) and subcutaneous (one cat; 4.1%). At the time of diagnosis, 16 cats (66.7%) were free of metastasis as determined by staging evaluation, seven cats (29.2%) had metastasis to the regional lymph nodes (six cats) or liver (one cat) confirmed by cytology or histopathology, and one cat (4.1%) had ultrasonographic findings suggestive of liver metastasis, with no liver sampling performed.
Most cats had received another form of treatment prior to the melanoma vaccine administration: surgery alone (15 cats; two cats had multiple surgeries); radiation therapy alone (one cat); surgery and radiation (three cats); surgery and chemotherapy (one cat); and no treatment (four cats). At the time the melanoma vaccine was initiated, microscopic disease status had been achieved in 15 of the cats (62.5%). Ten of them (41.7%) had incomplete resection of the cancer, while five of them (20.8%) had complete local control and no visible evidence of metastasis. The remaining nine cats (37.5%) had measurable disease burden.
Five cats (20.8%) received other forms of treatment concurrently with the melanoma vaccine: chemotherapy (two cats) or radiation therapy (five cats). The chemotherapy given was lomustine (this cat had a brain tumor) or vinorelbine (this cat was enrolled in a vinorelbine study).
Vaccination data
The records indicated that the intent of the veterinarians was to vaccinate these cats with Oncept on the schedule recommended for canine melanoma vaccination (every 2 weeks for four injections, followed by booster vaccines every 6 months). The 0.4 ml dose recommended for dogs was used for each vaccination in cats. The vaccine was administered transdermally using the standard Vet Jet needle-free transdermal device provided by Merial.
A total of 114 melanoma vaccines were administered to 24 cats (median 4; mean 4.7; range 2–11 per patient). All vaccines were administered close to the intended vaccination timing, except one cat that received two delayed vaccination boosters due to owner reasons (delay by 3 months and 2 months, respectively). The size of the transdermal injection nozzle used for vaccination was not specified for any cats. The location of vaccine administration was reported for 72 vaccines: 46 vaccines (63.9%) were administered in the medial thigh caudal to the femur, while 26 vaccines (36.1%) were administered in the caudal thigh (in the semimembranosus/semitendinosus muscles). The median time between diagnosis and the first vaccine administration was 27 days (mean 98 days; range 5–567 days).
Safety results
Physical and clinical adverse effects from vaccine administration were inferred for all 114 vaccines administered, based on veterinarian’s observations and owner reports. A total of 13 adverse events (11.4%) associated with the vaccine administration were reported in seven cats and are described in Table 1. All these adverse events were categorized as clearly related to the melanoma vaccine based on VCOG-CTCAE attribution standards (‘Definite’). These adverse effects were seen in seven of the 26 vaccines given in the caudal thigh (26.9%) and five of the 46 vaccines given in the medial thigh (10.9%). The location of the vaccine administration was not identified in one cat with adverse effects. One of the patients that exhibited pain on administration was reported to be fractious and was placed under general anesthesia for the remaining three induction vaccinations. This cat exhibited muscle fasciculations with each subsequent vaccine. One patient had a history of progressive and intermittent vomiting for more than a year over the course of three booster vaccines administered at 6 month intervals. This cat had a concurrent splenic mast cell tumor. This adverse effect was categorized as clearly not related to the melanoma vaccine as based on VCOG-CTCAE attribution standards (‘unrelated’), and was excluded from the frequency calculations above. None of the patients that exhibited the adverse effects described in Table 1 received any other therapies concurrent with the melanoma vaccine.
Table 1.
Physical and clinical adverse effects associated with the vaccine administration, based on veterinarian’s observations and owner reports
| VCOG-CTCAE category | Adverse event | Grade | Number of events | VCOG-CTCAE attribution standard | Description of events |
|---|---|---|---|---|---|
| Administration site conditions | Injection site reaction | 2 | 2 | Definite | Pain manifested by jumping and vocalizing at vaccine administration |
| Administration site conditions | Injection site reaction | 1 | 5 | Definite | Muscle fasciculation |
| Constitutional clinical signs | Lethargy | 1 | 3 | Probable | Lethargy of 1–2 days’ duration after vaccine administration |
| Dermatologic/skin | Hyperpigmentation | 1 | 1 | Definite | Mild hyperpigmentation at the injection site |
| Gastrointestinal | Anorexia | 2 | 1 | Probable | Decreased appetite for a few days after vaccine administration |
| Gastrointestinal | Nausea | 1 | 1 | Probable | Nausea for 1 day after vaccine administration |
| Gastrointestinal | Nausea | 1 | 1 | Unrelated | Progressive and intermittent vomiting for more than 1 year |
VCOG-CTCAE = Veterinary Cooperative Oncology Group’s common terminology criteria for adverse events
Hematological and/or biochemical data before and after melanoma vaccination was available for 17 cats. Eleven of these cats (64.7%) did not have negative changes during or after the vaccine. The remaining six cats (35.3%) had grade 1–4 hematological and/or biochemical changes, which are described in Table 2. These adverse effects were graded and categorized based on the VCOG-CTCAE attribution standards as doubtfully related to the melanoma vaccine (‘unlikely’; five cats) or possibly related to the melanoma vaccine (‘possible’; one cat). The five cats with abnormalities classified as unlikely related to the melanoma vaccine had concurrent conditions or received concurrent treatments that likely caused or greatly contributed to the adverse events noted. Cat 4 had progressive melanoma metastasis to the liver at the time abnormalities were found. Cat 11 received concurrent lomustine therapy for a presumed unrelated brain tumor. Cat 13 had progressive melanoma metastasis within the lungs at least (no evaluation of the abdominal organs was performed). Cat 15 had an event of anesthesia and splenic mast cell tumor. Cat 17 received methimazole and its bloodwork abnormalities were interpreted by the attending veterinarian as methimazole toxicity. Cat 1 that had a grade 1 hypoalbuminemia possibly attributable to the melanoma vaccine was not evaluated for other conditions that could cause hypoalbuminemia.
Table 2.
Hematological and biochemical changes found during and after melanoma vaccine administration. No information was available for cats 2, 3, 6, 19, 20, 21 and 24. Cats 5, 7, 8, 9, 10, 12, 14, 16, 18, 22 and 23 did not have negative changes
| Cat | Hematological and biochemical changes | VCOG-CTCAE classification | VCOG-CTCAE attribution standard |
|---|---|---|---|
| 1 | Mild decrease in albumin 2.5 g/dl (normal 3.0–4.5 g/dl) detected 2 weeks after second melanoma vaccine, which resolved 2 weeks later | Metabolic: low albumin (grade 1) | Possible |
| 4 | Non-regenerative anemia (PCV 23%) and increased ionized calcium (1.98 mmol/l; normal 1.12–1.32 mmol/l) prior to starting the vaccines. The iCa normalized (1.28 mmol/l) with fluid support. Anemia worse (PCV 13%) a few days post-vaccine; treated with blood transfusion. The cat received two more melanoma vaccines. Humane euthanasia was performed due to anorexia and anemia 10 days after the last vaccine | Blood/bone marrow: PCV (grade 4) | Unlikely |
| 11 | The cat developed persistent anemia (PCV 20.6–24.2.%) during the course of the lomustine/vaccine treatment | Blood/bone marrow: PCV (grade 2) | Unlikely |
| 13 | Persistent mild azotemia after the third melanoma vaccine: creatinine 2.3 mg/dl (normal 0.9–2.2 mg/dl), BUN 34 mg/dl (normal 1–34 mg/dl), which was not evaluated further (euthanasia elected). The cat had progressive melanoma metastasis in the lungs | Metabolic: creatinine (grade 1) | Unlikely |
| 15 | USG 1.018 and normal biochemical parameters initially, unchanged at the time of the first melanoma booster vaccine. Progressive anemia (PCV 26.5%, then 20%) and azotemia 1 month after that vaccine, which progressed over a year to severe azotemia, hypertension, retinal detachment and euthanasia (owing to poor quality of life). The cat had concurrent splenic mast cell tumor | Blood/bone marrow: PCV (grade 1, then grade 2) | Unlikely |
| 17 | Non-regenerative anemia, thrombocytopenia and clinical signs interpreted as methimazole toxicity by the clinician | Blood/bone marrow: PCV (grade 3) Blood/bone marrow: thrombocytopenia (grade 4) |
Unlikely |
VCOG-CTCAE = Veterinary Cooperative Oncology Group’s common terminology criteria for adverse events; PCV = packed cell volume; iCa = ionized calcium; BUN = blood urea nitrogen; USG = urine specific gravity
Discussion
The goal of this study was to evaluate the safety of the canine melanoma DNA vaccine (Oncept) in feline patients. The vaccine appeared to be well tolerated, with a low number of reported episodes of pain on administration, muscle fasciculation, depression, decreased appetite, nausea or increased pigmentation at the site of administration (11.4%). These adverse effects were minimal and of brief duration. The incidence of these adverse effects is lower than what has been reported in canine patients receiving the melanoma DNA vaccine. 42 Owners of the cats in this study were not instructed to keep daily logs of local reactions and therefore the incidence of adverse effects reported in this study may be an underestimation. The observed adverse events did not lead to discontinuation of melanoma vaccine therapy in any cats and there were no fatalities related to the vaccine. Overall, owners were compliant with the intended vaccination schedule with minor exceptions.
Hematological and biochemical parameters progressively worsened over the course of vaccination in 6/17 cats. In five cats the abnormalities were considered unlikely to be related to the melanoma vaccine, as these cats had concurrent conditions or received concurrent treatments that likely caused or greatly contributed to these abnormalities. The attending veterinarian interpreted the biochemical abnormalities found in cats 4 and 13 as cancer related, as these abnormalities were found during melanoma progression. Cat 11 received concurrent chemotherapy, which could have been contributory to the persistent anemia. The renal failure and anemia described in cat 15 could have been associated with progressive mast cell tumor or may have been related to age. Cat 17 had biochemical abnormalities interpreted by the attending veterinarian as ‘classical’ methimazole toxicity. 48 The grade 1 hypoalbuminemia found in cat 1 was classified as possibly related to the melanoma vaccine because no other explanation was available, but this patient was not thoroughly evaluated to rule out other causes. The abnormality resolved within 2 weeks. If related to melanoma vaccine, this abnormality was considered mild and transient.
The location of vaccine administration was recorded for 63% of the vaccines. Two-thirds of these doses were administered in the medial thigh, as indicated for dogs. One third of the doses were administered in the caudal thigh (semimembranosus/semitendinosus muscles). The administration of the vaccine in the caudal thigh, pointing the Vet Jet needle-free transdermal device cranially into the semimembranosus/semitendinosus muscles, may slow the injectate and provide more muscle to do this.
This study was not focused on determining the efficacy of the vaccine nor was it intended to assess survival. However, we note that most cats with melanoma ultimately die from this cancer. The ideal treatment plan could not be determined from this data. The cat population in the study was not uniform with regard to primary melanoma location, the timing of the melanoma vaccine therapy after diagnosis, and whether and which concurrent anticancer therapies were used. These factors preclude the accurate assessment of vaccine efficacy and confound survival data. As this xenogeneic vaccine has been found to be immunogenic in all species tested to date (ie, murine, canine, equine and human),39–46 it is expected that immunogenicity would also be consistent in the feline species. Appropriately powered, controlled, prospective studies are necessary to determine the immunogenicity and efficacy of the canine melanoma vaccine in cats with melanoma.
Conclusions
This study showed that the canine melanoma DNA vaccine (Oncept) can safely be administered to cats, with minimal risk of adverse effects.
Acknowledgments
The authors would like to acknowledge the oncologists that have provided cases for this study: Dr Cheryl L Harris (Veterinary Oncology and Referral Clinic, Milford, OH); Dr Kathryn Taylor (Veterinary Medical Care, Mount Pleasant, SC); Dr Janet Carreras (Gulf Coast Veterinary Diagnostic Imaging and Oncology, Houston, TX); Dr Rebecca Newman (Veterinary Medical Specialists of Pittsburgh, Pittsburgh, PA); Dr Sarah Gillings (Animal Cancer Specialists, Seattle, WA); Dr Susan Ettinger (Animal Specialty Center, Yonkers, NY); Dr Gerald Post (Veterinary Oncology and Hematology Center, Norwalk, CT); Dr Tracy LaDue (Southeast Veterinary Oncology, Orange Park, FL); Dr Nicole Northrup (The University of Georgia Veterinary Teaching Hospital, Athens, GA); Dr Kathy Andres (VCA San Francisco Veterinary Specialists and Emergency Service, San Francisco, CA); Drs Mike Kiselow and Casey Cadile (SAGE Centers for Veterinary Specialty and Emergency Care, Campbell, CA); Dr Joshua Lachowicz (BluePearl Veterinary Partners – Queens, New York, NY). This article is dedicated to Dr Casey Cadile (1973–2013), an amazing person and veterinary oncologist who generously shared her own experience to help others understand what going through cancer care means for those that cannot speak for themselves – our patients.
Footnotes
Philip J Bergman has previously received study support from Merial and currently serves as a consultant for numerous animal health companies, including Merial. He also receives a minor royalty stream from Merial through a patent in concert with co-investigators from Memorial Sloan-Kettering Cancer Center. The other two authors declare they have no conflict of interest.
Funding: The authors received no financial support for the research, authorship, and/or publication of this article.
Accepted: 30 November 2015
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