Canine Oral Melanoma: Xenogeneic DNA Vaccine
ACVIM 2008
Rosemary Calderon, LVT
New York, NY, USA

Canine Oral Melanoma

In dogs, melanoma is an aggressive tumor which, depending on location, can have a high rate of local recurrence and metastasis. Common sites for melanoma in dogs are the oral cavity, digits, eyes, and skin. Melanoma tends to metastasize to regional lymph nodes and lungs, but can also spread to the brain, skin, and other organs. Melanomas are the most common oral tumor in dogs, accounting for 30-40% of all oral tumors. It can occur along the lip, gums, palate and tongue.

Melanoma originates from melanocytes, which are normally found in the epidermis and mucosa of the oral cavity. The majority of melanomas contain pigment, but amelanotic melanomas represent approximately one-third of cases. Melanoma in the oral cavity is highly malignant, with frequent metastasis to the regional lymph nodes and lungs. The metastatic rate is dependent on location, size and stage. Staging for melanoma is based on the World Health Organization (WHO) Tumor, Node, Metastasis (TNM) system. The four stages depend on tumor size (T), lymph node metastasis (N), and distant metastasis (M).1 (See Table 1.)

Table 1. TNM staging system.

 

Tumor size
(diameter)

Lymph node
metastasis

Distant
metastasis

Stage I

< 2 cm

-

-

Stage II

> 2 cm and < 4 cm

-

-

Stage III

> 4 cm

+

-

Stage IV

Any size

+/-

+

Factors that have been shown to be prognostic for dogs with oral melanoma are tumor size, clinical stage, and the ability for the first treatment to achieve local tumor control. Treatment traditionally involves surgery, either alone or in combination with other modalities. If untreated, the median survival time is 65 days.1 For local tumor control, either surgery or radiation therapy is recommended. Following surgery alone, median survival time has been reported to be 150-318 days, with a less than 35% survival rate after 1 year. If the animal is Stage I the median survival time with surgery was 511 days. If the animal is Stage II or Stage III the median survival time with surgery was 164 days.1

In dogs treated with radiation therapy alone mean survival times range from 211-363 days, with a survival rate of 36-48% at 1-year and 21% at 2-years. Hypo-fractionated radiation is used to treat melanomas because it is thought they are poorly responsive to traditional fractionation protocols, because of the melanoma cells ability to repair DNA damage. With hypo-fractionated radiation therapy the response rates were 83-100%. There was a complete response rate in up to 70% of the cases. Dogs with a complete response had local recurrence 15-26% of the time, at a median time of 139 days. The most common cause of death was due to metastasis reported in 58% of cases at a median time of 311 days.1

Metastasis, mainly to lungs, is the cause of death in 14-67% of dogs. Chemotherapy has been used to treat melanoma, but has not been very successful. Some studies have shown a response of the primary tumor to chemotherapy. In one report on the use of carboplatin in dogs with gross disease there was a 28% overall response rate, but only 4% had a complete response. Other chemotherapy drugs have been used, but studies are limited and response rates and durations have not been promising.1

Immunogenic Tumor

Since melanoma is thought to be an immunogenic tumor, immunotherapy treatments have been investigated. Melanoma in humans is typically a cutaneous disease. There have been reports in humans of spontaneous immune response. One patient with metastatic disease underwent multi-modality treatment, but the tumor continued to grow. Then, several years later, the tumor spontaneously subsided. Both the tumor and blood were examined and it was discovered that the patient's T-cells had the ability to lyse autologous tumor in vitro. The T-cells targeted several molecules including tyrosinase, MART-1/melanin A and mutated CDK4.

Tyrosinase is a normal enzyme found in melanocytes that is essential in melanin synthesis. Tyrosinase is also found in melanoma cells. This was an important discovery since it showed that human T-cells could recognize a self-protein in cancer cells. Researchers thought it might be possible to immunize patients against specific targets. This would be difficult with the immune system being tolerant and not recognizing normal self-proteins.2

Xenogeneic DNA Vaccine

Typical vaccines for common infectious diseases help stimulate an immune response against pathogens by exposing the immune system to foreign proteins. Immunotherapy for cancer has been unsuccessful in the past because tumor cells do not typically express foreign proteins. Xenogeneic vaccines use DNA coding for the same protein, but from a different species, to try to overcome the immune system's reluctance to recognize self-antigens. By injecting DNA from a different species, the immune system is expected to see the protein product of this DNA as foreign and therefore have a response.

The tyrosinase gene is inserted into a double stranded DNA ring ("pING vector"). The DNA is then injected through a transdermal device, which deposits the vaccine into the muscle. The DNA is transcribed and translated and the resulting protein is presented to naïve T cells in the local draining lymph node via professional antigen presenting cells. This stimulates both antibody and T cell responses. The tyrosinase from a different species helps to stimulate the immune response yet the response is targeted against melanoma cells.

During the past seven years, collaboration between the Animal Medical Center (AMC) and Memorial Sloan-Kettering Cancer Center (MSKCC) has resulted in several clinical trials investigating potential xenogeneic vaccines. DNA for both murine and human tyrosinase, along with other potential antigens have been investigated.3,4,5

Merial® Vaccine

The USDA conditionally licensed Merial melanoma vaccine, which contains plasmid DNA expressing human tyrosinase. It is a therapeutic cancer vaccine indicated for use in Stage II and Stage III oral melanomas with local disease control. Local and locoregional disease, including lymph node metastasis, should be controlled with either surgery or radiation therapy. The first four vaccines are given every two weeks, followed by booster vaccines given every six months. Each vaccine is administered in the muscle of the medial thigh. It is administered with the Canine Transdermal Device, which is a high-pressure spring instrument produced by Bioject, Inc. This device ensures intramuscular injection, despite the size of the dog, increasing immunostimulation. Each vaccine aliquot contains 0.4 mL volume so no matter the size of the patient they all receive the same volume and amount of DNA. Very few side effects have been reported with the vaccine. Mild local injection reactions, such as mild erythema, have been noted in about 5% of the patients. There were also two dogs that developed vitiligo (autoimmune depigmentation). One dog developed a hematoma at the site that resolved. A transient low-grade fever may also be noted.2

Results 6

So far the data has shown median survival times for melanoma with the use of the xenogeneic vaccine is as follows:

 Stage I > 939 days with 92.8% survival

 Stage II > 908 days with 79% living 1 year and 63% living 2 years

 Stage III > 1646 days with 77% living 1 year, 65% living 2 years and 57% living 3 years

 Stage IV = 293 days with 40.5% living 1 year and 18.8% living 2 years

Follow up Care and Monitoring

After a patient receives their initial four vaccines, a booster vaccine is given every six months. Since melanoma is still considered a highly metastatic disease, it is also recommended that a physical examination, including assessment of draining lymph nodes, and three view thoracic radiographs be performed at least every three months to monitor for metastasis. Routine blood work should also be taken every six months. As of now there is no information available on how long a patient should continue to receive booster vaccines.

Other Possible Indications

The indications for the Merial vaccine are for Stage II and Stage III melanomas. During the study the AMC has treated Stage I to Stage IV melanomas. Partial and complete responses of metastatic lesions, such as pulmonary nodules, have been noted subsequent to vaccine administration. The vaccine has helped many animals live longer then expected from previous data reported.

References

1.  Withrow SJ, Vail DM. Small Animal Oncology ed.4, Saunders, St. Louis, MO, 2007.

2.  Wolchok JD, Bergman PJ, et al. Continuing Education for Veterinarians, vol. 29, No. 6(A), June 2007.

3.  Liao JC, Wolchok JD, et al. Cancer Immun. 2006 Apr 21; 6:8.

4.  Bergman PJ, Camp-Palau MA, et al. 2006 May 22;24 (21): 4582-5. Epub 2005 Aug 24.

5.  Bergman PJ, McKnight J, et al. Clin. Cancer Res. 2003 Apr; 9 (4): 1284-90.

6.  Bergman PJ; unpublished data

Speaker Information
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Rosemary Calderon, LVT
Animal Medical Center
New York, NY


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