Introduction

Oncology is making continual strides with therapies and diagnostics in an effort to help not only diagnose cancers earlier but offer novel therapies to owners.

Cancer Vaccines

Oncept Anti-CD20 LSA Vaccine

The canine melanoma xenogeneic DNA vaccine has been shown to be safe, results in the development of antibodies and T cells and is effective. Merial has gained conditional approval for its Oncept LSA vaccine, which uses the same concept but is designed to induce immunity to CD20. The concept is therapeutic immunization to be used on achieving remission with chemotherapy. In an abstract of 9 dogs, the survival time of vaccinates after completion of 25-week CHOP protocol was >734 days. Data suggest that the product needs to start early in the treatment protocol as the average time for the generation of the immune response is likely near one-month post completion of the vaccine. Assuming a 6-month protocol + vaccine post completion (2 months), the average remission duration = 6–8 months. Thus, most patients are relapsing likely prior to the vaccine being able to generate an effective response. Data from a recently completed trial in which patients were administered the LSA vaccine during the second cycle of chemotherapy, noted an improvement in remission duration of 4 months.

Where Are We Now With This Product?

Currently, Merial/BI is reviewing the data from the most recent study in order to submit to the USDA for full licensure.

Canine Osteosarcoma Vaccine

Listeria monocytogenes is a gram-positive, intracellular bacteria that are capable of inducing potent innate and adaptive immune responses. Through its expression of listeriolysin (LLO), a pore-forming protein that enables it to escape from the phagosome prior to lysosome fusion, it rapidly gains access to the cytoplasm of the cell and is then involved in the MHC I-processing pathway. This enables the induction of CD8+ cytotoxic T-cell responses. The use of a highly-attenuated form of L. monocytogenes has been proven effective to introduce target antigens into antigen-presenting cells (monocytes, macrophages, and dendritic cells). By genetically fusing the target antigen of interest to LLO, potent CD8+ T-cell responses can be generated against the target antigen. ADXS31-164 is a highly attenuated strain of L. monocytogenes that has a chimeric human HER2/neu antigen fused to its LLO. Using the same platform, a recombinant HER2/neu-expressing Listeria-based therapeutic vaccine (AT-014 or Canine Osteosarcoma Vaccine) has been licensed by Aratana.

In a small study, 18 dogs with appendicular osteosarcoma (OSA) treated first with amputation and chemotherapy (4 doses of carboplatin) then received one of four doses of ADXS31-164 intravenously every 3 weeks x3. The study reported low-grade, transient toxicities, and it appeared that ADXS31-164 broke peripheral tolerance and induced antigen-specific IFN-responses against the intracellular domain of HER2/neu in 15/18 dogs within 6 months of treatment. There was also a decrease in the incidence of metastatic disease and significantly improved survival times @ 1-, 2- and 3-year vs. historical control group). The median survival time of 11 historical control dogs was 316 days vs. 8 of the treated dogs with Grade I disease, that achieved a median survival time of 956 days. Eleven of the 18 treated dogs have surpassed the median survival time (MST) of the control group. Adverse events were mild to moderate and primarily consisted of fever, lethargy, and nausea/vomiting.

Where Are We Now With This Product?

Aratana currently has conditional licensure for this product in the USA and a larger safety study of >150 is underway the data from which will be used to obtain full licensure.

Chemotherapy

Tanovea CA-1™ VetDC

Tanovea™ was discovered by Gilead Sciences, Inc., and licensed to VetDC for use in animal cancer, (previously known as VDC-1101). This agent was designed to preferentially target and attack cancer cells implicated in lymphoma. The data from studies totaling well over 330 patients have shown Tanovea™ to be highly effective against LSA with a 60–80% overall response rate. Not surprisingly, responses are higher in naïve LSA vs. relapse and in dogs with a B cell phenotype. Data suggests Tanovea™ is well-tolerated with a similar side effect profile as other commonly used agents. The drug is given via the intravenous route at 1 mg/kg every 3 weeks. The FDA has recently given Conditional Approval and the drug is not restricted to only oncologists.

Although the majority of side effects associated with this agent are similar to those of most chemotherapeutics, two unique side effects (and one that is not unusual) occur, that clinicians need to recognize and know how to treat.

• Pulmonary fibrosis: this was recorded in a small percentage of the patients treated and the mechanism is unknown. As this was fatal in some cases, screening with thoracic films and exclusion of patients with pre-existing pulmonary issues, or particular breeds at risk of pulmonary fibrosis, is warranted.
• Dermatopathy: Occurred in a minority of patients and often appears along the pinna and chest. Per VetDC, resolution of the side effects occurs once discontinuing the protocol.

Where Are We Now With This Product?

The pivotal trial is currently underway as a multisite, randomized, double-blinded prospective study, the data from which will be submitted to the FDA to obtain full approval.

Cancer Screening/Detection

The CADETSM BRAF Assay

Transitional cell carcinoma (TCC) is the most common bladder cancer. Generally, diagnosis is based upon signalment, ultrasound, urine cytology, however, definitive diagnosis generally requires histopathology (cystoscopy, traumatic catheterization, surgical exploratory).

Recent studies identified a mutation (V595E) in the canine BRAF (cBRAF) gene in a large proportion of canine urothelial carcinoma (UC) and prostatic carcinoma (PC). In assessing various cancers including epithelial, mesenchymal, and hematopoietic, the V595E mutation was identified in canine UC and PC with the highest penetrance rates of up to 87%.

Knowing bladder and prostatic cancers shed tumor cells into the urine, the presence of the V595E mutation in urine is an excellent molecular diagnostic marker. The digital droplet PCR assay identified the mutation in free catch urine samples from 85% of canine urothelial carcinoma and prostate carcinoma patients.

The assay has since been validated in clinical cases, demonstrating the mutation is not present in the urine of healthy dogs, or from dogs that have benign bladder diseases. In cases with concurrent histopathology, there was concordance between BRAF mutation + in free-catch urine and pathology-based confirmation of a bladder/prostatic carcinoma. As such the presence of the mutation in canine urine is, therefore, a highly specific indicator of the presence of a TCC/UC.

CADET® BRAF Plus assay detects a second signature in >2/3 of non-BRAF TCCs, i.e., >10% of the 15% BRAF wild type TCCs. The PLUS assay launched commercially as an ADD-ON test for CADET®-BRAF wild type (mutation undetected) cases and this increases overall sensitivity 85% to >95%

Where Are We Now With This Product?

The product is available to all veterinarians and current trials are assessing the use of early detection followed by NSAID usage.

Appetite Stimulation

Entyce® (Aratana Therapeutics): Capromorelin mimics the action of the hunger hormone ghrelin. Ghrelin is a 28-amino acid peptide produced primarily in the stomach and binds the ghrelin receptor. It has a short half-life (~10 minutes) and accumulates in the bloodstream slowly between meals. Ghrelin binds to receptors which increases signaling in the hypothalamus, resulting in hunger, thereby increasing food intake. Secondary effects of ghrelin include the stimulation of growth hormone secretion by activation of GHS-Rs in the hypothalamus and pituitary gland, which subsequently increases insulin-like growth factor-1 production. This results in an increase in lean body mass. Capromorelin is an orally active small molecule which has more sustained effects vs. Ghrelin.

The drug has been shown to be safe in both cats and dogs and more specifically has been shown to cause increased food intake and weight gain in both laboratory and client-owned dogs and increased food intake/body weight in cats.

Mirataz® Kindred Bio: Mirtazapine is a commonly used appetite stimulant in cats. Recent pharmacodynamic studies have shown it is safe and can be an excellent appetite stimulant. Higher doses, however, are commonly associated with side effects such as vocalization, hyperexcitability, and tremors.

Thus, the recommendation is the use of smaller, more frequent doses. Still, a challenge is in the administration via a pill. Mirataz® (mirtazapine transdermal ointment is a novel formulation for topical use in cats that are resistant to pilling. Data has shown the product is not only safe but result in weight gain normal cats. This represents another option for cats with cancer.

References

1.  Mason N, et al. Clin Cancer Res. 2016;22–4380–90.

2.  Mochizuki H, et al. PLoS One. 2015;10(6):e0129534. doi: 10.1371/journal.pone.0129534.

3.  Thamm DH, et al. BMC Veterinary Research. 2014;10:30–34.

4.  Thamm DH, et al. J Vet Intern Med. 2017;31:872–8785.

5.  Zollers B, Wofford JA, Heinen E, et al. J Vet Intern Med. 2016;30:1851–1857.

6.  Rhodes L, Zoller B, Wofford JA, et al. Vet Med Sci. 2018;4:316.

7.  Johannes C. New Oncology Therapeutics on the Horizon VCS. 2015.

8.  Buhles W, Quimby JM, Labelle D, et al. DOI: 10.1111/ jvp.12691.