Originally published in the January 2015 issue of Veterinary Practice News
The year 2015 is an exciting time to be a veterinary oncologist as we shift away from decades-old chemotherapy regimens and toward a host of emerging therapies for veterinary cancer.
More pets are developing cancer, a leading cause of death in companion animals, because they are living longer. Newer therapies are the outcome of research based on need and predominantly from advances in the human oncology arena.
Animals with naturally occurring cancer are a driving force to industry, allowing pharmaceutical companies to continue their progress against the dreaded disease for the benefit of both people and companion animals.
Improving treatment outcomes stems from staging the patient (i.e., identifying the cancer within the body and any other diseases present) as cancer management is always planned in the best interest of the patient.
For the primary care veterinarian, a shift to twice-a-year exams focusing on a complete physical examination has facilitated early identification. In addition, combining laboratory testing and advanced imaging with thoracic radiographs and abdominal ultrasound has afforded early screening in managing many cancers and setting realistic expectations.
Indeed, many practitioners have reallocated their thinking—basic diagnostic tests are just as important as returning to the veterinarian for booster vaccinations. I have always believed we miss more by not looking than by not knowing, and this could not be truer in the practice of veterinary medicine. However, client acceptance of these recommendations continues to be based on financial decision-making, and preventive testing is limited in the ever-growing companion animal insurance market.
So what is new?
Lymphoma remains the most commonly referred oncology case. Despite decades of chemotherapy, the median survival time still hovers around eight to 14 months for most canine B-cell lymphomas treated with a CHOP protocol. To this regimen, immunotherapy is being added to standard therapies, including telomerase immunotherapy.1
This treatment targets canine telomerase, an enzyme responsible for limitless replication of tumor cells, present as a ubiquitous protein unregulated in the majority of animal and human cancers. Ongoing studies have expanded the use of this product to other tumor types, including hemangiosarcoma and melanoma. The author has experience with this immunotherapy and canine patients surviving more than four years. An intent to move the product toward commercial availability is ongoing. (www.takisbiotech.it)
A newer approach includes several monoclonal antibodies from Aratana Therapeutics Inc. of Kansas City, Kan.—caninized anti-CD52 for T-cell lymphoma and CD20 for B-cell lymphoma. Clinical studies are ongoing following an abstract and poster presented at the Veterinary Cancer Society’s 2014 annual meeting. Conditional licensure has been secured for CD52, and full licensure is anticipated in 2015. For more information or to find a clinical trial site, go to www.aratana.com.
Hematopoietic stem cell transfer involves the obliteration of cancer cells while noncancer cells are brought back from a prior stem cell harvest or from a compatible relative sharing the same genetic markers. This technology gained momentum several years ago, but the expense combined with high morbidity and limited availability has stagnated leaps forward. Several long-term survivors remain cancer-free, and the ability to reduce costs and more efficiently identify genetic compatibility will continue to see more data maturing from this procedure.
Osteosarcoma (OSA) continues to be a challenge in managing the distant metastasis inevitably developing after local control (radiation, amputation or limb sparing). A common feature of OSA is the expression of the TAAs HER2/neu or CSPG4.
Advaxis Inc. of Princeton, N.J. (www.advaxis.com) has developed technology that uses attenuated, live Listeria as a vector to deliver a tumor-associated antigen to activate the patient’s immune system. This protocol has been explored in OSA-affected people and dogs. Listeria monocytogenes strains have been engineered to induce an innate immune response and to express tumor-associated antigens, which induce tumor-specific T cell-mediated immunity. In addition, tumor antigens have been fused to virulence factor listeriolysin (LLO) in the Listeria bacterium.
The combination of the tumor antigen and LLO generates a strong immune response, which attacks the cancer. ADXS-cHER2 is an immunotherapy treatment based on this technology that targets the HER2 oncogene. An ongoing Phase I trial at the University of Pennsylvania is treating naturally occurring OSA pet dogs with ADXS-cHER2, after their standard-of-care treatment, and shows significantly prolonged overall survival over dogs that received the standard-of-care treatment without ADXS-cHER2. On this basis, Advaxis announced that it intends to initiate a clinical program of ADXS-cHER2 for the treatment of pediatric osteosarcoma. In addition, Advaxis signed a global licensing agreement with Aratana Therapeutics for ADXS-cHER2 for the treatment of osteosarcoma in dogs.
An additional HER2 immunotherapy in clinical trials is canine HER2 delivered via adenovirus vector with electrogenetransfer (EGT) using the prime/boost technology. This technology mimics the platform of the telomerase immunotherapy and has expanded beyond osteosarcoma to include other HER2-expressing tumors, including feline and canine mammary tumors and transitional cell carcinoma. For more information, go to www.petcancerinformation.com.
Malignant melanoma (MM) is another cancer with high metastatic potential, specifically for oral and digital variants. Traditional treatments for canine MM involve surgery, radiotherapy and chemotherapy and are efficient in controlling the tumor locally in up to 75 percent of animals, whether used alone or in combination. However the one-year survival rate does not exceed 30 percent because of metastasis.2-4
Oncept, from Merial Ltd. of Duluth, Ga., is a USDA-approved, xenogeneic DNA vaccine targeting tyrosinase. It may extend survival in dogs with locally controlled stage II-III oral melanoma and has been available to specialists for several years.
This vaccine provides compelling research publications. Nevertheless, a recent retrospective study conducted on a limited number of dogs questioned its efficacy, reminding us that mature data is needed. In my experience and with my research collaborators, immunotherapy is more like a marathon than a sprint, and early intervention appears crucial to positive outcomes.5-7
Another xenogeneic DNA vaccine from Europe was evaluated in client-owned dogs with surgically resected stage II-III CSPG4-positive, spontaneous oral melanoma and achieved promising results in terms of disease-free interval (DFI) and overall survival (OS) extension, adding the potential of a future option for a specific cancer.8
Mast Cell Tumors
Mast cell tumors are challenging to treat, and some theories state that many of the grade I and II on the older Patnaik classification may be a different neoplasm entirely, with more benign behavior vs. the Grade III classification, which is notoriously aggressive and highly metastatic. We know that many grade II mast cell tumors treated with surgery and incomplete margins never recur.9 The newer two-tier system, along with molecular panel evaluation, has greatly improved our ability to predict behavior and better manage these tumors. I envision a day when all mast cell tumors may be evaluated via histopathology with molecular and immunohistochemistry markers as opposed to the current standard of requesting additional markers for each mast cell tumor.
What is this panel? The panel includes grading MCTs according to a two-tier system—cell proliferation analysis (Ki-67, AgNORs), c-Kit PCR—to detect internal tandem duplication (ITD) mutations in exon 11 and exon 8, and KIT immunohistochemistry to analyze expression of this tyrosine kinase receptor. (www.animalhealth.msu.edu)
Treatment of these higher-grade mast cell tumors has expanded beyond chemotherapy to include the use of tyrosine kinase inhibitors (TKI’s) such as the drug toceranib. Toceranib (Palladia), from Zoetis Inc. of Florham Park, N.J., is a multikinase inhibitor that targets several receptor tyrosine kinases and is FDA-approved for the treatment of Patnaik grade II or III, recurrent, cutaneous mast cell tumors with or without regional lymph node involvement in dogs. More information may be found at www.mypalladia.com.
Another drug in the same class, Masitinib mesylate, Kinavet CA-1 is labeled for the treatment of recurrent or non-resectable grade II and grade III mast cell tumors that have not been previously treated with chemotherapy or radiation, except corticosteroids. This drug has conditional FDA approval. The key question is when to use these drugs, but as a blanket treatment for all mast cell tumors, this author does not agree it is appropriate.
Evaluation of the c-kit mutation with molecular panels and the use of c-kit staining with IHC appear to provide the most accurate justification for their use. In addition, combined use of both standard chemotherapies and TKI’s may be indicated though myelosuppression increases with the combination. Lastly, these drugs have their share of side effects as well as significant expense. Judicious use is both prudent and appropriate.
Paccal Vet-CA1 (paclitaxel for injection) is conditionally approved by the FDA and is indicated for the treatment of Nonresectable stage III, IV or V mammary carcinoma in dogs that have not received previous chemotherapy or radiotherapy and for resectable and nonresectable squamous cell carcinoma in dogs that have not received previous chemotherapy or radiotherapy. For more information go to www.paccalvet.com.
Also available are Tanovea (rabacfosadine) for lymphoma and VDC-597. VDC-597 is an orally available, dual-acting inhibitor of PI3K and mTOR proteins, both of which are implicated in many types of cancers, including sarcoma, lymphoma and solid tumors. For more information, go to www.vet-dc.com.
Electrochemotherapy is a therapeutic approach providing delivery into the cell interior of non-permeant drugs (bleomycin or cisplatin) with intracellular targets. It is based on the local application of short and intense electric pulses that transiently permeabilize cell membrane, thus allowing transport of molecules otherwise not permitted by a cellular membrane.
Applications for treatment of cutaneous and subcutaneous tumors has extended into internal tumors using minimally invasive approaches. (www.vetelectrochemotherapy.com)
The B7-1 (CD80) costimulatory molecule is usually expressed on the membrane of professional APCs, such as dendritic cells or B-cells, initially binding to CD28 on CD4+ (helper) T-cells, and subsequently acting as a second signal following antigen-TCR engagement.
Tumor cells usually lack expression of CD80 and without this costimulatory signal, T-cells may become clonally anergic when the TCR signal is delivered. B7-1 transduced tumor cells are expected to present both the antigen (TCR receptor) and the costimulatory (CD28- mediated) signals to CD8+ cytotoxic T lymphocytes (CTLs) simultaneously, leading to efficient activation of CTLs without requiring the assistance of CD4+ helper T-cells.
A recent clinical trial has begun, resulting in accessing the tumor and treating with B7-1 combined with human or canine GMCSF via electroporation (B7-1 IT) in combination with electrochemotherapy with bleomycin (ECT). The tumor burden is partitioned, and half of the tumor receives B7-1 IT while the other half receives ECT. The advantage of this therapy is a single treatment and the ability to affect the entire tumor burden within the body while accessing only a portion of that burden, allowing for systemic response, an option for patients with metastatic disease otherwise untreatable with conventional therapies. Current trials include single treatment lymphomas both naïve and rescue and metastatic cancers.10
Cancer is a complex biological process through which a normal cell acquires, step by step, new capabilities that cause its transformation into a tumorigenic and eventually malignant cell. An understanding of this biological complexity has spurred the development of increasingly comprehensive experimental models and favorable targets and technology.
A client’s first step is consultation with an oncologist. The Americal College of Veterinary Internal Medicine maintains a list of board-certified veterinary oncologists at www.acvim.org/PetOwners/FindaSpecialist.aspx. Are we on our way toward more cures in veterinary oncology? The future looks promising. l
For more information on clinical trials for your patients, go to www.vetcancertrials.org.
- A vaccine targeting telomerase enhances survival of dogs affected by B-cell lymphoma. Peruzzi D, Gavazza A, Mesiti G, Lubas G, Scarselli E, Conforti A, Bendtsen C, Ciliberto G, La Monica N, Aurisicchio L.Mol Ther. 2010 Aug;18(8):1559-67. doi: 10.1038/mt.2010.104. Epub 2010 Jun 8.
- Freeman KP, Hahn KA, Harris FD, King GK (2003) Treatment of dogs with oral melanoma by hypofractionated radiation therapy and platinum-based chemotherapy (1987-1997). J Vet Intern Med. 17: 96-101.
- Proulx DR, Ruslander DM, Dodge RK, Hauck ML, Williams LE, Horn B et al. (2003) A retrospective analysis of 140 dogs with oral melanoma treated with external beam radiation. Vet Radiol Ultrasound. 44: 352-9.
- Murphy S, Hayes AM, Blackwood L, Maglennon G, Pattinson H, Sparkes AH (2005) Oral malignant melanoma – the effect of coarse fractionation radiotherapy alone or with adjuvant carboplatin therapy. Vet Comp Oncol. 3: 222-9. doi: 10.1111/j.1476-5810.2005.00082.x
- Grosenbaugh DA, Leard AT, Bergman PJ, Klein MK, Meleo K, Susaneck S et al. (2011) Safety and efficacy of a xenogeneic DNA vaccine encoding for human tyrosinase as adjunctive treatment for oral malignant melanoma in dogs following surgical excision of the primary tumor. Am J Vet Res. 72: 1631-8. doi: 10.2460/ajvr.72.12.1631
- Bergman PJ, Camps-Palau MA, McKnight JA, Leibman NF, Craft DM, Leung C et al. (2006) Development of a xenogeneic DNA vaccine program for canine malignant melanoma at the Animal Medical Center. Vaccine. 24: 4582-5. doi: 10.1016/j.vaccine.2005.08.027
- Ottnod JM, Smedley RC, Walshaw R, Hauptman JG, Kiupel M, Obradovich JE (2013) A retrospective analysis of the efficacy of Oncept vaccine for the adjunct treatment of canine oral malignant melanoma. Vet Comp Oncol. 11: 219-29. doi: 10.1111/vco.12057
- Riccardo F, Iussich S, Maniscalco L, Lorda Mayayo S, La Rosa G, Arigoni M et al. (2014) CSPG4-specific immunity and survival prolongation in dogs with oral malignant melanoma immunized with human CSPG4 DNA. Clin Cancer Res. 20: 3753-62. doi: 10.1158/1078-0432.CCR-13-3042
- J Vet Intern Med. 2006 Jul-Aug;20(4):933-40. Recurrence rate, clinical outcome, and cellular proliferation indices as prognostic indicators after incomplete surgical excision of cutaneous grade II mast cell tumors: 28 dogs (1994-2002). Séguin B1, Besancon MF, McCallan JL, Dewe LL, Tenwolde MC, Wong EK, Kent MS.
- Non-viral immune electrogene therapy induces potent antitumour responses and has a curative effect in murine colon adenocarcinoma and melanoma cancer models. Forde PF, Hall LJ, de Kruijf M, Bourke MG, Doddy T, Sadadcharam M, Soden DM. Gene Ther. 2014 Nov 6. doi: 10.1038/gt.2014.95.
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Presumed masitinib-induced nephrotic syndrome and azotemia in a dog
Lauren Devine and David J. Polzin
Masitinib mesylate is a tyrosine-kinase inhibitor approved for the treatment of nonresectable or recurrent, Grade 2 or 3 mast cell tumors in dogs. This report describes nephrotic syndrome and acute kidney injury attributed to masitinib and illustrates the need for regular monitoring of serum creatinine concentration, urinalysis, and urine protein:creatinine ratio during its use.
Masitinib mesylate (Kinavet, AB Science, Short Hill, New Jersey, USA) is a tyrosine-kinase inhibitor that has been approved for the treatment of nonresectable or recurrent, Grade 2 or Grade 3 mast cell tumors in dogs (1–10). The primary effect of masitinib is selective and potent inhibition of c-KIT-dependent cell proliferation. Masitinib plays a role in the inhibition of platelet-derived growth factor receptor (PDGFR)-dependent cell proliferation and Src family kinases such as LYN, a contributor to IgE-induced mast cell degranulation in vitro (2,5,7,11). The effect of masitinib on renal function is theorized to be a direct inhibition of c-KIT on the renal tubules or on the glomerular cells that express PDGF receptors (1,7). Reported renal-related side effects of masitinib include proteinuria, nephrotic syndrome, and renal failure (2). To the authors’ knowledge, this is the first report describing a severe case of Masitinib-related nephrotic syndrome (NS) and acute kidney injury (AKI) with complete recovery of renal function based on biochemistry and urinalysis parameters.