Of all the treatment modalities available in veterinary clinical oncology, surgery remains the most commonly applied and the most likely to effect cure at present. Ultimately, however, local recurrence and/or distant metastatic spread result in the majority of tumour-related mortality in our patient population. As suggested by the title, this discussion will centre on new or novel advances in adjuvant therapy.

Where Are Novel Therapies Being Developed?

In North America, there is a major push through the Comparative Oncology Program of the National Cancer Institute (NCI-USA) headed by Chand Khanna to investigate novel drug and drug delivery systems in companion animal species with an eye to informing clinical trials in physician-based oncology. Several academic and specialty practices in the US have formed alliances under the umbrella of the Comparative Oncology Trials Consortium (COTC) to perform proof-of-concept trials of novel treatments that come into the system from academia, 'Big Pharma' (pharmaceutical companies) and the NCI. The flow of information and products that are being developed through these trials is not unidirectional, however, and drugs and drug delivery systems investigated for human use in these veterinary trials are being passed on to the animal health divisions of pharmaceutical companies for marketing in veterinary practice. Additionally, a consortium in the US (Canine Comparative Oncology and Genomics Consortium (CCOGC)), also administered through the NCI, is collecting tumour tissues from over 3,000 pet dogs with cancer in a tissue repository that can be utilised by veterinary and basic science researchers to look for novel treatment targets. Finally, the animal health divisions of major pharmaceutical companies in both the US and Europe are realising the importance of running clinical trials through veterinary centers in order to get licensure for products in canine and feline species. Several examples involving these new consortiums and clinical efforts will be presented.

Immunotherapeutics

Non-Specific Immune Enhancement

The classic example in the veterinary literature is the use of L-MTP-PE, a liposome-encapsulated bacterial cell wall component. Macrophages and monocytes activated by muramyl tripeptide (MTP) acquire the ability to recognise and destroy neoplastic cells by a variety of mechanisms. L-MTP-PE not only increases monocyte tumouricidal activity but also causes increases in plasma concentrations of tumour necrosis factor-alpha (TNFα), and interleukin-6 (IL-6), among other cytokines. We have used L-MTP-PE immunotherapy in dogs with osteosarcoma (OS), haemangiosarcoma and malignant melanoma in randomised blinded trials involving several hundred dogs and L-MTP-PE significantly prolongs the metastasis-free intervals and overall survival times when given alone or following chemotherapy in OS and haemangiosarcoma. We are currently investigating this product in combination with radiation therapy and more specific immunotherapy using anticancer vaccines (see below). Other nonspecific immune-based therapies under study in veterinary medicine include the use of non-steroidal antiinflammatory drugs and liposome IL-2/SEA (staphylococcal enterotoxin A) therapy.

Anti-Cancer Vaccines

Vaccines have been used to prevent infectious disease for over 200 years. Ironically, their widespread use in veterinary medicine is one of the reasons cancer is such an important disease in veterinary practice owing to the extended lifespan of the patients under our care. In the case of infectious disease, the immune system must recognise and attack non-self antigens that are foreign. This is in contrast to cancer vaccines where the immune system must recognise and attack 'self' antigens that are derived from the host and are likely present on normal host tissues. Since the immune system has evolved through the millennia to become 'tolerant' of self (so called anergy) and spare normal tissues (otherwise, immune-mediated disease would be rampant), methods of safely breaking 'self-tolerance' are important to the development of anti-cancer vaccines. Our laboratory and others have investigated several novel vaccine approaches to treating melanoma and non-Hodgkin's lymphoma. Whole-cell vaccine approaches have been used extensively in veterinary clinical trials and have the advantage of simplicity, as well as not requiring prior knowledge of which antigens are important as all potential antigens present in the tumour cell are used. Additionally, whole-cell vaccines can be genetically altered (transfected) to produce adjuvant peptides (e.g., granulocyte macrophage colony stimulating factor (GM-CSF)) at the site of vaccination, such that both antigen and adjuvant are presented together. Whole cells can also be programmed to over-express tumour-associated antigens (TAAs) in the hopes of eliciting a more robust immune response. Other approaches include strategies to elicit immune responses to xenogeneic antigens (antigens derived from another species) (e.g., xenogeneic gp100 and tyrosinase) in the hope of creating cross-reaction between the xenogeneic homologues and self-molecules, breaking tolerance and ultimately resulting in a clinically relevant immune response. These strategies have been investigated either through genetically engineered whole-cell approaches, or through the use of xenogeneic DNA vaccines; that is, specific sequences of DNA injected into the host are decoded and the message translated into specific antigens that professional antigen-presenting cells utilise, resulting in an antigen-specific immune response. This strategy has been employed by Phil Bergman's group at the Animal Medical Center in dogs with melanoma with some success and this vaccine currently has provisional approval in the US under an FDA license. Other active areas of cancer vaccine development include combining vaccine strategies with radiation (radio-immunotherapy) and chemotherapy to take advantage of the so-called abscopal effect as well as vaccine strategies designed to target the 'normal' host stroma and vasculature that support tumours, rather than the tumour itself. Examples of current and future investigations of these strategies in pet dogs will be presented.

Development of Less Toxic Prodrugs

Development of prodrugs that are less systemically toxic than their active by-product that can be delivered safely and only converted to active drug in tumour locations would greatly increase the safety and therapeutic index of anti-cancer drugs. We have synthesised pro-drug analogues of novel cytotoxic agents with activity against canine non-Hodgkin's lymphoma that effectively load peripheral blood mononuclear cells and lymphocytes. In clinical trials with pet dogs, these agents have significant activity against lymphoid malignancies and are much less toxic to the patient than their non-pro-drug predecessors.

Growth Factor-Targeted Therapy

A criticism of basic or bench molecular cancer research over the past decades has been that the study of such basic cell growth and differentiation mechanisms have not translated into clinically meaningful treatment strategies. That criticism has recently been shattered with the approval of several 'targeted therapies' in physician-based oncology such as STI-571 (imatinib mesylate, Gleevec^TM) therapy for chronic myelogenous leukaemia (CML) and other tumours in humans. Gleevec^TM (STI-571) is one of the most important validations of the cancer research effort for the past 30 years. Gleevec^TM is a molecule that selectively inhibits autophosphorylation of several important tumour growth factor receptors including bcr-abl, c-kit and the platelet-derived growth factor (PDGF) receptor. Growth factors and their receptors contribute to tumour cell transformation, growth, apoptosis, invasion, angiogenesis and metastasis. Single agent Gleevec^TM therapy has resulted in long-term control of CML in 90% of patients treated, representing a remarkable breakthrough.

In veterinary-based oncology, several groups have been investigating the use of growth factor-based therapies including c-kit, bcl-2 and c-met targeting strategies for canine mast cell tumours, feline and canine sarcomas and haematopoietic tumours. Importantly, some of these are currently in phase I/II/III trials in veterinary patients and likely to become available to the practitioner by the end of the decade. Several examples will be presented.

Targeting Tumour Blood Supply and Host Support Systems

Theoretically, it may not be necessary to target cancer cells themselves; rather, if the normal host stroma (blood vessels and supporting cells) that provide nutrients and infrastructure to growing tumours could be targeted, the end result of inhibiting tumour growth could be achieved. This concept has several advantages, in particular, normal host cells are more genetically stable than tumour cells and are therefore much less likely to develop drug resistance mechanisms than are their genetically unstable cancer cell counterparts. We and others have investigated several anti-blood vessel (anti-angiogenic) therapies as well as mechanisms of inhibiting stromal support of tumours. Similarly, the concept of low-dose, continuous delivery of cytotoxic agents, sometimes called 'metronomic' chemotherapy has been introduced. With metronomic delivery, a more frequent (e.g., daily) low dose (well below standard cytotoxic doses) of the drug is given continuously. There is significant in vitro and in vivo (in rodent tumour models) evidence to suggest that cytotoxic agents applied in this fashion affect the endothelium of growing tumour vasculature and exert their effects through an anti-angiogenic mechanism rather than through tumour cell cytotoxicity. The theorised outcome of metronomic chemotherapy is stabilisation rather than regression of disease. Administration of chemotherapeutics in this fashion also has the possible advantage of being less toxic because doses well below the maximum tolerated dose (MTD) are used.