Horizon therapy: On the horizon and round the corner (Proceedings)

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 tumor related mortality in our patient population. As suggested by the title, this discussion will center 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 (NCU-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 USA 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 USA (Canine Comparative Oncology and Genomics Consortium [CCOGC]), also administered through the NCI is collecting tumor tissues from over 3000 pet dogs with cancer in a tissue repository that can be utilized by veterinary and basic science researchers to look for novel treatment targets. Finally, the animal health divisions of major pharmaceutical companies in both the USA and Europe are realizing 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

Nonspecific 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 recognize and destroy neoplastic cells by a variety of mechanisms. L-MTP-PE not only increases monocyte tumoricidal activity but also causes increases in plasma concentrations of tumor necrosis factor-alpha (TNFa), and interleukin-6 (IL-6) among other cytokines. We have used L-MTP-PE immunotherapy In dogs with osteosarcoma (OSA), hemangiosarcoma, and malignant melanoma in randomized 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 OSA and hemangiosarcoma. Negotiations are currently underway for licensing of L-MTP-PE for use in dogs. We are currently investigation this product in combination with radiation therapy and more specific immunotherapy using anti-cancer vaccines (see subsequent). Other non-specific immune based therapies under study in veterinary medicine include the use of nonsteroidal anti-inflammatory drugs and liposome IL-2/SEA therapy.

Anti-Cancer Vaccines

Vaccines have been used to prevent infectious disease for over two hundred 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 life-span of the patients under our care. In the case of infectious disease, the immune system must recognize and attack non-self antigens that are foreign. This is in contrast to cancer vaccines where the immune system must recognize 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 (i.e., 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 vaccines 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 tumor cell are used. Additionally, whole cell vaccines can be genetically altered (transfected) to produce adjuvant peptides (e.g., 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 TAAs in the hopes of eliciting a more robust immune response. Other approaches include strategies to elicit immune responses to xenogeneic antigens (e.g., xenogeneic gp100 and tyrosinase) in the hope of creating cross-reaction between the xenogeneic homologs 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 utilize, 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 USA 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 tumors, rather than the tumor 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 byproduct that can be delivered safely and only converted to active drug in tumor locations would greatly increase the safety and therapeutic index of anticancer drugs. We have synthesized prodrug analogs 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-prodrug 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 (Gleevec) therapy for chronic myelogenous leukemia (CML) and other tumors in humans. Gleevec (STI-571) is one of the most important validations of the cancer research effort for the past 30 years. Gleevec is a molecule that selectively inhibits autophosphorylation of several important tumor growth factor receptors including Bcr-Abl, c-kit, and the PDGF receptor. Growth factors and their receptors contribute to tumor cell transformation, growth, apoptosis, invasion, angiogenesis, and metastasis. Single agent gleevec 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 tumors, feline and canine sarcomas, and hematopoietic tumors. 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 Tumor 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 tumors could be targeted, the end-result of inhibiting tumor growth could be achieved. This concept has several advantages, in particular, normal host cells are more genetically stable than tumor 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 (antiangiogenic) therapies as well as mechanisms of inhibiting stromal support of tumors. 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 are given continuously. There is significant in vitro and in vivo (in rodent tumor models) evidence to suggest that cytotoxic agents applied in this fashion affect the endothelium of growing tumor vasculature and exert their affects through an anti-angiogenic mechanism rather than through tumor cell cytotoxicity. The theorized outcome of metronomic chemotherapy is stabilization 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 MTD are used.

Methods to Enhance Bidirectional Flow of Information Gained

As previously mentioned, our wish is not to have important data generated in companion animals, and indeed promising drug and therapeutic strategies that are developed solely benefit physician-based oncology. We strive to ensure important breakthroughs and advanced treatments flow back into veterinary-based oncology standard-of-care. Ultimately, all therapies developed and marketed for human patients will be available by off-label use to veterinarians and veterinary patients; however, these often are at excessively high cost, at least until patents expire and more economical generic products become available. Approaches to ensure more rapid and economical access to veterinary markets include ensuring cross-talk between the human and animal health divisions of major pharmaceutical companies early in drug investigation, promoting a "second to lead" approach (see below), and communicating successes with smaller veterinary based pharmaceutical and marketing companies. In the former case, when drug development leads to a product that may not be suitable for use in humans for various reasons (e.g., other alternatives already exist, uncommon tumor incidence), a superior, more common, or acceptable veterinary use may exist and communication between the human and veterinary development groups can result in shifting the market focus. In the latter case, recent negotiations with veterinary based drug marketers have resulted in groups moving for FDS licensure of drugs with indications specific for veterinary species resulting in formulations (e.g., dosing size) becoming available that are better suited to companion animal species.

The "Second-to-Lead" Approach

In today's rapidly accelerating drug development environment, most pharmaceutical companies take advantage of accelerating the process of chemical synthesis methods to the extent that it is now possible to produce compound libraries to screen for novel bioactivities. This powerful new technology has begun to help pharmaceutical companies find new drug candidates quickly, save significant money in preclinical development costs and ultimately change their fundamental approach to drug discovery. The result is that rather than one particular drug being available for investigation, a "library" of similar drugs is codiscovered that have nearly identical structure and function. In this case, moving one forward through the human health division and another in parallel through the animal health division has several advantages. Investigations in one can serve to inform development of the other in clinical trials without compromising marketing strategies that will allow less expensive and species-licensed products to become available to companion animals. This is best illustrated in the current development of small molecule tyrosine kinase signalling pathway inhibitors, where second-to-lead molecules are currently being field-tested in veterinary patients prior to licensure in companion animal species.