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Therapeutic Monoclonal Antibodies: Emerging Silver Bullets for Treating Cancer Timothy M. Fan, DVM, Phd, DACVIM (Oncology, SAIM)

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Therapeutic Monoclonal Antibodies: Emerging Silver Bullets for Treating Cancer Timothy M. Fan, DVM, Phd, DACVIM (Oncology, SAIM) Therapeutic monoclonal antibodies: Emerging silver bullets for treating cancer Timothy M. Fan, DVM, PhD, DACVIM (Oncology, SAIM) CANCER IMMUNOTHERAPY In industrialized countries, where the practice of preventative veterinary medicine has nearly eliminated morbidity and mortality associated with infectious disease processes (parasitic infestations and lethal viral infections), the development of cancer is among the most life-threatening disease conditions for the geriatric companion animal population. Recent statistics suggest that 25% of companion dogs will be diagnosed with cancer and die from this disease. Conventional therapeutic modalities instituted for the treatment of various tumor histologies in dogs and cats include surgery, radiation therapy, and systemic chemotherapy. Despite multimodality treatment protocols, the management of resistant micrometastatic disease and surgically-inoperative neoplasms remains problematic in companion animals and people. To reduce cancer-related mortalities, the development of novel therapeutics warrants investigation and intensive research. Efforts have been focused on exploiting the host’s immune response against cancer cells, a field of study known as tumor immunotherapy. The first formal observations that the body’s immune system may participate in combatting cancer cells came from an orthopedic surgeon by the name of William Coley, in the late 19th century. While working at New York Cancer Hospital, today known as Memorial Sloan-Kettering Cancer Center, Dr. Coley made the observation that prior to the accepted use of antiseptics which reduced the incidence of post-operative infections, the likelihood for curing cancers with surgical resection appeared higher. This curious observation prompted William Coley to consider the hypothesis that concurrent infections may stimulate the host’s immune response to recognize and eliminate not only bacterial pathogens, but also malignantly transformed cells. The convictions held by Dr. Coley where strong enough for him to institute the infusion of killed bacteria, known as Coley’s toxin, into terminal human cancer patients suffering from inoperable sarcomas. Interestingly and supporting his hypothesis, approximately 15% of human cancer patients experienced significant tumor reduction following the administration of Coley’s toxin. Although William Coley is credited for the inception of tumor immunotherapy, the field of study has progressed considerable over the past century. Today, therapeutics being intensively researched, commercially developed, or clinically instituted include agents which complement or stimulate the host immune system including lymphokines, vaccines, and antibody therapies. Based upon the mechanism of activity, these above treatment strategies may be categorized as either active or passive cancer immunotherapeutics. Active immunotherapies- Immune strategies directly eliciting the host’s immune response to recognize specific tumor-associated antigens, thereby initiating the production of both cell-mediated and humoral immune responses are categorized as active immunotherapies. Strategies which directly stimulate the immune system include tumor vaccines and cytokine therapies. The principle behind cancer vaccines is to stimulate a specific, adaptive immune response against tumor-associated antigens, whereby the generation of memory effector T cells will provide continuous antitumor immunity for the lifespan of the host. Another form of active immunotherapy involves the use of cytokines, which are soluble proteins produced and liberated by many cell lineages responsible for shaping the potency, longevity, and specificity of the cellular immune response. Passive immunotherapies- In addition to strategies which stimulate active immune responses, antibody- based passive immunotherapies have definitively found a niche for the successful treatment of cancer in people, but not companion animals, given the absence for commercially produced recombinant canine antibodies. Through their recognition and binding to surface tumor-associated antigens, antibody-based immunotherapies are able to exert antitumor immune effects in cancer patients through multiple mechanisms including agglutination of cancer cells, neutralization of key signaling proteins necessary for tumor progression, or blocking of receptor binding sites required for cellular mitogenesis and angiogenesis. Furthermore, monoclonal antibodies are able to “tag” cancer cells for immune recognition, thereby facilitating tumor destruction by means of antibody dependent cellular cytotoxicity. With the discovery of hybridoma fusion technology first described in 1992, the large-scale, commercial production of various chimeric and humanized monoclonal antibodies have been approved by the FDA, and currently instituted for the treatment of people diagnosed with lymphoid malignancies, breast carcinoma, and colorectal cancers. It would be hoped that enough financial gain could be leveraged by animal health companies to also develop such production capabilities already in practice for people with cancer. Tumor histologies in companion animals where immunotherapies have been investigated- Although the frontiers of tumor immunotherapy have been well-developed and explored in human oncology, immunotherapeutic strategies remain in their infancy in companion animal medicine. However, over the past 5-10 years there has been a tremendous interest in developing immunotherapeutics for the management of cancer. Of particular interest in veterinary oncology has been the development and testing of immune strategies for the treatment of the most common tumors: lymphoma, mast cell tumor, and osteosarcoma. In addition to this BIG 3, oral melanoma has been the focused interest for the evaluation of vaccine strategies. The commercialization of antibodies holds significant promise for the mass production of therapeutic antibody strategies. By the nature of the antibody structure with antigen binding domain, anticancer activities can be exerted by 3 primary mechanisms being: 1) Neutralization/blockade- antibody binding or sequestration of key proteins involved in promoting tumor cell growth or blood vessel development. 2) Opsonization- allows for the enhanced recognition of tumor cells by immune cells that can promote (a) phagocytosis, (b) antibody-dependent cellular cytotoxicity, and (c) mast cell activation. 3) Complement activation- direct activation of proteases to attack and degrade tumor cells marked for destruction. One specific target (called checkpoint inhibitors) that holds significant promise is the development and testing of antibodies that “block” the cellular interactions between tumor cells and activated T lymphocytes. This blocking antibody strategy is currently being testing in dogs with melanoma and lymphoma; however, the concept of blocking checkpoint inhibitors has broad applicability to many different tumor histologies in veterinary medicine including aggressive sarcomas. .
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