It has long been believed that one function of the adaptive immune system is to detect and destroy abnormal cells such as cancer cells. If true, it follows that the immune system may well be manipulated to enhance such immunity. On consideration, however, it is apparent that when a cancer develops in an animal it must have already defeated the immune system. For many years, immunologists have attempted to treat cancers by means of immunotherapy. Progress was distressingly slow. Successes were limited to rare cancers and even when immunotherapy worked, results were unpredictable and inconsistent. That has now changed. Vaccines against cancers are still at an early stage in their development, but new techniques involving both passive and active immunotherapy have begun to yield exciting results. Progress has not been confined to human cancers. Encouraging results are increasingly being obtained in the treatment of cancers in our domestic animals. One reason for recent successes is that we have increasingly recognized that cancers are immunosuppressive. They employ multiple strategies to evade or suppress the host’s immune system. Thus treatments that reverse this immunosuppression have the potential to “turn on” the immune system and destroy the cancer. It has been estimated that about 17% of human cancers arise as a result of infection. Many different human pathogens including the bacterium Helicobacter pylori, hepatitis viruses B and C, Epstein-Barr virus, herpesvirus, and human papilloma virus are oncogenic. Prophylactic vaccination against these agents is therefore a practical way to prevent cancers developing. There are established successful and effective vaccines against oncogenic viruses such as hepatitis B and human papillomavirus, the causes of hepatocellular carcinoma and cervical cancer, respectively. The most important of these in veterinary medicine are the vaccines against feline leukemia. These vaccines usually contain high concentrations of the major viral antigens, and immunity is almost entirely directed against viral glycoproteins. Other important vaccines are those directed against Marek’s disease, a T cell tumor of chickens caused by a herpesvirus. The immune response evoked by these vaccines has two components. First, humoral and cell-mediated responses act directly on the virus to reduce the number of virions available to infect cells. Second, an immune response is provoked against virus-encoded antigens on the surface of tumor cells. Both the antiviral and antitumor immune responses act synergistically to protect the birds against Marek’s disease. A major advance in cancer immunotherapy has been the development of bioengineered monoclonal antibodies that may be directed against specific tumor cell antigens or against molecules that promote tumor growth. There are now more than 75 US Food and Drug Administration (FDA)–approved, monoclonal antibodies used in the treatment of human cancers. For example, in 1987 the FDA approved rituximab, a monoclonal antibody directed against the B-cell surface antigen CD20. Rituximab has revolutionized the treatment of B cell lymphomas in humans. The anti-CD20 binds to the malignant B cells and triggers their apoptosis. Canine B cells also express CD20 although canine monoclonal anti-CD20 does not appear to cause B cell tumor apoptosis. Canine CD20 is structurally sufficiently different from the human molecule so that Rituximab will not bind it. Caninized monoclonal antibodies against canine CD20 have been developed and some deplete B cells. Initially these monoclonal antibodies were derived exclusively from mice. However, as monoclonal antibody technology has improved, it has proved possible to “humanize” the murine antibodies by attaching the mouse antigen-binding region to a human immunoglobulin backbone. A similar process can produce “caninized” monoclonal antibodies for use in dogs (Chapter 12). These monoclonal antibodies can be directed against the cancer cells to destroy them through the process of antibody-dependent cellular cytotoxicity. Alternatively, monoclonal antibodies may be used to block growth-promoting factors or their receptors or they may enhance the activity of anticancer immune cells. Several caninized monoclonal antibodies directed against lymphomas have undergone clinical trials although with disappointing results to date. Blontress (Aratana Therapeutics), is a caninized monoclonal antiCD20 antibody licensed as an aid in the treatment of dogs with B-cell lymphoma. It enhances antibody-dependent cellular cytotoxicity and promotes macrophage phagocytosis of tumor cells. The antibody is administered intravenously over a period of at least 15 minutes. Two doses on week one, at two to three day intervals, followed by one dose a week for seven weeks. Its use is accompanied by appropriate chemotherapy. Encouraging results in treating canine B cell lymphomas have been obtained by a method that combines administration of anti-CD20 with a blockade of CD47. (CD47 is expressed on tumor cells and acts as a checkpoint regulator by inhibiting their phagocytosis by macrophages.) The antiCD20 kills the tumor cells and the CD47 ensures their removal. US Department of Agriculture (USDA) has approved a DNA-plasmid vaccine directed against CD20 for the treatment of canine B cell lymphomas. Bevacizumab is a humanized monoclonal antibody directed against vascular epithelial growth factor. Vascular endothelial growth factor (VEGF) promotes angiogenesis, blood vessel growth. This monoclonal antibody inhibits the growth of cancers by preventing the development of their blood supply. Preliminary studies suggest that this product may be effective in treating some canine sarcomas. Recent remarkable advances in the treatment of some human cancers have resulted from the use of monoclonal antibodies that prevent signaling by checkpoint molecules (Fig. 23.1). Checkpoint molecules are cell surface receptors that transmit signals, that control immune responses by suppressing T cell proliferation and cytotoxicity. The first of these molecules to be identified was CTLA-4. CTLA-4 is expressed on the surface of naïve and effector T cells. Ligands acting through CTLA-4 deliver suppressive signals to the T cells and prevent their activation. Conversely, if CTLA-4 signaling is blocked, then T cell responses are activated. CTLA-4 blockade in tumor bearing animals therefore results in a significant increase in T-cell mediated tumor cytotoxicity and the development of new antitumor T cells. Studies on humans have shown that administration of a monoclonal antibody against CTLA-4 (Ipilimumab) results in a significant increase in T cell antitumor activity and dramatic remissions in many (but not all) patients.
Anticancer vaccines
Preventative vaccines
Passive immunization
Monoclonal antibodies
Checkpoint inhibition
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