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3 Therapeutic and Prophylactic Cancer Vaccines: Emerging Perspectives from Allogeneic and Infectious Disease Vaccines Roopa Srinivasan Agni Consulting Services, San Marcos, California, U.S.A. INTRODUCTION Cancer remains a major cause of death worldwide despite multiple approaches to therapy and prevention. Nonsurgical methods of treatment include chemotherapy and/or radiotherapy that target rapidly dividing cells. Of the more recently developed treatment modalities for cancer are biological therapies such as hormonal and antibody therapeutics, and vaccines. The past two decades have seen the science of tumor immunology evolve into a distinct discipline forming the basis of cancer vaccines. Of particular relevance to the development of tumor vaccines has been the presence of immunity to tumor antigens. This is of significance, given that tumor antigens arise from self-tissue. However, the challenge of breaking through host immune tolerance to effectively mount a robust antitumor response still remains. The immune system has evolved to combat parasites, bacteria, and viruses based on recognition of foreign antigens on these pathogens. Consequently, vaccines have been effective in the induction of protective immunity to infectious 55
56 Srinivasan disease agents. Gardasil TM (Merck & Co., Inc., New Jersey, U.S.A.), the first cancer vaccine approved by the FDA, is a prophylactic vaccine against cervical cancer in young women (1). The vaccine is a quadrivalent virus–like particle (VLP) vaccine and offers protection by generating neutralizing antibodies against the human papillomavirus (HPV). This vaccine does not protect women who are already infected with the papilloma virus and who may consequently develop cervical cancer. While traditionally the immune system has evolved to protect the host from invading pathogens, it is also believed to be triggered when it perceives a “danger” signal by the host’s self-tissue (2). In cancer, such signals may be associated with the existence of tumor immunity as seen with clinical examples of spontaneous regressions in melanoma, gastrointestinal, lung, and breast cancers (3). In addition, histopathology of tumor sections has revealed infiltrating lymphocytes around the tumor bed, and recent studies indicate that ovarian cancer patients with such infiltrates in tumors have an improved prognosis compared with similarly staged patients without lymphocytic infiltrates (4). Therefore, the immune repertoire may contain autoreactive immune cells capable of rejecting tumors, when activated appropriately. However, in spite of clear animal model data demonstrating the potential therapeutic benefit of cancer vaccines, with the exception of those for viral-mediated cancers, therapeutic tumor vaccines have had only limited success in humans. More recent studies are looking at enhancing tumor-specific responses using immune modulators in an attempt to translate them to effective tumor protection. Different types of cancer vaccines have induced tumor immunity and a correlative antitumor response in syngeneic mouse tumor models, leading to their efficacy testing in human. Most noteworthy examples of therapeutic cancer vaccines that are in various stages of development are plasmid or viral-vector DNA, dendritic cells (DCs) pulsed with peptide or RNA, allogeneic whole tumor cells, allogeneic tumor-cell lysate, cytokine-transduced tumor cells, heat shock proteins, and autologous T-cell therapy (5,6). Among the prophylactic vaccines, the one that was recently approved is Gardasil TM for the prevention of cervical cancer; precancerous genital lesions; and genital warts due to HPV) types 6, 11, 16, and 18 in young women (1). Allogeneic tumor vaccines as potential form of a therapeutic vaccine were tested in large randomized phase 3 trials. The two allogeneic tumor-cell vaccines that were tested in phase 3 trials for melanoma were Melacine 1 (Corixa Corporation Washington, U.S.A./GlaxoSmithKline, England, UK) and Canvaxin TM (CancerVax Corporation, California, U.S.A./Micromet, Inc., Maryland, U.S.A.). Both vaccines had showed efficacy in the early stages of clinical development. However, pivotal trials did not indicate a clinical benefit and the trials were discontinued. <strong>Ph</strong>ase 3 trials with GVAX 1 (Cell Genesys, California, U.S.A.) are ongoing for the treatment of prostate cancer. In this chapter, we will discuss the potential that some of the allogeneic tumor vaccines have offered and the reasons for their failure in becoming a successful therapeutic agent. We will
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Translational Medicine Series 6 Can
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TRANSLATIONAL MEDICINE SERIES 1. Pr
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Informa Healthcare USA, Inc. 52 Van
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Preface Throughout the last 20 year
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Preface vii Table 1 A Diverse Techn
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Preface . . . . v Contributors . .
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Contributors Pedro Alves Ludwig Ins
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1 Factoring in Antigen Processing i
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110 Schroter and Minev proteins (2,
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7 Multimodality Immunization Approa
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Multimodality Immunization Approach
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8 Bidirectional Bedside Lab Bench P
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Development of Novel Immunotherapeu
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206 Index Antigenic peptides degrad
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208 Index Chromogens, enzymatic act
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210 Index Freund’s adjuvants. See
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212 Index Langerhans cells, 133, 13
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Oncology and Immunology about the b
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