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Therapeutic and Prophylactic Cancer Vaccines 57 also examine the possible criteria that contributed to the success of Gardasil TM and consider some of these ideas in the development of therapeutic cancer vaccines. ALLOGENEIC VACCINES There is growing evidence that a variety of cancers can be clinically treated by vaccines. This was seen in two randomized phase 3 studies where an autologous tumor-cell-vaccine approach as an adjuvant for the treatment of colorectal and renal cancers provided clinical benefit (7,8). Several vaccine strategies (DC/peptide or RNA, protein or DNA) have employed a single-antigen approach in which either an overexpressed or uniquely expressed tumor antigen or epitope that is identified on tumor tissue is targeted. The limitation of this approach lies in both the chosen antigen as well as the major histocompatibility complex type of the patient (in the case of peptide immunization). Polyvalent tumor vaccines that are allogeneic or autologous should, at least in theory, overcome these limitations. Tumor cells as polyvalent vaccines have been attractive as they are the richest source of antigens. With a wide array of potential tumor antigens (some or possibly most of them unknown), they could potentially activate and amplify every facet of the immune system for both cellular and humoral antitumor responses. These cell lines can be manipulated in vitro, such as addition of cytokine genes to enhance potential antitumor effect (9). In addition (as with whole tumor-cell vaccines), professional antigen-presenting cells (APCs) such as DCs may phagocytize apoptotic tumor cells from the vaccine and effectively cross-prime T cells with a host of immunogenic epitopes (10). Added to its therapeutic appeal is the idea that allogeneic vaccines share a manufacturing advantage. Allogeneic cell lines for use as whole cells, lysates, or genetic manipulations can be initially difficult to establish in vitro and they require antigenic consistency and proof of stability. However, once established, this approach provides unlimited material for vaccination by overcoming the requirement for tumor tissue and/or leukapheresis from the patient (as for some autologous vaccines) and consequently the delay in preparation of vaccine. They can be consistently manufactured in large lots that can be used to treat multiple patients and be fully tested before release. Whole tumor cells, lysates, and genetically modified tumors have been tried as allogeneic vaccines in clinical trials. Allogeneic Whole Tumor Cells Some of the earliest attempts at inducing an antitumor response were in melanoma, where intact allogeneic cell lines were used as a vaccine (11). Canvaxin TM is a whole, multicell polyvalent vaccine consisting of a mixture of three sublethally irradiated allogeneic melanoma lines that are of different HLA haplotypes
58 Srinivasan expressing various known tumor antigens (12). Canvaxin TM has the potential benefit of viable but nonreplicating cells so that they may continue to express and present antigen. Tumor-cell profiling by flow cytometry indicated the expression of gangliosides, tyrosinase, TRP-1/gp75, Melan-A, and gp100. The assurance that irradiation of the final product is effective and that cells have been rendered replication-incompetent is of critical importance for allogeneic tumor whole-cell vaccines. This was achieved at irradiation doses at which the cell could not replicate while maintaining antigenic integrity. Canvaxin TM was extensively tested in phase 1 and 2 clinical trials with the results indicating a statistically significant increase in median and five-year survival of stage III and IV surgically resected patients with melanoma when compared with matched historical controls (13,14). The promising clinical benefit was correlated with vaccine-induced immune responses (11,15–18). Early phase 2 nonrandomized clinical trial results indicated a strong cellular delayed type hypersensitivity (DTH) along with high anti-TA99 IgM and anti- GD2, -GD3, -GM2, and -GM3 ganglioside IgM titers in patients with resected melanoma (19). Serum complement–dependent cytotoxicity for melanoma cell lines in vitro also increased over baseline levels when patients were administered this polyvalent vaccine (15). Canvaxin TM was tested in a postsurgical adjuvant setting in large double-blinded, randomized phase 3 trials for AJCC stage III and IV melanoma (20,21). The trials compared patients vaccinated with either Canvaxin TM or placebo, with both arms having received BCG with the first two doses. All patients were observed for overall survival (OS) and disease-free survival (DFS). In spite of encouraging immune responses to Canvaxin TM in early studies, both trials were discontinued because the independent Data and Safety Monitoring Board found that the data were unlikely to provide significant evidence of an OS benefit for these melanoma patients treated with Canvaxin TM , when compared with those on the control arm (6,22,23). The control arm in these pivotal trials, which included BCG without the allogeneic cell component of the vaccine, did better than expected. The vaccinated patients in phase 1 and 2 trials were compared to matched historical controls that did not receive BCG. Autologous tumor vaccines, with BCG as a component, have been shown to be effective in randomized trials for stage II and III colon carcinoma (7,24,25). While the importance of randomized phase 2 trials is becoming increasingly recognized and implemented, it is perhaps crucial when immune adjuvants form a component of the vaccine regimen. Allogeneic Tumor-Cell Lysate These vaccines are conceptually similar to whole-cell vaccines, except that protein and other cellular components from the lysate serve as the immunogens. Melacine 1 is a mechanically disrupted cell lysate from 20 10 6 tumorcell equivalents of two allogeneic melanoma lines given with a proprietary
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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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Factoring in Antigen Processing in
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Factoring in Antigen Processing in
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108 Luptrawan et al. 66. Dunn GP, B
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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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Figure 8.5 A schematic representati
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8 Bidirectional Bedside Lab Bench P
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Development of Novel Immunotherapeu
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Diagnostic Approaches to Maximize T
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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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214 Index [Peptide vaccines] invest
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216 Index TCRL. See TCR-like immuno
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Oncology and Immunology about the b
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