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Preclinical Models and Clinical Situation 33 Studies showing that large numbers of tumor-specific T cells isolated from a tumor immune donor can induce tumor regression upon adoptive transfer to a tumorbearing syngeneic recipient, highlight this kinetics problem, and offer a potential solution, although a particularly daunting one in practice (3–5). One might consider turning to more recently developed models of spontaneous tumors in rodents where the latency period between the transforming events and the lethal tumor-bearing state is relatively long and thus provides a more realistic window for immune activation. Unfortunately, these models are not amenable to treatment with personalized vaccines that are produced from each individual host’s tumor for at least two reasons. The first is practical. One must wait for a large enough primary tumor mass and/or metastases to develop such that sufficient tissue can be harvested for vaccine production. This assumes surgery can be performed on individual mice, that mice survive surgery on potentially multiple anatomical sites, that the window for immune activation after surgery and prior to death due to tumor recurrence will be wide enough, and that surgery can be performed on sufficient numbers of individual mice to run studies that stand up to statistical scrutiny. Second, the models where mice develop spontaneous tumors driven by viral oncogenes like SV40 T antigen under a tissue-specific promoter (e.g., RIP-TAg model) are complicated by the expression of the dominant viral protein in the tumor itself. This expression would likely mask or make irrelevant any immune response to individualized antigens and does not reflect the antigen profile of most tumors in humans where viral proteins are not a component of the proteome (6). This second issue may be less of a concern with other transgenic models where mammalian oncogenes are manipulated to drive transformation or where tumor suppressor genes are deleted (7,8). However, the practical reasons related to surgery on individual mice apply to these models as well. In conclusion, models of spontaneous tumor formation are really only useful for testing off-the-shelf, shared antigen vaccines. Various approaches to immunotherapy in preclinical models are discussed below, and details of studies comparing the relative efficacy in the early-stage/ minimal residual disease setting versus more advanced setting are provided in Table 1. Tumor-Derived Heat Shock Protein-Peptide Complexes Heat shock proteins (HSPs) are a group of proteins found in all cells in all life forms. They function as chaperones, helping proteins fold while also transporting them throughout the cell. In their chaperone function, they bind with a large repertoire of proteins and peptides. Recent studies demonstrate an essential role of HSPs (complexed with antigenic peptides) in the priming of immune response by cells undergoing necrotic death (22). Tumor-derived complexes of HSPs and their associated peptides have been tested extensively in animal models of cancer. The published literature indicates that HSPPCs are active against established disease in nine tumor models tested,
34 Levey Table 1 Examples of Preclinical Activity in Rodents Treated with Autologous Cancer Vaccines: Effect of Tumor Burden on Outcome Cancer type Vaccine type Efficacy Disease settings Early: treatment started 5 days after tumor challenge Advanced: treatment started 9 days after tumor Fibrosarcoma HSPPC-96 100% complete tumor rejection (cure) in early setting vs. 0% cure in advanced disease setting (9) challenge Early: treatment started 5 days after surgical resection of primary tumor Advanced: treatment started 9 days after surgical resection of primary tumor Early: treatment started 3 days after tumor challenge Advanced: treatment started 10 days after tumor challenge Early: treatment started 3 days after tumor challenge Advanced: treatment started 7 days after tumor challenge Early: treatment started 1 day after tumor challenge Advanced: treatment started 7 days after tumor challenge Early: treatment started 6 days after tumor challenge Moderately advanced: treatment started 10 days after tumor challenge Advanced: treatment started 14 days after tumor challenge Lung HSPPC-96 100% of mice alive at day 33 in vaccine group in early setting compared with 4% in control group (P < .04) vs. 60% survival in advanced disease (9) 36% prolongation of mean survival time (MST) over control treatment (P ¼ .0012) in early setting vs. no difference in MST in advanced disease (10) 40% of mice alive at day 60 (end of study) in vaccine group in early setting compared with 0% in control group (P < .04) vs. no difference in survival in advanced disease (11) 100% of mice alive at day 100 (end of study) in early setting compared with 0% in control group vs. 0% alive in advanced disease (12) Glioma GM-CSF–transduced tumor cells Melanoma GM-CSF–transduced tumor cells Leukemia GM-CSF–transduced tumor cells 80% complete tumor rejection (cure) in early setting vs. 43% cure in moderately advanced disease setting and 14% cure in advanced disease setting (13) Mastocytoma IL-12–transduced tumor cells
Page 1 and 2: Translational Medicine Series 6 Can
Page 3 and 4: TRANSLATIONAL MEDICINE SERIES 1. Pr
Page 5 and 6: Informa Healthcare USA, Inc. 52 Van
Page 8 and 9: Preface Throughout the last 20 year
Page 10 and 11: Preface vii Table 1 A Diverse Techn
Page 12 and 13: Preface . . . . v Contributors . .
Page 14 and 15: Contributors Pedro Alves Ludwig Ins
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84 Luptrawan et al. Dendritic cells
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86 Luptrawan et al. of cancer cells
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88 Luptrawan et al. NK cells can ki
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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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9 Diagnostic Approaches for Selecti
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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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