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Preclinical Models and Clinical Situation 37 including fibrosarcoma, leukemia, melanoma, and lung, colon, prostate, and breast cancers (9,23–28). Across these studies, HSPs have been shown to significantly slow tumor growth, elicit complete tumor regression, and/or prolong survival. Cytokine-Secreting Tumor Cells Tumor cells that have been modified to produce cytokines such as interleukin 2 (IL-2), IL-6, IL-12, interferon g (IFN-g), macrophage colony-stimulating factor (M-CSF), and granulocyte-macrophage colony-stimulating factor (GM-CSF) have been evaluated as vaccine preparations in models of established disease. Two related types of cancer cells—3LL Lewis and D122 lung cancer cells— have been widely utilized in these studies. At least 10 studies testing autologous, cytokine-producing 3LL or D122 cells in therapy have demonstrated significant benefit (29–38). Other published rodent models in which autologous, cytokineproducing tumor cells have demonstrated significant antitumor activity in therapeutic settings include models of melanoma, sarcoma, glioma, lymphoma, leukemia, squamous cell carcinoma, mastocytoma, mesothelioma, and prostate, breast, kidney, colon, bladder, and pancreatic cancers (10–15,39–51). B7-Expressing Tumor Cells Proper activation of the immune system requires not only presentation of antigens on the surface of antigen-presenting cells but also expression of the B7 family of costimulatory proteins. Therefore, one strategy in cancer vaccine development is the modification of tumor cells to express B7 in order to make the tumor cells more immunogenic. This vaccine strategy often includes cytokine treatment as well to further enhance immunogenicity. In animal studies of this approach, complete regression of established tumors and/or prolongation of survival have been demonstrated in models of myeloma, hepatoma, glioma, fibrosarcoma, lymphoma, mesothelioma, mastocytoma, melanoma, and breast and colon cancers (16–18,52–58). Tumor Cells Mixed with BCG Another method of autologous immunotherapy involves vaccination with whole tumor cells mixed with the adjuvant BCG, which is designed to enhance immune response to vaccination. A variant of this approach is to first modify the tumor cells with a hapten, followed by mixing the cells with BCG prior to administration. The hapten binds to proteins on the tumor cell, which is believed to further increase the immunogenicity of the vaccine. A number of studies have examined the efficacy of autologous haptenmodified or unmodified tumor cells mixed with BCG in treatment of cancer in rodents. Among the benefits observed in the studies were significant improvements in relapse-free survival and overall survival in models in which the primary
38 Levey tumor is surgically removed. In other models, improvement in overall survival and reduction in the metastatic disease burden in lungs were observed. Animal models included those for breast, liver, and bladder cancers (19,20,59–65). Lymphoma-Derived Immunoglobulin (Idiotype) Idiotype is the unique antigenic portion of the immunoglobulin produced by cancerous B cells, such as those found in lymphomas and myelomas. The idiotype protein itself or the DNA encoding the idiotype have been used as experimental autologous vaccines to generate immune response against the specific cancer from which the protein or DNA were derived. In rodent models of established lymphoma and myeloma, a variety of idiotype vaccine approaches have demonstrated significant survival benefit. Generally, optimal efficacy has been achieved using the specific idiotype protein or encoding DNA in combination with other nonspecific immune modulators (e.g., IL-2, IL-12, GM-CSF, Flt3 ligand) or cyclophosphamide chemotherapy. In some studies, dendritic cells pulsed with the idiotype protein were used to treat mice as a form of cellular immunotherapy (21,66–69). DO THE PRECLINICAL STUDIES PREDICT OUTCOMES IN HUMAN TRIALS? In the clinical setting, a number of studies have tested many of the same personalized vaccine approaches described above in patients with melanoma, colon cancer, non–small cell lung cancer, and lymphoma (Table 2). Among these were two randomized, controlled trials where efficacy findings can be interpreted Table 2 Examples of Clinical Activity in Patients Treated with Autologous Cancer Vaccines: Effect of Tumor Burden on Outcome Treatment Indication Comments Reference HSPPC-96 (Oncophage 1 / Vitespen) Stage IV metastatic melanoma (randomized study) M1a patients in the vaccine arm 70 survived longer than those in the PC arm (626 vs. 383 days, P ¼ .177). Survival was comparable in both arms for M1b patients (297 vs. 320 days, P ¼ .478), and longer in the PC arm for M1c patients (299 vs. 226 days, P ¼ .015). Impact of number of doses was examined using landmark analyses to correct potential biases. Patients who received >10 doses of vaccine survived longer than those who received PC (478 vs. 377 days, P ¼ .072). (Continued)
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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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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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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