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Peptide-Based Active Immunotherapy in Cancer 121 were emulsified with IFA and administered with SD-9427 (progenipoietin)—an agonist of granulocyte colony-stimulating factor and the FLT-3 receptor (80). This study found that the SD-9427 combined with a multipeptide vaccine was generally well tolerated, and that the majority of patients with resected melanoma mounted an antigen-specific immune response against the multipeptide vaccine. Butterfield et al. studied the induction of T-cell responses to HLA- A*0201 immunodominant peptides derived from alpha-fetoprotein (AFP) in patients with hepatocellular cancer (81). In this study the authors tested the immunologic paradigm that high concentrations of soluble protein contribute to the maintenance of peripheral tolerance/ignorance to self-protein. They confirmed that the patients’ T-cell repertoire was capable of recognizing AFP in the context of MHC class I even in an environment of high circulating levels of this oncofetal protein. Our group identified two HLA-A2-restricted peptides derived from hTRT, and induced hTRT-specific CTL in vitro (19). More important, we also demonstrated that the hTRT-specific CTL lysed a variety of HLA-A2positive cancer cell lines, but not HLA-A2-negative cancer cell lines. All of these cancer cell lines were hTRT positive as determined by the TRAPeze assay (Intergen). A phase I clinical trial was performed by Vonderheide et al. to evaluate the clinical and immunologic impact of vaccinating advanced cancer patients with the HLA-A2-restricted hTRT I540 peptide presented with keyholelimpethemocyaninbyexvivogeneratedautologousdendriticcells(82).It was found that hTRT-specific T lymphocytes were induced in four of seven patients with advanced breast or prostate carcinoma after vaccination with dendritic cells pulsed with hTRT peptide. It is important to note that no significant toxicity was observed despite concerns of telomerase activity in rare normal cells. These results demonstrated the immunologic feasibility of vaccinating patients against telomerase and provided rationale for targeting selfantigens with critical roles in oncogenesis. An interesting study utilized the flt3 ligand as a systemic vaccine adjuvant with the E75 HLA-A2 epitope from HER-2/neu (83). Twenty patients with advanced-stage prostate cancer were enrolled in this study. Dendritic cells were markedly increased in the peripheral blood of subjects receiving flt3 ligand with each repetitive cycle, but augmentation of antigen-presenting cells within the dermis was not observed. No significant peptide-specific T-cell responses were detected. The authors concluded that the inability of fit3 ligand to augment the number of peripheral skin antigen-presenting cells may have contributed to the absence of robust peptidespecific immunity detectable in the peripheral blood of immunized subjects treated with flt3 ligand. Recently, Hueman et al. performed clinical trials in breast cancer patients to test the HER2/neu peptide vaccine (E75) (84,85). Blood samples from 22 healthy individuals and 22 patients, including pre- and post-vaccination samples from seven vaccinated HLA-A2þ patients, were obtained. Vaccination with E75 resulted in CD4þ T cell recruitment and was associated with a significant decrease in circulating regulatory T cells and TGF-beta levels in the majority of the vaccinated patients. These results
122 Schroter and Minev illustrate that successful cancer vaccination strategies may require the modification of complex immune interactions. CONSIDERATIONS ON PEPTIDE VACCINE DESIGN AND APPLICATION A difficulty with the use of peptide vaccines is the fact that the T-cell responses usually do not last long enough to have a significant effect on the tumor. To address this issue, Davila et al. examined the role of synthetic oligodeoxynucleotide (ODN) adjuvants containing unmethylated cytosine-guanine motifs (CpG-ODN) and CTLA-4 blockade in enhancing the antitumor effectiveness of peptide vaccines intended to elicit CTL responses (86). This study found that combination immunotherapy consisting of vaccination with a synthetic peptide corresponding to an immunodominant CTL epitope derived from tyrosinaserelated protein-2 administered with CpG-ODN adjuvant and followed by systemic injection of anti-CTLA-4 antibodies increased the survival of mice against the poorly immunogenic B16 melanoma. These findings suggest that peptide vaccination applied in combination with a strong adjuvant and CTLA-4 blockade is capable of eliciting durable antitumor T-cell responses that provide survival benefit. These findings bear clinical significance for the design of peptide-based therapeutic vaccines for cancer patients. From a clinical perspective, immunization with peptides may be preferable to immunization with recombinant vaccinia viruses because of its safety and because it is not associated with diminished immune responses in patients immunized against smallpox. Immunizing with minimal determinant constructs may avoid the possible oncogenic effect of full-length proteins containing ras, p53, or other potential oncogenes. In addition to their safety, peptide vaccines can be designed to induce well-defined immune responses and synthesized in large quantities with very high purity and reproducibility. Another potential advantage of peptide vaccines over whole proteins or DNA vaccines is the ability to identify the specific epitopes of the tumor antigens to which an individual is able to mount an immune response, but not a state of immune tolerance (87). In addition, in vivo or in vitro immunization with peptide antigens “packaged” in dendritic cells or other antigen-presenting cells (discussed below) opens an exciting opportunity for eliciting powerful CTL responses. A disadvantage of peptide vaccines is their poor immunogenicity and monospecificity of the induced immune response. Another limiting factor for the use of peptide vaccines in outbred populations is that T cells from individuals expressing different MHC molecules recognize different peptides from tumor or viral antigens in the context of self-MHC. However, the use of synthetic peptides from TAA that are presented by common MHC molecules may overcome this problem. Poor immunogenicity caused by rapid degradation of the peptides by serum peptidases may be corrected by modifications or incorporation of the peptides into controlled release formulations. Overall, personalized peptide vaccines may serve as an efficient therapeutic modality for cancer (88).
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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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2 Outlining the Gap Between Preclin
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Preclinical Models and Clinical Sit
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Table 1 Examples of Preclinical Act
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56 Srinivasan disease agents. Garda
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58 Srinivasan expressing various kn
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60 Srinivasan The above-mentioned a
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62 Srinivasan (69). In another stud
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64 Srinivasan patients with prostat
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66 Srinivasan 33. Salgia R, Lynch T
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68 Srinivasan 67. Werness BA, Levin
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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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