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Peptide-Based Active Immunotherapy in Cancer 111 others (11,21). In breast cancer and other adenocarcinomas, a polymorphic epithelial mucin (22) and HER2/neu proto-oncogene (23) have been characterized as tumor antigens. Promising novel approaches for identification of TAA have been developed recently. Applying a combination of techniques, such as “suppression subtractive hybridization” and “transmembrane trapping,” Di Cristina et al. identified a large panel of cDNA fragments encoding a variety of TAA, representing novel tumor-specific targets (24). Furukawa et al. studied the roles of ganglioside GD3 in human malignant melanomas and those of GD2 in small cell lung cancer as modulators of the malignant properties of cancer, suggesting their function as novel targets for cancer therapy (25). Recently, it was found that regulator of G-protein signaling 5 (RGS5) is broadly unregulated in a wide variety of malignant cells and that RGS5-specific CTL lines possess antigenspecific and HLA-restricted cytolytic activity against tumor cells (26). Newly identified TAA-derived peptides also demonstrated a strong potential to be particularly useful in the treatment of hematologic malignancies (27,28). In contrast to class I TAA, little attention has been paid to the identification of class II TAA, mostly because of the difficulties in their identification. However, a growing number of studies confirm the important role of CD4þ Tcellsin controlling tumor growth (29). Several important studies on cancer patients demonstrated the essential role of the CD4þ T cells for optimal CTL induction (30,31). Klyushnenkova et al. were able to successfully stimulate CD4þ T lymphocytes from HLA-DRB1*1501-positive donors, with prostatic acid phosphatase–derived class II–restricted peptides showing their potential as a new target for peptide-based immunotherapy (32). These findings confirm that tumor-specific CD4þ T lymphocytes are required for optimal induction of CTL against the autologous tumors. Therefore, both class I and class II peptides should be used to optimize the therapeutic effect of the peptide-based cancer vaccines. PRECLINICAL AND CLINICAL STUDIES The identification of peptide sequences recognized by CTL has led to attempts to directly induce CTL responses in vivo (33,34). Successful immunization of mice has been accomplished with peptides formulated with immunostimulating complex (35), entrapped in liposomes (36), encapsulated in microspheres (37), and osmotically loaded into syngeneic splenocytes (38) or coated on their surface (39). Effective immune responses were also elicited in mice with a mutant p53 peptide in adjuvant (40), or with either mutant or wild-type p53 peptides loaded on dendritic cells (41). We showed in two murine antigenic systems that fusion peptides with a synthetic ER signal sequence at the NH2-terminus of the minimal peptide were more effective than the minimal peptide alone in generating specific CTL responses (42). Furthermore, we found that the CTL response was MHC class II independent, could not be attributed to increased hydrophobicity of the fusion peptides, and was very effective in prolonging the survival of
112 Schroter and Minev tumor-challenged mice. More recently, we identified two HLA-A2.1-restricted peptides from hTRT and demonstrated that in vivo immunization of HLA-A2.1 transgenic mice generated a specific CTL response against both hTRT peptides (19). Based on the induction of CTL responses in vitro and in vivo, and the susceptibility to lysis of tumor cells of various origins by hTRT-specific CTL, we suggested that hTRT could serve as a universal cancer vaccine. Recently, Adotevi et al. identified CTL epitopes in hTRT restricted by HLA-B*0702 molecule, a common MHC class I allele (43). These new epitopes were found to induce primary human CTL against various hTRT-positive tumor cells. To study the clinical application of hTRT, Brunsvig et al. conducted a phase I/II study in patients will non-small cell lung cancer (NSCLC) (44). The authors investigated the safety, tolerability, and clinical response to vaccination with a combination of telomerase-derived peptides. Twenty-six patients received intradermal (i.d.) administrations of these peptides and granulocyte-macrophage colony-stimulating factor (GM-CSF). It was found that the treatment was well tolerated with minor side effects and the selected peptides are immunogenic and safe to use in patients with NSCLC. Increasing number of studies report peptide vaccination of cancer patients (Table 1). Spontaneous CTL reactivity against the melanoma antigens Melan A/ MART-1, tyrosinase, and gp100 is frequently detected in melanoma patients and healthy individuals (45–47). These findings suggest that CTL responses against “self” antigens are induced spontaneously in patients and healthy individuals and may be boosted by appropriate vaccination. Immunizations with a MAGE-3derived peptide without any adjuvant induced limited tumor regressions in five out of 17 patients with melanoma (48). More recently, the same group used an HLA- A1-restricted MAGE-3 peptide to immunize 39 patients with metastatic melanoma. Of the 25 patients who received the complete treatment, seven displayed significant tumor regressions: three regressions were complete and two led to a disease-free state, which persisted for more than two years after the beginning of treatment (49). Salgaller et al. reported generation of CTL specific for one of three gp100-derived peptides in patients vaccinated with peptide in incomplete Freund’s adjuvant (IFA) (50). Immunization of three patients with advanced melanoma with peptide-pulsed autologous antigen-presenting cells led to induction of peptide-specific CTL (51). The peptide used in this study was derived from MAGE-1 and was restricted to HLA-A1.1. The lack of any therapeutic response observed in this trial might be explained by the advanced stage of the disease in these patients. In another study, nine melanoma patients were vaccinated weekly for four weeks with a combination of peptides derived from MART-1, tyrosinase, and gp100 proteins (52). Successful immunization against peptides could be detected in vitro in two of six patients against the tyrosinase peptide, three of six patients against the MART-1 peptide, and none of six patients receiving the gp100 peptide. More recently, 18 patients with melanoma were immunized with a peptide derived from MART-1, emulsified with IFA (34). An enhancement of cytotoxic activity against MART-1 was detected with minimal toxicity for patients with local irritation at the site of (text continues on page 117)
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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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Preclinical Models and Clinical Sit
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56 Srinivasan disease agents. Garda
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58 Srinivasan expressing various kn
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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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