Clinical trials using various immunotherapies, active immunization with tumor antigens, or tumor cell-derived products, and adoptive immunotherapy using antitumor immune cells were conducted in various cancers, most extensively in melanoma, and tumor regression was observed in some patients. Active Immunization Immunizations with synthetic peptides, particularly MHC class I-binding epitopes, were performed in various trials. Since native epitopes have relatively low immunogenicity, various immunoaugmenting methods, including coadministration of adjuvants and cytokines [incomplete Freund adjuvant (IFA), IL-2, IL-12, or GM-CSF], were applied to achieve efficient immunization. Tumor regression in melanoma patients was observed in various clinical trials using melanocytespecific antigens such as MART-1 and gp100 and, in particular, the HLA high-binding modified peptide. Since CD4+ T cells appear to be directly and indirectly important in tumor rejection, combined immunization with both Th and CTL antigens is being attempted. Immunization with proteins containing multiple Th and CTL epitopes may be effective, although production of recombinant GMP-grade proteins is costly, and modifications such as particle formation may be required for effective presentation of MHC class I-restricted epitopes. To facilitate peptide immunization in melanoma, coadministration of the anti-CTLA4 antibody, which blocks regulatory T cells and negative feedback regulation of T-cell activation, was carried out. Although tumor regression along with autoimmune reactions was observed, augmentation of the immune response to the administered peptides was not observed in peripheral blood.24 In pancreatic cancer, intradermal immunization with the mutated K-ras peptides and GM-CSF resulted in the induction of a memory CD4+ T-cell response and prolonged survival, compared with nonresponders.15 Immunization with the MUC1 peptide and BCG resulted in augmented immune responses without tumor regression.22 Immunization with recombinant viruses or plasmids containing tumor antigen cDNA (DNA immunization) rather than peptide/proteins may be applied. In melanoma clinical trials, a generation of neutralizing antibodies against viral proteins appeared to interfere with the induction of immune response to tumor antigens following immunization with recombinant adenovirus and vaccinia virus.25 However, recent protocols using a recombinant fowlpox virus containing the modified gp100 cDNA or the ER signal sequence-conjugated gp100-epitope minimal gene demonstrated frequent induction of tumor reactive T cells.26 Interestingly, tumor regression was observed in patients after subsequent administration of IL-2.
Intramuscular immunization with the recombinant gp100 plasmids appeared to be insufficient to induce an antitumor T-cell response.27 DC are the most potent professional APC that can process antigens for both MHC class I and II pathways and activate both naive CD4+ T cells and CD8+T cells in vivo. In murine studies, immunization with DC pulsed with tumor antigens resulted in better antitumor effects than direct peptide administration. In immunization trials using DC pulsed with tumor lysates or synthetic peptides, tumor regression was observed in patients with various cancers, including melanoma, prostate cancer, colon cancer, and B-cell lymphoma.28 Although most clinical trials have used monocyte-derived DC, peripheral blood DC as well as CD34+ cell-derived DC have been used in some protocols.29 Antigen loading on DC using various antigens including RNA, cDNA, recombinant virusand cell-penetrating peptide conjugated proteins has also been exploited. DC fused with tumor cells and leukemia clone- derived DC have also been used in clinical trials. K-ras- specific T cells were detected in pancreatic cancer patients following multiple intravenous infusions of peptide-pulsed antigen presenting mononuclear cells obtained by leukapheresis, although no therapeutic effect in patients was observed. In addition, no tumor regression was observed following immunization with DC transfected with MUC1 cDNA. A decrease in tumor marker was observed in a patient with a pancreatic neuroendocrine tumor, following immunization with DC pulsed with autologous tumor lysates. Intratumoral administration of immature DC following intraoperative irradiation is currently being conducted in Japan. Thus far, any antitumor effects observed in these DC-based clinical trials for pancreatic cancer are weak. Protocols for the optimal use of DC in immunotherapy, including the source of DC, kinds of tumor antigens, methods for maturation and antigen loading, site and schedule for administration, remain to be determined. Based on murine experiments, immunization with more immunogenic tumor cells that are modified using various techniques, including hapten conjugation, foreign antigen introduction, and transfection with various genes such as cytokines (eg, GM-CSF, IL-2, TNF-_, IFN-_, IL-4) have been employed in melanoma, prostate cancer, and lung cancer. Strong antitumor effects, however, were not observed in the reported clinical trials. In pancreatic cancer, vaccination with GM-CSF transduced allogeneic pancreatic cancer cell lines along with adjuvant radiation and chemotherapy following surgical excision demonstrated possible benefit in disease-free survival, which appeared to be associated with the increase of postvaccination DTH responses against autologous tumor cells.
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