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      Universal cancer peptide-based therapeutic vaccine breaks tolerance against telomerase and eradicates established tumor.

      Clinical cancer research : an official journal of the American Association for Cancer Research
      Animals, CD4-Positive T-Lymphocytes, immunology, physiology, CD8-Positive T-Lymphocytes, Cancer Vaccines, Cell Line, Tumor, Cell Proliferation, Cytotoxicity, Immunologic, Dendritic Cells, Humans, Melanoma, Experimental, therapy, Mice, Mice, Transgenic, Peptide Fragments, T-Lymphocytes, T-Lymphocytes, Cytotoxic, Telomerase, Th1 Cells, Xenograft Model Antitumor Assays

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          Abstract

          To evaluate CD4(+) helper functions and antitumor effect of promiscuous universal cancer peptides (UCP) derived from telomerase reverse transcriptase (TERT). To evaluate the widespread immunogenicity of UCPs in humans, spontaneous T-cell responses against UCPs were measured in various types of cancers using T-cell proliferation and ELISPOT assays. The humanized HLA-DRB1*0101/HLA-A*0201 transgenic mice were used to study the CD4(+) helper effects of UCPs on antitumor CTL responses. UCP-based antitumor therapeutic vaccine was evaluated using HLA-A*0201-positive B16 melanoma that express TERT. The presence of a high number of UCP-specific CD4(+) T cells was found in the blood of patients with various types of cancer. These UCP-specific T cells mainly produce IFN-γ and TNF-α. In HLA transgenic mice, UCP vaccinations induced high avidity CD4(+) T(H)1 cells and activated dendritic cells that produced interleukin-12. UCP-based vaccination breaks self-tolerance against TERT and enhances primary and memory CTL responses. Furthermore, the use of UCP strongly improves the efficacy of therapeutic vaccination against established B16-HLA-A*0201 melanoma and promotes tumor infiltration by TERT-specific CD8(+) T cells. Our results showed that UCP-based vaccinations strongly stimulate antitumor immune responses and could be used to design efficient immunotherapies in multiple types of cancers. ©2012 AACR.

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