Development of novel antitumor immunogenetherapy using artificial cancer antigen-secreting tumors.

• Project/Area Number: 15590353
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Sapporo Medical University
• Principal Investigator: TAMURA Yasuaki Sapporo Medical University, School of Medicine, Assistant Professor, 医学部, 講師 (80322329)
• Co-Investigator(Kenkyū-buntansha): ATO Noriyuki Sapporo Medical University, School of Medicine, Professor, 医学部, 教授 (50158937)
• Project Period (FY): 2003 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥3,300,000 (Direct Cost: ¥3,300,000); Fiscal Year 2004: ¥1,400,000 (Direct Cost: ¥1,400,000); Fiscal Year 2003: ¥1,900,000 (Direct Cost: ¥1,900,000)
• Keywords: Survivin / tumor antigen / cytotoxic T cell / Heat shock protein / HLA-A24 / 癌免疫療法 / 細胞傷害性リンパ球 / 樹状細胞

Research Abstract

By this Grant-in-Aid for Scientific Research, we have examined the ability of secretary form of Survivin-Fc chimera protein for induction of Survivin- specific CTL.
1. We have demonstrated that Survivin, inhibitor of apoptosis, is the tumor antigen and CD8+ T cells recognize the Survivin- derived peptide and HLA-A24 MHC class I complex.
2. First, we have made the gene encoding Survivin fused with adeno E3-derived signal sequence and Fe portion of IgG. K562 cells were transfected with this gene and established couple of stable clones (ssSVN-K562).
3. Quantity of secreted Survivin protein in the culture supernatant was measured. Less thanlong/ml of Survivin protein was detected.
4. CD8+ T cells from HLA-A24-positive, tumor-bearing patients were cocultured with autologous dendritic cells and ssSVN-K562. However, Survivin-specific CTLs were unable to induce. We reasoned that such a low amount of secreted Survivin could not stimulate CTLs.
5. Next, we have established the tumor cell clones (CT-26 and EG.7), which were transfected with Hsp72 or Hsc73 gene fused with adeno E3-derived signal sequence. It is well established that Hsp72 and Hsc73 bind broad array of tumor antigen peptide within the cells. Tumor challenge assay revealed that these clones become immunogenic and some tumor clones were rejected spontaneously. Furthermore, immunization with these clones elicits powerful CTL responses against parental tumor lines. In addition, treatment with irradiated Hsp secreting tumor for established tumors revealed the growth retardation of tumors and showed the survival benefits (manuscript in submitting). We also demonstrated that secretary form of Hsp72 and Hsc 73 binds an antigenic peptide, such as Ova-derived peptide.
6. These data suggest that transfection with secretary form of Hsp72 or Hsc73 gene to tumor cells might bea promising immunogenetherapy.

Research Products

• [Journal Article] Aberrant expression and potency as a cancer immunotherapy target of IAP family, Livin/ML-IAP in Lung Cancer. (2005)
  • Author(s): Hariu, H.
  • Journal Title: Clin.Cancer Res. 11 Pages: 1000-1009
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] A potent immunogenic general cancer vaccine that targets survivin, an inhibitor of apoptosis proteins. (2005)
  • Author(s): Idenoue, S.
  • Journal Title: Clin Cancer Res. 11 Pages: 1474-1482
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Aberrant expression and potency as a cancer immunotherapy target of IAP family, Livin/ML-IAP in Lung Cancer (2005)
  • Author(s): Harlu, H., Hirohashi, Y., Torigoe, T., Tamura, Y., Aketa, K., Kitamura, H., Idenoue, S., Hariu, M., Kamiguchi, K., Mano, Y., Kanaseki, T., Tsukahara, T., Shijubo, N., Sato, N.
  • Journal Title: Clin. Cancer Res. 11 Pages: 1000-1009
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] A potent immunogenic general cancer vaccine that targets survivin, an inhibitor of apoptosis proteins (2005)
  • Author(s): Idenoue, S., Hirohashi, Y., Torigoe, T., Sato, Y., Tamura, Y., Hariu, H., Yamamoto, M., Kurotaki, T., Tsuruma, T., Asanuma, H., Kanaseki, T., Ikeda, H., Kashiwagi, K., Okazaki, M., Sasaki, K., Sato, T., Ohmura, T., Hata, F., Yamaguchi, K., Hirata, K., Sato, N.
  • Journal Title: Clin. Cancer Res. 11 Pages: 1474-82
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Phase I clinical study of anti-apoptosis protein, survivin-derived peptide vaccine therapy for patients with advanced or recurrent colorectal cancer. (2004)
  • Author(s): Tsuruma, T.
  • Journal Title: J.Translational Med. 2 Pages: 19-29
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Tumor-derived heat shock protein70-pulsed dendritic cells elicit tumor-specific cytotoxic T lymphocytes (CTLs) and tumor immunity. (2004)
  • Author(s): Ueda, G.
  • Journal Title: Cancer Science 95 Pages: 248-253
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Phase I clinical study of anti-apoptosis protein, survivin-derived peptide vaccine therapy for patients with advanced or recurrent colorectal cancer (2004)
  • Author(s): Tsuruma, T., Hata, F., Torigoe, T., Furuhata, T., Idenoue, S., Kurotaki, T., Yamamoto, M., Yagihashi, A., Ohmura, T., Yamaguchi, K., Katsuramaki, T., Yasoshima, T., Sasaki, K., Mizushima, Y., Minamida, H., Kimura, H., Akiyama, M., Hirohashi, Y., Asanuma, H., Tamura, Y., Shimozawa, K., Sato, N., Hirata, K.
  • Journal Title: J. Translational Med. 2 Pages: 19-29
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Tumor-derived heat shock protein70-pulsed dendritic cells elicit tumor-specific cytotoxic T lymphocytes (CTLs) and tumor immunity (2004)
  • Author(s): Ueda, G., Tamura, Y., Hirai, I., Kamigichi, K., Ichimiya, S., Torigoe, T., Hiratsuka, H., Sunakawa, H., Sato, N.
  • Journal Title: Cancer Sci. 95 Pages: 248-253
  • NAID: 10013721926
  • Description: 「研究成果報告書概要(欧文)」より
• [Book] Annual Review免疫2005;熱ショック蛋白質(HSP)-ペプチド複合体による新しいMHCクラスI抗原提示経路 (2004)
  • Author(s): 田村保明
  • Total Pages: 8
  • Publisher: 中外医学社
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Ueda, G., Tamura, Y.et al.: "Tumor-derived Heat Shock Protein70-pulsed Dendritic Cells Elicit Tumor-specific Cytotoxic T Lymphocytes (CTLs) and Tumor Immunity."Cancer Science. 95. 248-253 (2004)
• [Publications] Tamura, Y., Sato, N.: "Heat Shock Proteins : Chaperoning of innate and adaptive immunities."Jpn.J.Hyperthermic Oncol.. 19. 131-138 (2003)
• [Publications] Kojima, T., Tamura, Y., et al.: "Granulocyte-macrophage colony-stimulating factor gene-transduced tumor cells combined with tumor-derived gp96 inhibit tumor growth in mice."Hum.Gene Ther.. 14. 715-728 (2003)
• [Publications] Kashiwagi, K., Tamura, Y., et al.: "Analysis of a Shared Pancreatic Cancer Antigen Recognized by an HLA-A^*2601-Restricted Cytotoxic T-Lymphocyte Clone."Pancreas. 26. E81-E88 (2003)
• [Publications] 田村 保明: "免疫2004 HSPによる自然免疫-獲得免疫のリンクと癌ワクチン"中外医学社. 9 (2004)