Development of pancreatic cancer vaccine therapy using genetically modified dendritic cells via ubiquitin-proteasome pathway

2010 Fiscal Year Final Research Report

• Project/Area Number: 20790964
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Digestive surgery
• Research Institution: Wakayama Medical University
• Principal Investigator: OJIMA Toshiyasu Wakayama Medical University, 医学部, 学内助教 (60448785)
• Project Period (FY): 2008 – 2010
• Keywords: 樹状細胞 / 細胞傷害性T細胞 / メソテリン

Research Abstract

Mesothelin (MSLN) is an attractive candidate as a molecular target for pancreatic cancer immunotherapy. The purpose of this study was to demonstrate that cytotoxic T lymphocytes (CTLs) generated from peripheral blood mononuclear cells (PBMCs) by stimulation with genetically-modified dendritic cells (DCs) expressing MSLN could produce specific anti-tumor immunity against pancreatic cancer cells endogenously expressing MSLN. MSLN-specific CTLs induced by in vitro stimulation with DC-AxCAMSLN killed pancreatic cancer cell lines expressing MSLN in an HLA-restricted fashion. These CTLs also showed cytotoxic activity against autologous LCL pulsed with multiple MSLN-derived epitope peptides. In addition, CD8+ T cells, as well as CD4+ T cells, sorted from these CTLs showed significant production of interferon-gannma when stimulated with DC-AxCAMSLN. These results therefore suggest the potential of developing future clinical applications of the vaccines using genetically-modified DCs expressing MSLN.

Research Products

• [Journal Article] Optimal Period for the Prophylactic Administration of Neutrophil Elastase Inhibitor for Patients with Esophageal Cancer Undergoing Esophagectomy. (2011)
  • Author(s): Iwahashi M, Nakamori M, Nakamura M, Ojima T, Naka T, Yamaue H
  • Journal Title: World J Surg 9[Epub ahead of print]
  • Peer Reviewed
• [Journal Article] Dendritic cells adenovirally-transduced with full length mesothelin cDNA elicit mesothelin-specific cytotoxicity against pancreatic cancer cell lines in vitro. (2011)
  • Author(s): Miyazawa M, Iwahashi M, Ojima T, Katsuda M, Nakamura M, Nakamori M, Ueda K, Naka T, Hayata K, Iida T, Yamaue H
  • Journal Title: Cancer Lett 305(1) Pages: 32-39
  • Peer Reviewed
• [Journal Article] Tumor-infiltrating CD4+ Th17 cells produce IL-17 in tumor microenvironment and promote tumor progression in human gastric cancer. (2011)
  • Author(s): Iida T, Iwahashi M, Katsuda M, Ishida K, Nakamori M, Nakamura M, Naka T, Ojima T, Ueda K, Hayata K, Nakamura Y, Yamaue H
  • Journal Title: Oncol Rep 25(5) Pages: 1271-1277
  • Peer Reviewed
• [Journal Article] Vaccination with peptides derived from cancer-testis antigens in combination with CpG-7909 elicits strong specific CD8+ T cell response in patients with metastatic esophageal squamous cell carcinoma. (2010)
  • Author(s): Iwahashi M, Katsuda M, Nakamori M, Nakamura M, Naka T, Ojima T, Iida T, Yamaue H
  • Journal Title: Cancer Sci 101(12) Pages: 2510-2517
  • Peer Reviewed
• [Journal Article] Clinicopathological characteristics of remnant gastric cancer after a distal gastrectomy. (2010)
  • Author(s): Ojima T, Iwahashi M, Nakamori M, Nakamura M, Naka T, Katsuda M, Iida T, Tsuji T, Hayata K, Takifuji K, Yamaue H
  • Journal Title: J Gastrointest Surg 14(2) Pages: 277-281
  • Peer Reviewed
• [Journal Article] Bacillus Calmette-Guerin cell-wall skeleton enhances the killing activity of cytotoxic lymphocyte-activated human dendritic cells transduced with the prostate-specific antigen gene. (2009)
  • Author(s): Fujii R, Iwahashi M, Kikkawa K, Inagaki T, Kohjimoto Y, Ojima T, Mori T, Kuramoto T, Nishizawa S, Azuma I, Yamaue H, Shinka T, Hara I
  • Journal Title: BJU Int 104(11) Pages: 1766-1773
  • Peer Reviewed
• [Journal Article] Optimal dose of preoperative enteral immunonutrition for patients with esophageal cancer. (2009)
  • Author(s): Nakamura M, Iwahashi M, Takifuji K, Nakamori M, Naka T, Ishida K, Ojima T, Iida T, Katsuda M, Hayata K, Yamaue H
  • Journal Title: Surg Today 39(10) Pages: 855-860
  • Peer Reviewed
• [Journal Article] Association of allogeneic blood transfusions and long-term survival of patients with gastric cancer after curative gastrectomy. (2009)
  • Author(s): Ojima T, Iwahashi M, Nakamori M, Nakamura M, Naka T, Katsuda M, Iida T, Hayata K, Yamaue H
  • Journal Title: J Gastrointest Surg 13(10) Pages: 1821-1830
  • Peer Reviewed
• [Journal Article] Evaluation of double tract reconstruction after total gastrectomy in patients with gastric cancer : prospective randomized controlled trial. (2009)
  • Author(s): Iwahashi M, Nakamori M, Nakamura M, Naka T, Ojima T, Iida T, Katsuda M, Ueda K, Yamaue H
  • Journal Title: World J Surg 33(9) Pages: 1882-1888
  • Peer Reviewed
• [Journal Article] Analysis of the prognostic factors and evaluation of surgical treatment for synchronous liver metastases from gastric cancer. (2009)
  • Author(s): Ueda K, Iwahashi M, Nakamori M, Nakamura M, Naka T, Ishida K, Ojima T, Yamaue H
  • Journal Title: Langenbecks Arch Surg 394(4) Pages: 647-653
  • Peer Reviewed
• [Journal Article] Influence of overweight on patients with gastric cancer after undergoing curative gastrectomy : an analysis of 689 consecutive cases managed by a single center. (2009)
  • Author(s): Ojima T, Iwahashi M, Nakamori M, Nakamura M, Naka T, Ishida K, Ueda K, Katsuda M, Iida T, Tsuji T, Yamaue H
  • Journal Title: Arch Surg 144(4) Pages: 351-358
  • Peer Reviewed
• [Presentation] 腫瘍抗原遺伝子導入樹状細胞を用いた癌ワクチン療法 (2010)
  • Author(s): 尾島敏康, 岩橋誠, 中村公紀, 宮澤基樹, 中森幹人, 勝田将裕, 飯田武, 早田啓治, 辻俊明, 山上裕機
  • Organizer: 第23回日本バイオセラピー学会
  • Place of Presentation: 大阪
  • Year and Date: 2010-12-09
• [Presentation] 胃癌腫瘍微小環境におけるTregおよびTh17の動態解析 (2010)
  • Author(s): 飯田武, 岩橋誠, 勝田将裕, 中森幹人, 中村公紀, 石田興一郎, 中禎二, 尾島敏康, 早田啓治, 辻俊明, 山上裕機
  • Organizer: 第110回日本外科学会
  • Place of Presentation: 名古屋
  • Year and Date: 2010-04-09
• [Presentation] Mesothelin遺伝子導入樹状細胞を用いた膵癌に対する特異的CTLの誘導 (2010)
  • Author(s): 宮澤基樹, 岩橋誠, 尾島敏康, 勝田将裕, 中禎二, 中村公紀, 山上裕機
  • Organizer: 第110回日本外科学会
  • Place of Presentation: 名古屋
  • Year and Date: 2010-04-09
• [Presentation] 癌治療を実践する外科医が行う基礎研究の意義 (2010)
  • Author(s): 岩橋誠, 中森幹人, 中村公紀, 中禎二, 尾島敏康, 上田健太郎, 勝田将裕, 松田健司, 山上裕機
  • Organizer: 第110回日本外科学会
  • Place of Presentation: 名古屋
  • Year and Date: 2010-04-09
• [Presentation] Mesothelin遺伝子導入樹状細胞を用いた膵癌免疫療法 (2009)
  • Author(s): 宮澤基樹, 岩橋誠, 尾島敏康, 勝田将裕, 中村公紀, 中禎二, 中森幹人, 山上裕機
  • Organizer: 第22回日本バイオセラピー学会
  • Place of Presentation: 大阪
  • Year and Date: 2009-11-26
• [Presentation] 胃癌腫瘍微小環境におけるTh17およびTregの動態からみた癌免疫逃避機構の解析 (2009)
  • Author(s): 飯田武, 岩橋誠, 勝田将裕, 中森幹人, 中村公紀, 石田興一郎, 中禎二, 尾島敏康, 早田啓治, 辻俊明, 山上裕機
  • Organizer: 第22回日本バイオセラピー学会
  • Place of Presentation: 大阪
  • Year and Date: 2009-11-26
• [Presentation] CpG-ODNによる癌抗原特異的エフェクター細胞の効率的誘導と抗腫瘍活性増強効果 (2009)
  • Author(s): 勝田将裕, 岩橋誠, 中森幹人, 中村公紀, 松田健司, 中禎二, 尾島敏康, 飯田武, 宮澤基樹, 角田卓也, 中村祐輔, 山上裕機
  • Organizer: 第22回日本バイオセラピー学会
  • Place of Presentation: 大阪
  • Year and Date: 2009-11-26
• [Presentation] 進行食道癌に対するCpG-B併用新規腫瘍抗原ペプチドワクチン療法:第I相臨床試験の結果からみた将来展望 (2009)
  • Author(s): 岩橋誠, 勝田将裕, 中森幹人, 中村公紀, 飯田武, 中禎二, 尾島敏康, 松田健司, 角田卓也, 中村祐輔, 山上裕機
  • Organizer: 第22回日本バイオセラピー学会
  • Place of Presentation: 大阪
  • Year and Date: 2009-11-26
• [Presentation] 癌ワクチン療法後の再燃腫瘍に対する腫瘍RNA導入樹状細胞を用いた治療戦略の検討 (2009)
  • Author(s): 中禎二, 岩橋誠, 中村公紀, 尾島敏康, 勝田将裕, 松田健司, 中森幹人, 宮澤基樹, 石田興一郎, 山上裕機
  • Organizer: 第21回日本バイオセラピー学会
  • Place of Presentation: 東京
  • Year and Date: 2009-11-18
• [Presentation] Tumor-infiltrating CD4+T cells secreting IL-17 Th17 promotes tumor growth in human gastric cancer (2009)
  • Author(s): 飯田武, 岩橋誠, 勝田将裕, 石田興一郎, 中森幹人, 中村公紀, 中禎二, 尾島敏康, 山上裕機
  • Organizer: 第68回日本癌学会
  • Place of Presentation: 横浜
  • Year and Date: 2009-10-02
• [Presentation] CpG-ODNs augment cytotoxic activity of peptide-specific CTLs from patients with esophageal cancer (2009)
  • Author(s): 勝田将裕, 岩橋誠, 中森幹人, 中村公紀, 松田健司, 中禎二, 尾島敏康, 飯田武, 宮澤基樹, 山上裕機
  • Organizer: 第68回日本癌学会
  • Place of Presentation: 横浜
  • Year and Date: 2009-10-01
• [Presentation] Immunotherapy using genetically modified DCs co-expressing CEA and GM-CSF (2009)
  • Author(s): 尾島敏康, 岩橋誠, 中村公紀, 中森幹人, 中禎二, 勝田将裕, 飯田武, 早田啓治, 上田健太郎, 山上裕機
  • Organizer: 第68回日本癌学会
  • Place of Presentation: 横浜
  • Year and Date: 2009-10-01
• [Presentation] Phase I trial of vaccination of tumor specific peptides combined with CpG-B for patients with esophageal cancer (2009)
  • Author(s): 岩橋誠, 勝田将裕, 中森幹人, 中村公紀, 宮澤基樹, 松田健司, 中禎二, 尾島敏康, 飯田武, 角田卓也, 中村祐輔, 山上裕機
  • Organizer: 第68回日本癌学会
  • Place of Presentation: 横浜
  • Year and Date: 2009-10-01
• [Presentation] 消化器癌ワクチンの臨床応用進行食道癌に対するCpG-B併用URLC10およびTTKエピトープペプチドワクチン療法の第I相臨床試験 (2009)
  • Author(s): 勝田将裕, 岩橋誠, 松田健司, 宮澤基樹, 中森幹人, 中村公紀, 中禎二, 尾島敏康, 飯田武, 山上裕機
  • Organizer: 第64回日本消化器外科学会
  • Place of Presentation: 大阪
  • Year and Date: 2009-07-17
• [Presentation] Mesothelin遺伝子導入樹状細胞を用いた膵癌免疫療法 (2008)
  • Author(s): 宮澤基樹, 岩橋誠, 尾島敏康, 勝田将裕, 飯田武, 中禎二, 中森幹人, 中村公紀, 松田健司, 山上裕機
  • Organizer: 第21回日本バイオセラピー学会
  • Place of Presentation: 東京
  • Year and Date: 2008-11-18
• [Presentation] 腫瘍抗原遺伝子導入樹状細胞を用いた癌ワクチン療法(臨床応用に向けて) (2008)
  • Author(s): 尾島敏康, 岩橋誠, 中村公紀, 中森幹人, 宮澤基樹, 中禎二, 上田健太郎, 勝田将裕, 飯田武, 山上裕機
  • Organizer: 第21回日本バイオセラピー学会
  • Place of Presentation: 東京
  • Year and Date: 2008-11-18
• [Presentation] CEA遺伝子Th1-type cytokine遺伝子導入樹状細胞を用いた癌ワクチン療法-CEA transgenic miceを用いた検討- (2008)
  • Author(s): 尾島敏康, 岩橋誠, 中村公紀, 中森幹人, 中禎二, 上田健太郎, 石田興一郎, 勝田将裕, 飯田武, 宮澤基樹, 山上裕機
  • Organizer: 第46回日本癌治療学会
  • Place of Presentation: 名古屋
  • Year and Date: 2008-10-30