Overcome to avoidance from the anti-leukemia immunity by using combination therapy with HSP and dendritic cells targeted to both tumor and tumor angiogenesis

• Project/Area Number: 20591143
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Hematology
• Research Institution: Asahikawa Medical College
• Principal Investigator: SATO Kazuya Asahikawa Medical College, 医学部, 講師 (50360988)
• Co-Investigator(Kenkyū-buntansha): MIZUKAMI Yuusuke 旭川医科大学, 医学部, 講師 (30400089) ; OHTAKE Takaaki 旭川医科大学, 医学部, 講師 (10359490) ; IKUTA Katsuya 旭川医科大学, 医学部, 講師 (00396376)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2010: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2009: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2008: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 腫瘍血管内皮 / 熱ショック蛋白(HSP) / VEGF / 白血病特異免疫 / 腫瘍血管新生 / 細胞不死化 / IGF / hTERT / 白血病 / VEGFR1 / 不死化 / 熱ショックタンパク(HSP)

Research Abstract

In this study, we tried induction of the anti-leukemia immunity by using heat shock protein (HSP) targeted to both tumor and tumor angiogenesis. We demonstrated the presence of tumor angiogenesis in the A20-bearing mouse by endothelium cell (EC)-marker CD31 immunostaining. It was difficult to obtain the enough amount of EC by MACS with anti-CD31 antibody (Ab). We therefore originated GFP transduced A20-cells, and then GFP-negative fraction was sorted from A20-tumor tissue. Now we tried to separate the A20-tumor-associated EC (A20-EC) by using sorted GFP-negative fraction. To increase the number of EC, a vector containing immortalizing gene teromerase reverse transcriptase (TERT) was constructed. After successful A20-EC separation, transduction of TERT gene to A20-ESs and expansion of them will be performed, and then purification of A20-EC-derived HSP will be planed. To obtain the useful information of tumor endotherial antigen in the B-cell neoplasms, the specimen of solitary plasmacytoma in POEMS syndrome, which is known as one of the angiogenic B-cell neoplasms, was immunostained with angiogenic factors, and we demonstrated that the expression levels of VEGF and IGF were very high in the tumor. In addition, we showed the possibility that anti-idiotype Ab of mouse B-cell neoplasm may inhibit the angiogenesis in the microenvironment of the B-cell tumor through humoral immunity by the CDC. These findings enable the approach by novel immunotherapy against tumor ECs with unique motifs, such as HSPs derived from B-cell neoplasm associated ECs or anti-idiotype Ab.

Research Products

• [Journal Article] Development of POEMS syndrome after an initial manifestation of solitary plasmacytoma (2011)
  • Author(s): Shindo M, Sato K, Yamamoto M, Toki Y, Hatayama M, Ito S, Ichiki K, Okamura N, Hosoki T, Ikuta K.Inamura J, Watanabe S, Torimoto Y, Kohgo Y
  • Journal Title: Int J Hematol. (Epub ahead of print)
  • NAID: 10029535777
• [Journal Article] Loss of ABCB7 gene : pathogenesis of mitochondrial iron accumulation in erythro blasts in refractory anemia with ringed sideroblast with isodicentric(X)(q13). (2011)
  • Author(s): Sato K, Torimoto Y, Hosoki T Ikuta K, Takahashi H, Yamamoto M, Ito S, Okamura N, Ichiki K, Tanaka H, Shindo M, Hirai K, Mizukami Y, Otake T, Fujiya M, Sasaki K, Kohgo Y
  • Journal Title: International Journal of Hematology Volume: 93 Pages: 311-318
  • NAID: 10029533807
  • Peer Reviewed
• [Journal Article] Development of POEMS Syndrome after an Initial Manifestation of Solitary Plas macytoma (2011)
  • Author(s): Motohiro Shindo, Kazuya Sato, Masayo Yamamoto, Yasumichi Toki, Mayumi Hatayama, Satoshi Ito, Kazuhiko Ichiki, Naoka Okamura, Takaaki Hosoki, Katsuya Ikuta, Junki Inamura, Shinji Watanabe, Yoshihiro Torimoto, Yutaka Kohgo
  • Journal Title: International Journal of Hematology Volume: (in press)
  • Peer Reviewed
• [Journal Article] Transplanting normal vascular proangiogenic cells to tumor-bearing mice triggers vascular remodeling and reduces hypoxia in tumors. (2010)
  • Author(s): Sasajima J, Mizukami Y, Sugiyama Y, Nakamura K, Kawamoto T, Koizumi K, Fujii R, Motomura W, Sato K, Suzuki Y, Tanno S,Fujiya M, Sasaki K, Shimizu N, Karasaki H, Kono T, Kawabe J, Ii M, Yoshiara H, Kamiyama N, Ashida T, Bardeesy N, Chung DC, Kohgo Y.
  • Journal Title: Cancer Res. Volume: 70 Pages: 6283-6292
  • Peer Reviewed
• [Journal Article] Hedgehog promotes neovascularization in pancreatic cancers by regulating Ang-1 and IGF-1 expression in bone-marrow derived pro-angiogenic cells. (2010)
  • Author(s): Nakamura K, Sasajima J, Mizukami Y, Sugiyama Y, Yamazaki M, Fujii R, Kawamoto T, Koizumi K, Sato K, Fujiya M, Sasaki K, Tanno S, Okumura T, Shimizu N, Kawabe J, Karasaki H, Kono T, Ii M, Bardeesy N, Chung DC, Kohgo Y.
  • Journal Title: PLoS One 5
  • NAID: 120004138817
  • Peer Reviewed
• [Journal Article] Induction of leukemia-specific antibodies by immunotherapy with leukemia-cell-derived heat shock protein 70 (2009)
  • Author(s): Jimbo J, Sato K, Hosoki T, Shindo M, Ikuta K, Torimoto Y, Kohgo Y
  • Journal Title: Cancer Sci. 99 Pages: 1427-1434
  • NAID: 10024008778
  • Peer Reviewed
• [Journal Article] Jimbo J, Sato K, Hosoki T, Shindo M, Ikuta K, Torimoto Y, Kohgo Y (2008)
  • Author(s): Induction of leukemia-specific antibodies by immunotherapy with leukemia-cell-derived heat shock protein 70
  • Journal Title: Cancer Sci. 99(7) Pages: 1427-34
• [Presentation] A Crucial Cytotoxic Role of Anti-Idiotypic Antibody in Inununotherapy for B-Cell Neoplasms with Tumor Cell-Derived Heat Shock Protein 70. (2009)
  • Author(s): Kazuya Sato, Junko Jimbo, Naoka Okamura, Takaaki Hosoki, Motohiro Shindo, Katsuya Ikuta, Yusuke Mizukami, Yoshihiro Torimoto, Yutaka-Kohgo
  • Organizer: アメリカ血液学会
  • Place of Presentation: Ernest N. Morial Convention Center(ニューオリンズ)
  • Year and Date: 2009-12-05
• [Presentation] A crucial cytotoxic role of anti-idiotypic antibody in immunotherapy for B-cell neoplasms with tumor cell-derived heat shock protein 70 (2009)
  • Author(s): Kazuya Sato, Junko Jimbo, Naoka Okamura, Takaaki Hosoki, Motohiro Shindo, Katsuya Ikuta, Yusuke Mizukami, Yoshihiro Torimoto, Yutaka Kohgo.
  • Organizer: Abstract for the 48th Annual Meeting, The American Society of Hematology(New Orleans)
• [Presentation] マウス白血病細胞に対する熱ショック蛋白70を用いた免疫療法における液性免疫応答の誘導 (2008)
  • Author(s): 神保絢子、佐藤一也、細木卓明、進藤基博、生田克哉、鳥本悦宏、高後裕
  • Organizer: 日本血液学会
  • Place of Presentation: 京都国際会議場
  • Year and Date: 2008-10-10
• [Presentation] マウス白血病細胞に対する熱ショック蛋白70を用いた免疫療法における液性免疫応答の誘導Humoral immune responses in immunotherapy with HSP70 against leukemia in mice
  • Author(s): 神保絢子、佐藤一也、細木卓明、進藤基博、生田克哉、鳥本悦宏、高後裕
  • Organizer: 第70回日本血液学会是学術集会
  • Place of Presentation: 京都