"Cell-in-cell" activity-based tumor-specific delivery of biologics

• Project/Area Number: 25293283
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Okayama University
• Principal Investigator: FUJIWARA Toshiyoshi 岡山大学, 医歯(薬)学総合研究科, 教授 (00304303)
• Co-Investigator(Kenkyū-buntansha): KAGAWA Shunsuke 岡山大学, 大学病院, 准教授 (00362971) ; SHIRAKAWA Yasuhiro 岡山大学, 大学院医歯薬学総合研究科, 准教授 (60379774)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥18,330,000 (Direct Cost: ¥14,100,000、Indirect Cost: ¥4,230,000); Fiscal Year 2015: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000); Fiscal Year 2014: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000); Fiscal Year 2013: ¥9,620,000 (Direct Cost: ¥7,400,000、Indirect Cost: ¥2,220,000)
• Keywords: 癌 / 遺伝子 / 細胞・組織 / 医療・福祉 / トランスレーショナルリサーチ / ﾄﾗﾝｽﾚｰｼｮﾅﾙﾘｻｰﾁ

Outline of Final Research Achievements

"Cell-in-cell" denotes an invasive phenotype in which one cell actively internalizes in another. The novel human T-cell line HOZOT, established from human umbilical cord blood, was shown to penetrate a variety of human cancer cells but not normal cells. Here, we report a new, intriguing approach using HOZOT cells to transmit biologics such as oncolytic viruses into human cancer cells by cell-in-cell invasion. HOZOT cells were successfully loaded via human CD46 antigen with an attenuated adenovirus containing the fiber protein of adenovirus serotype 35 (OBP-401/F35), in which the telomerase promoter regulates viral replication. OBP-401/F35–loaded HOZOT cells were efficiently internalized into human cancer cells and exhibited tumor-specific killing by release of viruses, even in the presence of anti-viral neutralizing antibodies. Moreover, intraperitoneal administration of HOZOT cells loaded with OBP-401/F35 significantly suppressed peritoneally disseminated tumor growth in mice.

Research Products

• [Journal Article] Targeted photodynamic virotherapy armed with a genetically encoded photosensitizer. (2016)
  • Author(s): Takehara K, Kagawa S, Fujiwara T, et al.
  • Journal Title: Molecular Cancer Therapeutics Volume: 15 Issue: 1 Pages: 199-208
  • DOI: 10.1158/1535-7163.mct-15-0344
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Trastuzumab-Based Photoimmunotherapy Integrated with Viral HER2 Transduction Inhibits Peritoneally Disseminated HER2-Negative Cancer (2016)
  • Author(s): Ishida M, Kagawa S, Shimoyama K, Takehara K, Noma K, Tanabe S, Shirakawa Y, Tazawa H, Kobayashi H, Fujiwara T
  • Journal Title: Molecular Cancer Therapeutics Volume: 15 Issue: 3 Pages: 402-411
  • DOI: 10.1158/1535-7163.mct-15-0644
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Experimental curative fluorescence-guided surgery of highly-invasive glioblastoma multiforme selectively labeled with a killer-reporter adenovirus (2015)
  • Author(s): Yano S, Miwa S, Kishimoto H, Toneri M, Hiroshima Y, Yamamoto M, Bouvet M, Urata Y, Tazawa H, Kagawa S, Fujiwara T, Hoffman RM
  • Journal Title: Mol Ther Volume: 23 Issue: 7 Pages: 1182-1188
  • DOI: 10.1038/mt.2015.63
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Color-coding cancer and stromal cells with genetic reporters in a patient-derived orthotopic xenograft (PDOX) model of pancreatic cancer enhances fluorescence-guided surgery. (2015)
  • Author(s): Yano S, Hiroshima Y, Maawy A, Kishimoto H, Suetsugu A, Miwa S, Toneri M, Yamamoto M, Katz MH, Fleming JB, Urata Y, Tazawa H, Kagawa S, Bouvet M, Fujiwara T, Hoffman RM.
  • Journal Title: Cancer Gene Ther Volume: 22 Issue: 7 Pages: 344-50
  • DOI: 10.1038/cgt.2015.26
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Clinical Significance of MLH1 Methylation and CpG Island Methylator Phenotype as Prognostic Markers in Patients with Gastric Cancer. (2015)
  • Author(s): Shigeyasu K, Nagasaka T, Mori Y, Yokomichi N, Kawai T, Fuji T, Kimura K, Umeda Y, Kagawa S, Goel A, Fujiwara T
  • Journal Title: PLoS One Volume: 10 Issue: 6 Pages: e0130409-e0130409
  • DOI: 10.1371/journal.pone.0130409
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Biological ablation of sentinel lymph node metastasis in submucosally invaded early gastrointestinal cancer. (2015)
  • Author(s): Kikuchi S, Kishimoto H, Tazawa H, Hashimoto Y, Kuroda S, Nishizaki M, Nagasaka T, Shirakawa Y, Kagawa S, Urata Y, Hoffman RM, Fujiwara T.
  • Journal Title: Mol Ther. Volume: 23(3) Issue: 4 Pages: 501-509
  • DOI: 10.1136/gutjnl-2014-306957
  • NAID: 120005537574
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Biological ablation of sentinel lymph node metastasis in submucosally invaded early gastrointestinal cancer. (2015)
  • Author(s): Kikuchi S, et al.
  • Journal Title: Molecular Therapy Volume: 23 Issue: 3 Pages: 501-509
  • DOI: 10.1038/mt.2014.244
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Establishment of a non-invasive semi-quantitative bioluminescent imaging method for monitoring of an orthotopic esophageal cancer mouse model. (2014)
  • Author(s): Kuroda S, et al.
  • Journal Title: PLoS One Volume: 9 Issue: 12 Pages: e114562-e114562
  • DOI: 10.1371/journal.pone.0114562
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Selective methioninase-induced trap of cancer cells in S/G2 phase visualized by FUCCI imaging confers chemosensitivity. (2014)
  • Author(s): Yano S, et al.
  • Journal Title: Oncotarget Volume: 5 Pages: 8729-8736
  • Peer Reviewed
• [Journal Article] Spatial-temporal FUCCI imaging of each cell in a tumor demonstrates locational dependence of cell cycle dynamics and chemoresponsiveness. (2014)
  • Author(s): Yano S, et al.
  • Journal Title: Cell Cycle Volume: 13 Issue: 13 Pages: 2110-2119
  • DOI: 10.4161/cc.29156
  • Peer Reviewed
• [Journal Article] Dual programmed cell death pathways induced by p53 transactivation overcome resistance to oncolytic adenovirus in human osteosarcoma cells. (2013)
  • Author(s): Hasei, J.
  • Journal Title: Molecular Cancer Therapeutics Volume: 12 Issue: 3 Pages: 314-325
  • DOI: 10.1158/1535-7163.mct-12-0869
  • Peer Reviewed
• [Journal Article] A novel synergistic effect of iron depletion on antiangiogenic cancer therapy. (2013)
  • Author(s): Ohara T, Noma K, Urano S, Watanabe S, Nishitani S, Tomono Y, Kimura F, Kagawa S, Shirakawa Y, Fujiwara T
  • Journal Title: International Journal of Cancer Volume: 132 Issue: 11 Pages: 2705-2713
  • DOI: 10.1002/ijc.27943
  • Peer Reviewed
• [Journal Article] Multicenter phase II study of S-1 and docetaxel combination chemotherapy for advanced or recurrent gastric cancer patients with peritoneal dissemination. (2013)
  • Author(s): Shigeyasu, K.
  • Journal Title: Cancer Chemotherapy and Pharmacology Volume: 71 Issue: 4 Pages: 937-943
  • DOI: 10.1007/s00280-013-2086-0
  • Peer Reviewed
• [Journal Article] A genetically engineered oncolytic adenovirus decoys and lethally traps quiescent cancer stem-like cells into S/G2/M-phases. (2013)
  • Author(s): Yano S, Tazawa H, Hashimoto Y, Shirakawa Y, Kuroda S, Nishizaki M, Kishimoto H, Uno F, Nagasaka T, Urata Y, Kagawa S, Hoffman RM, Fujiwara T
  • Journal Title: Clin Cancer Res Volume: 19 Issue: 23 Pages: 6495-6505
  • DOI: 10.1158/1078-0432.ccr-13-0742
  • Peer Reviewed
• [Journal Article] A simple detection system for adenovirus receptor expression using a telomerase-specific replication-competent adenovirus (2012)
  • Author(s): Sasaki, T.
  • Journal Title: Gene Therapy Volume: (Epub ahead of print) Issue: 1 Pages: 112-118
  • DOI: 10.1038/gt.2011.213
  • Peer Reviewed
• [Presentation] 胃癌における蛍光発現ウイルスによる腹腔洗浄液診断：生物学的悪性度指標としての可能性. (2013)
  • Author(s): 香川俊輔
  • Organizer: 第113回日本外科学会定期学術集会（シンポジウム）
  • Place of Presentation: 福岡
• [Presentation] テロメラーゼ活性を指標とする血中遊離癌細胞の高感度検出法の開発と遺伝子解析技術への応用. (2013)
  • Author(s): 重安邦俊
  • Organizer: 第113回日本外科学会定期学術集会（ワークショップ）
  • Place of Presentation: 福岡