The focus of this project is on the potential of developing a new treatment modality for metastatic colon carcinoma by somatic gene therapy, using a combination of suicide and cytokine genes. The project is based on the following hypotheses (1) tumor cells killed in vivo by the suicide gene will undergo phagocytosis by antigen presenting cells which process and present the tumor antigen(s) to the T cells; (2) this process, as well as subsequent T-cell responses, will be enhanced in the presence of local cytokine expression; (3) long-term anti-tumoral T-cell responses can be established in the combination treated animals. In particular the investigator will examine the role of GM-CSF in the in vivo antigen presentation, and the proposed connection between proper antigen presentation. local cytokine expression, and long term immunity by in vitro antigen presentation assay and primed APC adoptive transfer experiments. Also, he will determine whether the combination gene therapy can establish tumor specific memory cytotoxic T cells by the frequency analysis of memory cytotoxic T cell precursors and whether these memory T cells can be clonally expanded into effector cytotoxic T cells and confer protective immunity in syngeneic irradiated naive animals by memory T cell adoptive transfer. He believes that the scientific information generated by axis study can be utilized to further improve the development in combination gene therapy against metastatic colon carcinoma in vivo.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA075175-03
Application #
2896108
Study Section
Experimental Immunology Study Section (EI)
Program Officer
Finerty, John F
Project Start
1997-09-01
Project End
2000-08-31
Budget Start
1999-09-01
Budget End
2000-08-31
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
114400633
City
New York
State
NY
Country
United States
Zip Code
10029
Li, Qingsheng; Pan, Ping-Ying; Gu, Peidi et al. (2004) Role of immature myeloid Gr-1+ cells in the development of antitumor immunity. Cancer Res 64:1130-9
Qiao, J; Doubrovin, M; Sauter, B V et al. (2002) Tumor-specific transcriptional targeting of suicide gene therapy. Gene Ther 9:168-75
Martinet, O; Divino, C M; Zang, Y et al. (2002) T cell activation with systemic agonistic antibody versus local 4-1BB ligand gene delivery combined with interleukin-12 eradicate liver metastases of breast cancer. Gene Ther 9:786-92
Pan, Ping-Ying; Zang, Yunjuan; Weber, Kaare et al. (2002) OX40 ligation enhances primary and memory cytotoxic T lymphocyte responses in an immunotherapy for hepatic colon metastases. Mol Ther 6:528-36
Sung, Max W; Chen, Shu-Hsia; Thung, Swan N et al. (2002) Intratumoral delivery of adenovirus-mediated interleukin-12 gene in mice with metastatic cancer in the liver. Hum Gene Ther 13:731-43
Kusmartsev, S A; Li, Y; Chen, S H (2000) Gr-1+ myeloid cells derived from tumor-bearing mice inhibit primary T cell activation induced through CD3/CD28 costimulation. J Immunol 165:779-85
Martinet, O; Ermekova, V; Qiao, J Q et al. (2000) Immunomodulatory gene therapy with interleukin 12 and 4-1BB ligand: long- term remission of liver metastases in a mouse model. J Natl Cancer Inst 92:931-6
Chen, S H; Pham-Nguyen, K B; Martinet, O et al. (2000) Rejection of disseminated metastases of colon carcinoma by synergism of IL-12 gene therapy and 4-1BB costimulation. Mol Ther 2:39-46
Qiao, J; Chen, S H; Pham-Nguyen, K B et al. (1999) Construction and characterization of a recombinant adenoviral vector expressing human interleukin-12. Cancer Gene Ther 6:373-9
Tjuvajev, J G; Chen, S H; Joshi, A et al. (1999) Imaging adenoviral-mediated herpes virus thymidine kinase gene transfer and expression in vivo. Cancer Res 59:5186-93