This proposal deals with practical applications of glycosyl- phoshatidylinositol (GPI) protein tranfer, with the objectives geares towards clinical translation down the road. The overall goal is to develop immunotherapies for cancer which which use eith engineered tumor cells themselves (painted with costimulator-GPI proteins, such as B7-1-GPI and B7-2-GPI) or antigenically engineered professional antigen-presenting cells (APCs)(painted with MHC-GPI. Tumor peptide antigen complexes) as cellular vaccines to elicit systemic anti-tumor responses. Accomplishments to data have contributed towards the use of protein transfer as a tool for producing each of these kinds of cellular vaccines. Significantly, protein transfer, unlike gene transfer, is reality applicable to primary tumor cells and professional APCs that are difficult to transfect and facilitaes the simultanceous expression of multiple proteins at the cell surface. The present proposal consists of five specific amis which are intended to serve as a platform for cancer therapeutics development and later clinical trials with adjuvant cancer vaccines: (1) ex vivo and in vivo studies with B7-1GPI and B7-2-GPI proteins will be completed; (2) The usefulness of other (non-B7) costomulator.GPIs for immunogenic tumore cell engineering, along with other potentially agents, will be evaluated; (3) The feasibilty of generating immunogenic tumor cells in the situ within tumor beds will be determined; (4) Functional studies with HLA-A2.1'GPIs bearing well-defined tumor peptide antigens will be conducted; and (5) Additional developmental work on GPI protein transfer per se will be performed.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA074958-02
Application #
2748946
Study Section
Special Emphasis Panel (ZRG2-ET-1 (01))
Program Officer
Kelsey, Morris I
Project Start
1997-09-01
Project End
1999-07-31
Budget Start
1998-08-01
Budget End
1999-07-31
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Pathology
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Razmara, Marjaneh; Hilliard, Brendan; Ziarani, Azadeh K et al. (2009) Fn14-TRAIL, a chimeric intercellular signal exchanger, attenuates experimental autoimmune encephalomyelitis. Am J Pathol 174:460-74
Razmara, Marjaneh; Hilliard, Brendan; Ziarani, Azadeh K et al. (2008) CTLA-4 x Ig converts naive CD4+CD25- T cells into CD4+CD25+ regulatory T cells. Int Immunol 20:471-83
Orbach, Ariel; Rachmilewitz, Jacob; Parnas, Miram et al. (2007) CTLA-4 . FasL induces early apoptosis of activated T cells by interfering with anti-apoptotic signals. J Immunol 179:7287-94
Tone, Yukiko; Kojima, Yoshitsugu; Furuuchi, Keiji et al. (2007) OX40 gene expression is up-regulated by chromatin remodeling in its promoter region containing Sp1/Sp3, YY1, and NF-kappa B binding sites. J Immunol 179:1760-7
Tykocinski, Mark L; Chen, Aoshuang; Huang, Jui-Han et al. (2003) New designs for cancer vaccine and artificial veto cells: an emerging palette of protein paints. Immunol Res 27:565-74
Chen, Aoshuang; Zheng, Guoxing; Tykocinski, Mark L (2003) Quantitative interplay between activating and pro-apoptotic signals dictates T cell responses. Cell Immunol 221:128-37
Moody, D Branch; Briken, Volker; Cheng, Tan-Yun et al. (2002) Lipid length controls antigen entry into endosomal and nonendosomal pathways for CD1b presentation. Nat Immunol 3:435-42
Blank, Stephanie V; Rubin, Stephen C; Coukos, George et al. (2002) Replication-selective herpes simplex virus type 1 mutant therapy of cervical cancer is enhanced by low-dose radiation. Hum Gene Ther 13:627-39
Zheng, G; Chen, A; Sterner, R E et al. (2001) Induction of antitumor immunity via intratumoral tetra-costimulator protein transfer. Cancer Res 61:8127-34
Chen, A; Zheng, G; Tykocinski, M L (2000) Hierarchical costimulator thresholds for distinct immune responses: application of a novel two-step Fc fusion protein transfer method. J Immunol 164:705-11

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