T-cell recognition of autologous melanoma is vitally dependent on the expression by tumor cells of tumor associated antigens in the context of self MHC class I encoded gene products. In both murine and human studies, transduction with the gene for gamma-IFN increases the surface membrane expression of these important molecules by the tumor cells and results in dramatic improvement of T-cell responses following stimulation with the modified tumor cells. The enhanced response is directed not only toward modified tumor cells, but against the unmodified tumor cells as well. The goals of this proposal are to examine the T-cell responses following stimulation with autologous tumor cells which have been modified by transduction with the gene for human gamma-IFN. We will determine the changes in the level of expression of HLA class I molecules on the surface of the gene modified tumor cells and examine the changes in T-cell activation and recognition of parental and gamma-IFN gene modified tumor cells using cytotoxicity, blastogenesis, and elaboration of immune cytokines by the T-cells. In a model system in which expression of the HLA-A2 restricting allele is down regulated by the tumor cells, we will examine the effects following re-expression of this allele subsequent to transduction with the gene for human gamma-IFN. We will also examine in this system unique (public?) restriction patterns of autologous melanoma specific HLA class I restricted cytotoxic T-cells which share no serologically defined class I molecules with their melanoma tumor targets. We will also examine the modification of tumor specific immune status in patients undergoing active immunization with a vaccine prepared from ~-IFN gene modified autologous tumor cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA064949-02
Application #
2107708
Study Section
Special Emphasis Panel (SRC (72))
Project Start
1994-08-08
Project End
1998-05-31
Budget Start
1995-06-01
Budget End
1996-05-31
Support Year
2
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Duke University
Department
Surgery
Type
Schools of Medicine
DUNS #
071723621
City
Durham
State
NC
Country
United States
Zip Code
27705
Zennadi, R; Abdel-Wahab, Z; Seigler, H F et al. (2001) Generation of melanoma-specific, cytotoxic CD4(+) T helper 2 cells: requirement of both HLA-DR15 and Fas antigens on melanomas for their lysis by Th2 cells. Cell Immunol 210:96-105
Yang, S; Kittlesen, D; Slingluff Jr, C L et al. (2000) Dendritic cells infected with a vaccinia vector carrying the human gp100 gene simultaneously present multiple specificities and elicit high-affinity T cells reactive to multiple epitopes and restricted by HLA-A2 and -A3. J Immunol 164:4204-11
Yang, S; Vervaert, C E; Burch Jr, J et al. (1999) Murine dendritic cells transfected with human GP100 elicit both antigen-specific CD8(+) and CD4(+) T-cell responses and are more effective than DNA vaccines at generating anti-tumor immunity. Int J Cancer 83:532-40
Yang, S; Vervaert, C E; Seigler, H F et al. (1999) Tumor cells cotransduced with B7.1 and gamma-IFN induce effective rejection of established parental tumor. Gene Ther 6:253-62
Yang, S; Darrow, T L; Seigler, H F (1997) Generation of primary tumor-specific cytotoxic T lymphocytes from autologous and human lymphocyte antigen class I-matched allogeneic peripheral blood lymphocytes by B7 gene-modified melanoma cells. Cancer Res 57:1561-8
Yang, S; Darrow, T L; Vervaert, C E et al. (1997) Immunotherapeutic potential of tumor antigen-pulsed and unpulsed dendritic cells generated from murine bone marrow. Cell Immunol 179:84-95
Stidham, K R; Ricci, W M; Vervaert, C et al. (1996) Modulation of specific active immunization against murine melanoma using recombinant cytokines. Surg Oncol 5:221-9
Darrow, T L; Abdel-Wahab, Z; Quinn-Allen, M A et al. (1996) Recognition and lysis of human melanoma by a CD3+, CD4+, CD8- T-cell clone restricted by HLA-A2. Cell Immunol 172:52-9