Post immunity might well be an important mechanism by which malignant tumors can be contained or even destroyed by selected patients. The mechanisms by which tumors evade the immune system are most certainly varied and complex. Suboptimal expression of human histocompatibility antigens present on the surface of human tumor cells may prevent effective presentation of tumor specific antigens. The immune system could be relatively blind to the tumor cell, at least with regard to Class I MHC- restricted cytotoxic T lymphocytes. Retroviral vectors will be used to transfer the human gamma interferon gene into autologous tumor cells obtained from selected patients with metastatic melanoma. We will attempt to upregulate the expression of class I histocompatibility antigens and cellularly detectable tumor associated antigens by genetically transducing the cells with the gene for human gamma interferon. Also, the secreted gamma interferon should serve to activate an enhanced cytotoxic T-cell response. Short term tissue culture cells will be obtained from patients with more than one metastatic site. The cell cultures will be transduced with the gamma interferon-retroviral vector. After selection the cells will be briefly irradiated and will be utilized for subsequent serial immunizations. The study is designed to determine the safety, clinical response and biologic response (immune responses) in patients with metastatic melanoma who have failed other forms of therapy. The serially immunized patients will divide tumor samples, tumor infiltrating lymphocytes, and peripheral blood lymphocytes for in vitro studies designed to characterize the cell mediated immune response in the immunized patients. Appropriate clinical measurements will be completed in an effort to quantitate the potential therapeutic efficacy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA064959-02
Application #
2107719
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
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; 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
Dong, X D; Abdel-Wahab, Z; Dematos, P et al. (1999) MCA106 fibrosarcoma cells transduced with granulocyte/macrophage colony-stimulating factor are not superior to the wild-type cells in suppressing the growth of hepatic metastases. J Surg Oncol 71:36-45
Abdel-Wahab, Z; DeMatos, P; Hester, D et al. (1998) Human dendritic cells, pulsed with either melanoma tumor cell lysates or the gp100 peptide(280-288), induce pairs of T-cell cultures with similar phenotype and lytic activity. Cell Immunol 186:63-74
DeMatos, P; Abdel-Wahab, Z; Vervaert, C et al. (1998) Pulsing of dendritic cells with cell lysates from either B16 melanoma or MCA-106 fibrosarcoma yields equally effective vaccines against B16 tumors in mice. J Surg Oncol 68:79-91
DeMatos, P; Abdel-Wahab, Z; Vervaert, C et al. (1998) Vaccination with dendritic cells inhibits the growth of hepatic metastases in B6 mice. Cell Immunol 185:65-74
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
Abdel-Wahab, Z; Dar, M; Osanto, S et al. (1997) Eradication of melanoma pulmonary metastases by immunotherapy with tumor cells engineered to secrete interleukin-2 or gamma interferon. Cancer Gene Ther 4:33-41
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
Abdel-Wahab, Z; Weltz, C; Hester, D et al. (1997) A Phase I clinical trial of immunotherapy with interferon-gamma gene-modified autologous melanoma cells: monitoring the humoral immune response. Cancer 80:401-12

Showing the most recent 10 out of 11 publications