The overall goal of this project is to develop genetically-engineered tumor vaccines for the treatment of human malignant melanoma. We propose to focus on improving the immunogenicity of melanomas by transduction with cytokine genes. Two melanoma vaccine trials will be conduced. A RAC-approved IL-2 trial will use a transduced """"""""universal cell line"""""""" mixed with untransduced autologous tumor and clinically test the hypothesis that bystander production of this cytokine will stimulate a tumor-specific immune response. An IRB-submitted IL-7 vaccine trial is based on our extensive basic and preclinical testing of this cytokine. The IL-7 clinical trial will be the first occasion in which this cytokine is tested in humans. Uniform protocol design and immunological end-points will allow a direct comparison of these two cytokines. We will conduct preclinical testing of GM-CSF/IL-3 hybrid gene transduction of experimental tumors and human melanoma. Our preliminary results with IL-3 suggest that this is a superior cytokine in increasing immunogenicity of transduced murine experimental tumors We also plan to develop novel strategies for cytokine-based tumor vaccines using recombinant adenovirus (AdV) vectors. AdV vectors bearing marker and cytokine genes will be tested in ex vivo and in vivo tumor transduction models. In summary, a clinically-oriented Project is proposed to test the ability of cytokine gene therapy to enhance the immunogenicity of human melanoma.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA059326-04
Application #
5209285
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
1996
Total Cost
Indirect Cost
Chen, R L; Reynolds, C P; Seeger, R C (2000) Neutrophils are cytotoxic and growth-inhibiting for neuroblastoma cells with an anti-GD2 antibody but, without cytotoxicity, can be growth-stimulating. Cancer Immunol Immunother 48:603-12
Penichet, M L; Challita, P M; Shin, S U et al. (1999) In vivo properties of three human HER2/neu-expressing murine cell lines in immunocompetent mice. Lab Anim Sci 49:179-88
Kutubuddin, M; Federoff, H J; Challita-Eid, P M et al. (1999) Eradication of pre-established lymphoma using herpes simplex virus amplicon vectors. Blood 93:643-54
Shau, H; Huang, A C; Faris, M et al. (1998) Thioredoxin peroxidase (natural killer enhancing factor) regulation of activator protein-1 function in endothelial cells. Biochem Biophys Res Commun 249:683-6
Challita-Eid, P M; Penichet, M L; Shin, S U et al. (1998) A B7.1-antibody fusion protein retains antibody specificity and ability to activate via the T cell costimulatory pathway. J Immunol 160:3419-26
Challita-Eid, P M; Abboud, C N; Morrison, S L et al. (1998) A RANTES-antibody fusion protein retains antigen specificity and chemokine function. J Immunol 161:3729-36
Arthur, J F; Butterfield, L H; Roth, M D et al. (1997) A comparison of gene transfer methods in human dendritic cells. Cancer Gene Ther 4:17-25
Toloza, E M; Hunt, K; Miller, A R et al. (1997) Transduction of murine and human tumors using recombinant adenovirus vectors. Ann Surg Oncol 4:70-9
Bui, L A; Butterfield, L H; Kim, J Y et al. (1997) In vivo therapy of hepatocellular carcinoma with a tumor-specific adenoviral vector expressing interleukin-2. Hum Gene Ther 8:2173-82
Butterfield, L H; Stoll, T C; Lau, R et al. (1997) Cloning and analysis of MART-1/Melan-A human melanoma antigen promoter regions. Gene 191:129-34

Showing the most recent 10 out of 31 publications