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Generation of CD8⁺ and CD4⁺ T-Cell Response to Dendritic Cells Genetically Engineered to Express the MART-1/Melan-A Gene¹

Department of Medicine, University of Connecticut Health Center, Farmington, Connecticut 06030 [A-P. D., L. L., N. G. C., B. M.]; and Division of Surgical Oncology, University of California Los Angeles, Los Angeles, California 90095 [L. H. B., J. S. E.]

Both CD8⁺ and CD4⁺ T cells have demonstrated roles in antitumor immune response in many animal tumor systems. In many human tumor systems, although abundant literature exists on the evidence of tumor antigen-specific CD8⁺ CTL response, only limited information is available on tumor antigen-specific CD4⁺ T-cell response. Using the MART-1/Melan-A (MART-1) antigen system as a prototype human tumor-associated antigen (TAA)- and dendritic cell (DC)-based MART-1 antigen presentation system (i.e., DCs transduced with an adenoviral vector-based construct carrying the MART-1 gene), we explored, in vitro, the feasibility of generating both CD8⁺ and CD4⁺ T-cell responses in the same individual. Here, we show that autologous DCs from both HLA-A2-positive melanoma patients and normal healthy individuals that are transduced with an adenoviral vector containing the MART-1 antigen are capable of inducing both MART-1-specific CD8⁺ and CD4⁺ T cells in in vitro coculture. After several rounds of stimulation, both the CD4⁺ and CD8⁺ T cells synthesized IFN- when they were specifically stimulated. The CD8⁺ T cells generated in such cocultures also recognized the MART-1_27–35 peptide, AAGIGILTV, in 4-h cytotoxicity assays. These observations, therefore, suggest that Th1-type responses can be generated, in vitro, by stimulation with DCs that are genetically modified to express a TAA. Although the outcome of this type of genetically engineered DC-based stimulation may vary from system to system, this type of in vitro antigen presentation may be very useful in more comprehensive analyses of CD4⁺ T-cell response to defined TAAs, and such genetically engineered autologous DCs might be better candidates to serve as surrogate cancer vaccines.

¹ This work was supported by United States Public Health Service Grant CA 61398 (to B. M.) and, in part, by NIH/National Cancer Institute Grants PO1 CA5926, RO1 CA77623, T32 CA75956, and K12 CA76905 and the Monkarsh Fund [to J. S. E.]. A. P-D. was supported by a grant from the Ministerio de Educacion y Ciencia del Gobierno Vasco.

² To whom requests for reprints should be addressed, at Department of Medicine, University of Connecticut Health Center, Farmington Avenue, Farmington, CT 06030. Phone: (860) 679-4236; Fax: (860) 679-1823.

Received 9/14/98. Accepted 10/19/98.

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