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Simultaneous Generation of CD8⁺ and CD4⁺ Melanoma-Reactive T Cells by Retroviral-Mediated Transfer of a Single T-Cell Receptor

Departments of ¹ Surgery and ² Medicine, University of Chicago, Chicago, Illinois; ³ Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California; and ⁴ Fred Hutchinson Cancer Center, Seattle, Washington

Requests for reprints: Michael I. Nishimura, University of Chicago, 5841 S Maryland Avenue, MC 7116, Chicago, IL 60637. Phone: 773-955-4040; Fax: 773-834-5295; E-mail: mnishimu{at}surgery.bsd.uchicago.edu.

Adoptive immunotherapy of cancer requires the generation of large numbers of tumor antigen–reactive T cells for transfer into cancer patients. Genes encoding tumor antigen–specific T-cell receptors can be introduced into primary human T cells by retroviral mediated gene transfer as a potential method of providing any patient with a source of autologous tumor-reactive T cells. A T-cell receptor–specific for a class I MHC (HLA-A2)–restricted epitope of the melanoma antigen tyrosinase was isolated from a CD4⁺ tumor-infiltrating lymphocyte (TIL 1383I) and introduced into normal human peripheral blood lymphocytes by retroviral transduction. T-cell receptor–transduced T cells secreted various cytokines when cocultured with tyrosinase peptide–loaded antigen-presenting cells as well as melanoma cells in an HLA-A2-restricted manner, and could also lyse target cells. Furthermore, T-cell clones isolated from these cultures showed both CD8⁺ and CD4⁺ transduced T cells could recognize HLA-A2⁺ melanoma cells, giving us the possibility of engineering class I MHC–restricted effector and T helper cells against melanoma. The ability to confer class I MHC–restricted tumor cell recognition to CD4⁺ T cells makes the TIL 1383I TCR an attractive candidate for T-cell receptor gene transfer–based immunotherapy.

Key Words: Immunotherapy • T cells • TCR • Affinity • Melanoma

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