Simultaneous generation of CD8+ and CD4+ melanoma-reactive T cells by retroviral-mediated transfer of a single T-cell receptor

• Published in: Cancer research (Chicago, Ill.) Vol. 65; no. 4; pp. 1570 - 1576
• Main Authors: ROSZKOWSKI, Jeffrey J, LYONS, Gretchen E, KAST, W. Martin, YEE, Cassian, VAN BESIEN, Koen, NISHIMURA, Michael I
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.02.2005
• Subjects: Antineoplastic agents; Biological and medical sciences; CD4-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - immunology; Cell Line, Tumor; Dermatology; Epitopes, T-Lymphocyte - immunology; Gene Transfer Techniques; Genetic Vectors - genetics; HLA-A2 Antigen - immunology; Humans; Immunotherapy, Adoptive - methods; Jurkat Cells; Lymphocytes, Tumor-Infiltrating - immunology; Medical sciences; Melanoma - genetics; Melanoma - immunology; Melanoma - therapy; Monophenol Monooxygenase - immunology; Pharmacology. Drug treatments; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - immunology; Retroviridae - genetics; Transduction, Genetic; Tumors of the skin and soft tissue. Premalignant lesions; Virus; T cell receptor; T-Lymphocyte; Malignant melanoma; Retroviridae; Transfer; Malignant tumor; Gene therapy
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-04-2076

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.