Generation of Renal Cell Carcinoma-specific CD4+ /CD8+ T Cells Restricted by an HLA-39 from a RCC Patient Vaccinated with GM-CSF Gene-Transduced Tumor Cells

ABSTRACT

BACKGROUND: Granulocyte-macrophage colony-stimulating factor (GM-CSF) gene- transduced tumor cell vaccines induce very potent systemic anti-tumor immunity in preclinical and clinical models. Our previous phase I clinical trial in patients with metastatic renal cell carcinoma (RCC) has demonstrated both immune cell infiltration at vaccine sites and T cell-mediated delayed-type hypersensitivity (DTH) response to whole tumor cell vaccines. METHODS: To investigate the immune responses to autologous genetically- modified tumor cell vaccines, tumor-specific CD8+ T cell lines were generated from peripheral blood lymphocytes (PBL) of a RCC patient 1.24 by repeated in vitro stimulation with either B7.1-transduced autologous RCC tumor cells or B7.1-transduced autologous tumor cells treated with interferon gamma (IFNgamma), and cloned by limiting dilution. RESULTS: Among several RCC-specific cytotoxic T lymphocytes (CTLs), a CD4+ /CD8+ double positive T cell clone (17/A2) appeared to recognize IFNgamma-treated autologous RCC restricted by HLA-B39. The 17/A2 also recognized other HLA-B39 positive RCC tumor cells after IFNgamma treatment. CONCLUSION: These results demonstrate that autologous RCC vaccination successfully generates the tumor-specific CTL 17/A2, and suggest that the presentation and recognition of the tumor antigen by the 17/A2 might be upregulated by IFNgamma.