Murine studies employing tumor cells genetically-modified to express cytokines have demonstrated the induction of potent immunity that can cure mice of pre-established tumors. Experiments aimed at dissecting the mechanism of this response have revealed that both CD8+ and CD4+ T cells are critical effectors of the systemic immunity generated. These studies have led to on-going clinical trials that are testing this approach for the treatment of patients with cancer. Although the specificity of the immune response seen in these models suggests that renal-specific antigens are being expressed by the tumor and recognized by the ensuing immune response, in most cases the identity of these antigens is unknown. Recently, the identification of several murine and human melanoma antigens has validated these earlier hypotheses, and has provided a strong impetus for the identification of other human tumor antigens that can be exploited therapeutically. Antigen identification requires methods for generating T cell lines and clones, and for isolating either the gene encoding the tumor antigen or the antigen itself. We have developed methods for routinely generating tumor-specific CD8+ T cells from lymphocytes isolated from vaccinated patients. In this proposal, we will test our hypothesis that T cells isolated from vaccinated individuals will identify relevant tumor rejection antigens that can be used for immunization. Drawing on our previous experience with antigen identification, and utilizing our unique source of banked pairs of autologous lymphocytes and tumor cells obtained from patients receiving a renal cell carcinoma vaccine (RCC), we will identify tumor antigens expressed by human RCC. CD8+ renal tumor-specific T cell lines and clones will be generated from lymphocytes isolated from patients with renal cancer following vaccination with a GM-CSF secreting renal tumor vaccine. A genetic approach will be used to identify genes encoding for MHC class I-restricted antigens. Defined antigens will be analyzed to determine their MHC binding kinetics, and employed to analyze the frequency of antigen-specific T cells in banked pre- and post-vaccination lymphocytes. This was originally submitted as an interactive RO1. In the previously accompanying funded proposal, my colleague Dr. Pardoll is attempting to isolate genes encoding for MHC class II-restricted RCC tumor antigens. These studies should shed light on the immunobiology of tumors. Ultimately, the identification of common renal antigens that are recognized by both CD4 and CD8 T cells will allow the development of generalized gene therapy vaccine approaches that can generate immune responses potent enough to treat RCC.
| Le, Dung T; Pardoll, Drew M; Jaffee, Elizabeth M (2010) Cellular vaccine approaches. Cancer J 16:304-10 |
| Zhou, Xianzheng; Jun, Do Youn; Thomas, Amy Morck et al. (2005) Diverse CD8+ T-cell responses to renal cell carcinoma antigens in patients treated with an autologous granulocyte-macrophage colony-stimulating factor gene-transduced renal tumor cell vaccine. Cancer Res 65:1079-88 |
