Our long-term objective is to develop a clinically effective and broadly applicable vaccine strategy for a wide range of cancer patients by inducing immunity against the protein subunit of human telomerase, telomerase reverse transcriptase (TERT). Telomerase is an attractive candidate for a broadly expressed tumor rejection antigen since telomerase is silent in normal tissues but reactivated and overexpressed in the majority of human solid tumors including prostate cancers. We have performed extensive preclinical studies demonstrating that autologous DC transfected with TERT RNA are a remarkable effective strategy to stimulate TERT-specific T cell responses from the PBMC of cancer patients in vitro. These responses were predominantly CD8+ T cell mediated due to the fact that antigen expressed from mRNA transfected DC will be channeled preferentially into the endogenous class I presentation pathway. In view of the fact that CD4+ T cells play a critically important role in the induction and maintenance of an antitumor response, we have shown that modified TERT transcripts containing the lysosomal targeting signal LAMP (LAMP-TERT) lead to increased stimulation of TERT-specific CD4+ cells by redirecting the TERT protein into the class II presentation pathway. Here we propose to translate these preclinical findings into a clinical setting by conducting a phase I clinical trial designed to evaluate the safety and bioactivity of TERT RNA and LAMP-TERT RNA transfected DC to stimulate potentially therapeutic immune responses in metastatic prostate cancer patients (Aim I).
In Aim 2 of this application, we propose to analyze these T cell responses by determining the presence, magnitude and duration of TERT-specific CD8+ and CD4+ T cell responses prior to and following vaccination by (a) analyzing changes in the post treatment cytokine profiles of activated T cells as assessed by an automated ELISPOT assay; (b) measuring the induction of TERT epitope-specific CTL subsets by tetramer analysis, (c) measure the functional capability of the in vivo generated CTL to specifically recognize and lyse TERT expressing cellular targets, d) determine the presence of CD4+ T cell responses by conventional proliferation assays or by novel, simplified whole blood assays using cytokine flow-cytometry.
In Aim 3 of this grant we seek to further improve the LAMP-TERT-driven stimulation of CD4+ T cell responses by using antisense oligonucleotide mediated inhibition methods directed against invariant chain expression. The proposed project will set the stage for scientifically valid phase II studies to assess the clinical efficacy of vaccinating prostate cancer patients with TERT RNA transfected DC and evaluate the utility of using TERT as antigen to treat a wide range of cancers, which overexpress TERT.
| Vieweg, Johannes; Dannull, Jens (2005) Technology Insight: vaccine therapy for prostate cancer. Nat Clin Pract Urol 2:44-51 |
| Vieweg, Johannes; Jackson, Andrew (2005) Modulation of antitumor responses by dendritic cells. Springer Semin Immunopathol 26:329-41 |
