Enhancement of Anti-Telomerase Immunity Against Prostate Cancer
Annual rept. 15 Oct 2005-14 Oct 2006
DUKE UNIV MEDICAL CENTER DURHAM NC
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The overall objective of this proposal is to enhance the efficacy of cancer vaccines by selectively eliminating or reducing CD4 regulatory T cells Treg expressing the high affinity CD25 IL-2-specific receptor IL-2R in patients with metastatic prostate cancer. Preclinical and clinical data from our laboratory see Reference 1 and Appendix A and others 2, 3 have shown that CD4CD25 Treg play an important role in the suppression of T cell responses and that elimination of Treg is capable of enhancing T-cell proliferation and cytolytic activity in vitro. We have also demonstrated that human Treg can selectively be depleted in cancer patients using the IL- 2diphtheria toxin conjugate denileukin diftitox, without inducing toxicity on other cellular subsets with intermediate or low expression of CD25 1. Most importantly, denileukin diftitox-mediated elimination of Treg followed by vaccination with tumor RNA-transfected DC significantly improved the stimulation of tumorspecific T-cell responses in RCC patients, when compared to vaccination alone. These findings formed the basis of this proposal aimed to augment a vaccine-induced T cell responses by pretreatment of prostate cancer patients with agents that can lead to the preferential depletion of the CD4CD25 regulatory T cells, such as agents which target and kill cells expressing the IL-2 receptor CD25 subunit.
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