Abstract 5581: Antigen-specific CTLA-4-regulated T-cell responses elicited in patients with prostate cancer treated by DNA immunization

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Abstract Background: We and others have been interested in plasmid DNA vaccines as a means of eliciting tumor antigen-specific CD4+ and CD8+ T-cell responses. We have investigated plasmid DNA vaccines encoding prostatic acid phosphatase (PAP), a well-characterized prostate tumor antigen, in rodent models and found these to be effective in eliciting antigen-specific CD8+ T cells with evidence of anti-tumor efficacy. Multiple immunizations at high plasmid doses, however, elicited antigen-specific IL-10 secretion. We have recently completed a phase I clinical trial evaluating a DNA vaccine encoding PAP in patients with minimal residual prostate cancer. In that trial, while in vitro PAP-specific T-cell responses were elicited in multiple patients following six biweekly immunizations, others did not have evidence of an immune response, and some responses were not detectable until months later. The current study was conducted to determine whether immunization might have elicited an antigen-specific regulatory T-cell response in some individuals. Methods: Peripheral blood mononuclear cells obtained from 21 patients prior to immunization, and two weeks after six biweekly immunizations, were evaluated for PAP-specific immune responses in a SCID mouse trans-vivo delayed-type hypersensitivity (DTH) assay. Specifically, DTH responses to PAP in PBMC were evaluated in the presence or absence of antibodies to regulatory molecules (IL-10, TGFß, CTLA-4, PD-1) to “uncover” antigen-specific regulatory mechanisms. Results: 8/21 individuals had a PAP-specific T-cell response following immunization that was not detectable pre-immunization and which was “uncovered” by CTLA-4 blockade. This response was found to persist in at least one individual for several months. IL-10- and TGFß-regulated responses were not detected. Baseline regulatory PAP-specific T cells could be detected that suppressed concurrent tetanus-specific DTH responses. 6/8 individuals with a detectable CTLA-4-regulated response experienced a favorable increase in PSA doubling time. Conclusions: Patients with prostate cancer can have PAP-specific regulatory T cells. Plasmid DNA immunization can elicit effector T cells specific for PAP that in many individuals is regulated by CTLA-4. Further studies are underway to characterize the regulatory T cell population(s), however these findings suggest that the efficacy of DNA vaccines might be further augmented by combination with anti-CTLA-4 blockade. In addition, these studies suggest that these trans-vivo DTH methods, in use for evaluating mechanisms of antigen-specific tolerance, could be more generally applied to the immune monitoring of anti-tumor vaccine clinical trials. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5581.