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Background: The androgen receptor (AR) is a key oncogenic driver of prostate cancer, and has been the primary focus of prostate cancer treatment for several decades. We have previously demonstrated that the AR is also an immunological target antigen, recognized in patients with prostate cancer, and targetable by means of vaccines in rodent models with delays in prostate tumor growth. The current study was performed to determine the safety and immunological efficacy of a GMP-grade plasmid DNA vaccine encoding the ligand-binding domain (LBD) of the AR, pTVG-AR., Methods: Groups of male mice (n = 6-10 per group) were evaluated after four or seven immunizations, using different schedules and inclusion of GM-CSF as a vaccine adjuvant. Animals were assessed for toxicity using gross observations, pathological analysis, and analysis of serum chemistries. Animals were analyzed for evidence of vaccine-augmented immunity by tetramer analysis. Survival studies using different immunization schedules and inclusion of GM-CSF were conducted in an autochthonous genetically engineered mouse model., Results: No significant toxicities were observed in terms of animal weights, histopathology, hematological changes, or changes in serum chemistries, although there was a trend to lower serum glucose in animals treated with the vaccine. There was specifically no evidence of toxicity in other tissues that express AR, including liver, muscle, hematopoietic, and brain. Vaccination was found to elicit AR LBD-specific CD8+ T cells. In a subsequent study of tumor-bearing animals, animals treated with vaccine had prolonged survival compared with control-immunized mice., Conclusions: These studies demonstrate that, in immunocompetent mice expressing the target antigen, immunization with the pTVG-AR vaccine was both safe and effective in eliciting AR-specific cellular immune responses, and prolonged the survival of prostate tumor-bearing mice. These findings support the clinical evaluation of pTVG-AR in patients with recurrent prostate cancer. Prostate 77:812-821, 2017. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Background: T cells infiltrate the prostates of prostate cancer patients undergoing neoadjuvant androgen deprivation. These prostate-infiltrating T cells have an oligoclonal phenotype, suggesting the development of an antigen-specific T-cell response. We hypothesized that androgen deprivation might elicit a prostate tissue-specific T-cell response that could potentially be combined with other immune-active therapies, and consequently sought to investigate the nature and timing of this T-cell response following castration., Methods: We investigated the phenotype and cytokine expression of T cells at various time points in the prostates of Lewis rats following surgical castration, and used adoptive transfer of prostate-infiltrating lymphocytes (PILs) to determine whether the infiltration by T cells was mediated by effects of castration on the prostate or lymphocytes., Results: Prostate T-cell infiltration shortly after castration was T(H) 1 biased up to approximately 30 days, followed by a predominance of T(H) 17-type cells, which persisted until at least 90 days post castration. PILs from sham-treated or castrate rats localized to the prostates of castrate animals., Conclusions: These observations suggest castration elicits a time-dependent prostate-specific T-cell infiltration, and this infiltration is likely mediated by effects of castration on prostate tissue rather than T-cells. These findings have implications for the timing of immunotherapies combined with androgen deprivation as treatments for prostate cancer., (Copyright © 2011 Wiley Periodicals, Inc.)

Background: Prostatic acid phosphatase (PAP) is a prostate cancer tumor antigen and is an immunological target in several active immunotherapy clinical trials for the treatment of prostate cancer. We and others have demonstrated that PAP-specific T-cell responses can be elicited and augmented following antigen-specific immunization in both humans and animal models. We have previously reported that prostate cancer patients immunized with a DNA vaccine encoding PAP (pTVG-HP) developed both CD4+ and CD8+ T-cell responses. PAP-specific, CD4+ T-cell proliferative responses were generated in three out of four HLA-DRB1*0101 patients suggesting the possibility that DR1-restricted epitopes exist., Methods: To identify PAP-specific HLA-DRB1*0101 restricted epitopes, we immunized HLA-A2.01/HLA-DRB1*0101 (A2/DR1) transgenic mice with the pTVG-HP DNA vaccine. To map DRB1*0101-restricted epitopes, splenocytes from immunized mice were screened against a library of overlapping 15-residue, PAP-derived peptides using an IFNγ ELISPOT assay., Results: We identified four HLA-DRB1*0101 epitopes for PAP in A2/DR1 mice (PAP(161-175) , PAP(181-195) , PAP(191-205) , and PAP (351-365) ). T cells specific for one epitope (PAP(181-195) ) were found to be augmented after immunization in a HLA-DRB1*0101+ prostate cancer patient., Conclusions: The identification of MHC class II epitopes may provide tools to directly monitor immune responses after vaccination and may be important for the design of future prostate cancer vaccines., (Published 2011 Wiley Periodicals, Inc.)

Background: We retrospectively explored changes in immunological parameters in men with biochemically recurrent prostate cancer treated with either 5 or 25 mg of lenalidomide in a randomized phase 2 trial, and determined whether those changes correlated with disease progression., Methods: Cytokine levels were compared for each patient at baseline and after 6 months of treatment with lenalidomide. Regression models for correlated data were used to assess associations of cytokine levels with lenalidomide treatment effect. Estimates were obtained using generalized estimating equations. Changes in circulating anti-prostate antibodies were evaluated using a high-throughput immunoblot technique., Results: Treatment with lenalidomide was associated with global changes in immunoreactivity to a number of prostate-associated antigens, as well as with changes in circulating levels of the T(H) 2 cytokines IL-4, IL-5, IL-10, and IL-13. Disease progression in treated patients was associated with an increase in circulating IL-8 levels, while IL-8 levels decreased significantly in non-progressors., Conclusions: Lenalidomide demonstrates immunomodulatory properties in patients with biochemically recurrent prostate cancer. The induction of novel anti-prostate antibodies is a potential mechanism for lenalidomide response. Changes in serum IL-8 levels may serve as a potential biomarker in treated patients. These hypotheses require formal testing in future prospective trials., (Copyright © 2011 Wiley Periodicals, Inc.)

Background: An important focus of tumor immunotherapy has been the identification of appropriate antigenic targets. Serum-based screening approaches have led to the discovery of hundreds of tumor-associated antigens recognized by IgG. Our efforts to identify immunologically recognized proteins in prostate cancer have yielded a multitude of antigens; however, prioritizing these antigens as targets for evaluation in immunotherapies has been challenging. In this report, we set out to determine whether the evaluation of multiple antigenic targets would allow the identification of a subset of antigens that are common immunologic targets in patients with prostate cancer., Methods: Using a phage immunoblot approach, we evaluated IgG responses in patients with prostate cancer (n = 126), patients with chronic prostatitis (n = 45), and men without prostate disease (n = 53)., Results: We found that patients with prostate cancer or prostatitis have IgG specific for multiple common antigens. A subset of 23 proteins was identified to which IgG were detected in 38% of patients with prostate cancer and 33% patients with prostatitis versus 6% of controls (P < 0.001 and P = 0.003, respectively). Responses to multiple members were not higher in patients with advanced disease, suggesting antibody immune responses occur early in the natural history of cancer progression., Conclusions: These findings suggest an association between inflammatory conditions of the prostate and prostate cancer, and suggest that IgG responses to a panel of commonly recognized prostate antigens could be potentially used in the identification of patients at risk for prostate cancer or as a tool to identify immune responses elicited to prostate tissue., (Copyright © 2010 Wiley-Liss, Inc.)

Background: Active immunotherapies are one approach being developed as novel treatments for prostate cancer. Critical to the success of these therapies is the identification of appropriate target antigens. We have been seeking to identify immunologically recognized proteins, cancer-testis antigens (CTA) in particular, in patients with prostate cancer that would be rational target antigens., Methods: Using a previously reported panel of 29 different CTA, we used sera from 98 patients with prostate cancer and 50 healthy male blood donor controls to detect CTA-specific IgG. We then further evaluated the expression of one antigen, SSX-2, in prostate cancer cell lines and tissues., Results: We identified IgG specific for NY-ESO-1, LAGE-1, NFX-2, and SSX-2 in at least 1/98 individuals with prostate cancer. We demonstrated that SSX-2 is a prostate CTA, and its expression is associated with metastatic prostate cancer. In addition, we report that the treatment of at least two human prostate cancer cell lines with the DNA methylation inhibitor 5-aza-2'-deoxycytidine induced the expression of SSX-2. In contrast, treatment of a normal prostate epithelial cell line (RWPE-1) with 5-aza-2'-deoxycytidine did not induce SSX-2 expression., Conclusions: Our findings suggest that SSX-2 could be further pursued as an immunotherapeutic target in prostate cancer, and that treatment with 5-aza-2'-deoxycytidine could be exploited to modulate antigen expression in combination with immunotherapeutic approaches.

Background: The androgen receptor (AR) is a steroid hormone receptor that is an essential regulator of prostate development, and the primary molecular target for the treatment of metastatic prostate cancer. In this report, we evaluated whether patients with prostate cancer have pre-existing immune responses specific for the AR as evidence that the AR also might be pursued as an immunological target antigen., Methods: The detection of auto-antibodies specific for the AR in patient sera was evaluated by ELISA and Western blotting. Peripheral blood mononuclear cells were analyzed for the presence of AR-specific T-cells, as measured by T-cell proliferation, interferon gamma (IFNgamma) and interleukin-10 secretion., Results: We found that a significantly higher frequency of prostate cancer patients have AR LBD-specific antibody responses than do healthy male volunteers [18/105 cancer patients (17.1%) vs. 0/41 healthy volunteers, P = 0.0049], and that these responses were present regardless of the patients' disease stage [8/46 organ-confined prostate cancer patients (17.4%), 3/22 metastatic androgen-dependent patients (13.6%), and 7/37 metastatic, androgen-independent patients (18.9%)]. These antibodies were pre-dominantly of the IgG isotype, and furthermore of the IgG(2) sub-isotype. In addition, we found that patients with antibody responses also had concurrent antigen-specific CD4+ and CD8+ T-cell proliferation and IFNgamma secretion when compared to patients without antibody responses., Conclusions: These data demonstrate that some patients with prostate cancer have pre-existing humoral and cellular immune responses specific for the AR, suggesting that tolerance against the AR is not absolute and that the AR may be a potential immunotherapeutic target antigen.

Background: Cytotoxic T cells (CTL) are considered one of the primary effector cell populations in antitumor immunity. Recent studies, however, have demonstrated the critical importance of helper T cells (Th), specifically interferon gamma (IFN gamma)-secreting Th1 cells, either by supporting an appropriate CTL environment or by recruiting other effector cells. We evaluated whether patients with prostate cancer have naturally occurring Th-cell responses specific for two prostate cancer-associated antigens, prostate-specific antigen (PSA) and prostatic acid phosphatase (PAP), and whether Th1-type responses to these antigens could be detected., Methods: Peripheral blood mononuclear cells (PBMC) were collected from 80 patients with prostate cancer and 20 male controls without prostate disease. Th-cell responses were evaluated by measuring antigen-specific proliferation. IFN gamma and IL-5 secretion in response to antigen stimulation was determined by enzyme-linked immunosorbent assay., Results: T cell proliferative responses specific for PSA and PAP could be detected in patients with prostate cancer. Six percent (5/80) of patients had T cell responses specific for PSA and 11% (9/80) for PAP. T cell responses specific for PSA were more prevalent in patients with metastatic disease (P = 0.02), whereas responses specific for PAP could be detected in patients irrespective of disease stage. IFN gamma-producing Th cells, specific for both PSA and PAP, could be identified in patients with prostate cancer., Conclusions: Patients with prostate cancer can have detectable Th-cell responses specific for the prostate cancer-associated proteins PSA and PAP. The presence of antigen-specific Th1 immune responses in prostate cancer patients suggests that an immune environment capable of supporting antigen-specific CTL may exist in vivo. Prostate 47:222-229, 2001., (Copyright 2001 Wiley-Liss, Inc.)