7007 Wisconsin Institutes for Medical Research

Madison, WI, United States

7007 Wisconsin Institutes for Medical Research

Madison, WI, United States
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Smith H.A.,University of Wisconsin - Madison | Maricque B.B.,University of Wisconsin - Madison | Eberhardt J.,DecisionQ Corporation | Petersen B.,DecisionQ Corporation | And 4 more authors.
Journal of Biomedicine and Biotechnology | Year: 2011

We previously demonstrated that IgG responses to a panel of 126 prostate tissue-associated antigens are common in patients with prostate cancer. In the current report we questioned whether changes in IgG responses to this panel might be used as a measure of immune response, and potentially antigen spread, following prostate cancer-directed immune-active therapies. Sera were obtained from prostate cancer patients prior to and three months following treatment with androgen deprivation therapy (n=34), a poxviral vaccine (n=31), and a DNA vaccine (n=21). Changes in IgG responses to individual antigens were identified by phage immunoblot. Patterns of IgG recognition following three months of treatment were evaluated using a machine-learned Bayesian Belief Network (ML-BBN). We found that different antigens were recognized following androgen deprivation compared with vaccine therapies. While the number of clinical responders was low in the vaccine-treated populations, we demonstrate that ML-BBN can be used to develop potentially predictive models. Copyright © 2011 Heath A. Smith et al.

Olson B.M.,University of Wisconsin - Madison | Johnson L.E.,University of Wisconsin - Madison | McNeel D.G.,University of Wisconsin - Madison | McNeel D.G.,7007 Wisconsin Institutes for Medical Research
Cancer Immunology, Immunotherapy | Year: 2013

The androgen receptor (AR) plays an essential role in the development and progression of prostate cancer. However, while it has long been the primary molecular target of metastatic prostate cancer therapies, it has not been explored as an immunotherapeutic target. In particular, the AR ligand-binding domain (LBD) is a potentially attractive target, as it has an identical sequence among humans as well as among multiple species, providing a logical candidate for preclinical evaluation. In this report, we evaluated the immune and anti-tumor efficacy of a DNA vaccine targeting the AR LBD (pTVG-AR) in relevant rodent preclinical models. We found immunization of HHDII-DR1 mice, which express human HLA-A2 and HLA-DR1, with pTVG-AR augmented AR LBD HLA-A2-restricted peptide-specific, cytotoxic immune responses in vivo that could lyse human prostate cancer cells. Using an HLA-A2-expressing autochthonous model of prostate cancer, immunization with pTVG-AR augmented HLA-A2-restricted immune responses that could lyse syngeneic prostate tumor cells and led to a decrease in tumor burden and an increase in overall survival of tumor-bearing animals. Finally, immunization decreased prostate tumor growth in Copenhagen rats that was associated with a Th1-type immune response. These data show that the AR is as a prostate cancer immunological target antigen and that a DNA vaccine targeting the AR LBD is an attractive candidate for clinical evaluation. © 2012 Springer-Verlag Berlin Heidelberg.

Alam S.,University of Wisconsin - Madison | McNeel D.G.,7007 Wisconsin Institutes for Medical Research
Expert Review of Vaccines | Year: 2010

Prostate cancer is a significant public health problem, and the most commonly diagnosed cancer in the USA. The long natural history of prostate cancer, the presence of a serum biomarker that can be used to detect very early recurrences, and the previous identification of multiple potential tissue-specific target antigens are all features that make this disease suitable for the development of anti-tumor vaccines. To date, many anti-tumor vaccines have entered clinical testing for patients with prostate cancer, and some have demonstrated clinical benefit. DNA vaccines represent one vaccine approach that has been evaluated in multiple preclinical models and clinical trials. The safety, specificity for the target antigen, ease of manufacturing and ease of incorporating other immune-modulating approaches make DNA vaccines particularly relevant for future development. This article focuses on DNA vaccines specifically in the context of prostate cancer treatment, focusing on antigens targeted in preclinical models, recent clinical trials and efforts to improve the potency of these vaccines. © 2010 Expert Reviews Ltd.

Smith H.A.,University of Wisconsin - Madison | McNeel D.G.,University of Wisconsin - Madison | McNeel D.G.,7007 Wisconsin Institutes for Medical Research
Clinical and Developmental Immunology | Year: 2010

Cancer-testis antigens (CTAs) represent an expanding class of tumor-associated proteins defined on the basis of their tissue-restricted expression to testis or ovary germline cells and frequent ectopic expression in tumor tissue. The expression of CTA in MHC class I-deficient germline cells makes these proteins particularly attractive as immunotherapeutic targets because they serve as essentially tumor-specific antigens for MHC class I-restricted CD8+ T cells. Moreover, because CTAs are expressed in many types of cancer, any therapeutic developed to target these antigens might have efficacy for multiple cancer types. Of particular interest among CTAs is the synovial sarcoma X chromosome breakpoint (SSX) family of proteins, which includes ten highly homologous family members. Expression of SSX proteins in tumor tissues has been associated with advanced stages of disease and worse patient prognosis. Additionally, both humoral and cell-mediated immune responses to SSX proteins have been demonstrated in patients with tumors of varying histological origin, which indicates that natural immune responses can be spontaneously generated to these antigens in cancer patients. The current review will describe the history and identification of this family of proteins, as well as what is known of their function, expression in normal and malignant tissues, and immunogenicity. Copyright © 2010 Heath A. Smith and Douglas G. McNeel.

McNeel D.G.,University of Wisconsin - Madison | McNeel D.G.,7007 Wisconsin Institutes for Medical Research | Smith H.A.,University of Wisconsin - Madison | Eickhoff J.C.,University of Wisconsin - Madison | And 4 more authors.
Cancer Immunology, Immunotherapy | Year: 2012

CTLA-4 blockade has demonstrated antitumor efficacy in human clinical trials. The antitumor mechanism is presumably mediated in part by the expansion of tumor-specific T cells. Androgen deprivation, the cornerstone of treatment for patients with metastatic prostate cancer, has been shown to elicit prostate tissue apoptosis and lymphocytic inflammation. We hypothesized that treatment with androgen deprivation, followed by an anti-CTLA-4 antibody, could augment a tumor-specific immune response elicited by androgen deprivation. We report here the results of a phase I trial evaluating a humanized monoclonal antibody targeting CTLA-4, CP-675,206 (tremelimumab), in combination with androgen deprivation using an antiandrogen. Eligible patients were those with PSA-recurrent prostate cancer after primary surgery and/or radiation therapy, not previously treated with androgen deprivation, and without radiographic evidence of metastatic disease. Subjects were treated in two cycles, 3 months apart, in which they received bicalutamide 150 mg daily days 1-28 and tremelimumab on day 29. The primary endpoint of the trial was safety. Secondary endpoints included measures of PSA kinetics and identification of a maximum tolerated dose. Eleven patients were enrolled and completed at least 1 year of follow-up. Dose-limiting toxicities included grade 3 diarrhea and skin rash. No favorable changes in PSA doubling time were observed in a period shortly after completing treatment; however, three patients experienced a prolongation in PSA doubling time detectable several months after completing treatment. The identification of delayed, prolonged favorable changes in serum PSA suggests that future studies could explore this combination in studies evaluating time to disease progression. © 2011 Springer-Verlag.

Lang J.M.,University of Wisconsin - Madison | Kaikobad M.R.,University of Wisconsin - Madison | Wallace M.,University of Wisconsin - Madison | Staab M.J.,University of Wisconsin - Madison | And 7 more authors.
Cancer Immunology, Immunotherapy | Year: 2011

Prior to the advent of VEGF-targeted therapies, renal cell carcinoma (RCC) was among the few solid tumors shown to respond to cytokine-based therapies such as interleukin-2 (IL-2) and interferon alpha. Previous work has shown that aminobisphosphonates, including zoledronic acid (ZA), are capable of activating human Vγ9 Vδ2 T cells in vitro, and these cells can be further expanded with IL-2. Moreover, these Vγ9 Vδ2 T cells have cytolytic activity in vitro to multiple human tumor cell lines. In the current report, we have conducted a pilot trial in patients with metastatic RCC, evaluating different doses of ZA in combination with low-dose IL-2 to determine whether combining these agents can promote in vivo proliferation of Vγ9 Vδ2 T cells and elicit an antitumor response. In 12 patients evaluated, no objective clinical responses were observed by RECIST criteria; however, two patients experienced prolonged stable disease. A modest increase in Vγ9 Vδ2 T-cell frequency could be detected by Day 8 of therapy in four of the nine patients who received at least one cycle of therapy, but not to the magnitude anticipated from preclinical models. Repeated administration of IL-2 and ZA resulted in both a diminished in vivo percentage of Vγ9 Vδ2 T cells as well as impaired expansion in vitro after the first cycle of therapy. These results suggest that repeated administration of IL-2 and ZA, at the doses and schedules used in this trial, may actually inhibit the proliferative capacity of Vγ9 Vδ2 T cell in patients with metastatic RCC. © 2011 Springer-Verlag.

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