Immunotherapy with MVA-BN®-HER2 induces HER-2-specific Th1 immunity and alters the intratumoral balance of effector and regulatory T cells

MVA-BN®-HER2 is a new candidate immunotherapy designed for the treatment of HER-2-positive breast cancer. Here, we demonstrate that a single treatment with MVA-BN®-HER2 exerts potent anti-tumor efficacy in a murine model of experimental pulmonary metastasis. This anti-tumor efficacy occurred despite a strong tumor-mediated immunosuppressive environment characterized by a high frequency of regulatory T cells (Treg) in the lungs of tumor-bearing mice. Immunogenicity studies showed that treatment with MVA-BN®-HER2 induced strongly Th1-dominated HER-2-specific antibody and T-cell responses. MVA-BN®-HER2-induced anti-tumor activity was characterized by an increased infiltration of lungs with highly activated, HER-2-specific, CD8+CD11c+ T cells accompanied by a decrease in the frequency of Treg cells in the lung, resulting in a significantly increased ratio of effector T cells to Treg cells. In contrast, administration of HER2 protein formulated in Complete Freund’s Adjuvant (CFA) induced a strongly Th2-biased immune response to HER-2. However, this did not lead to significant infiltration of the tumor-bearing lungs by CD8+ T cells or the decrease in the frequency of Treg cells nor did it result in anti-tumor efficacy. In vivo depletion of CD8+ cells confirmed that CD8 T cells were required for the anti-tumor activity of MVA-BN®-HER2. Furthermore, depletion of CD4+ or CD25+ cells demonstrated that tumor-induced Treg cells promoted tumor growth and that CD4 effector cells also contribute to MVA-BN®-HER2-mediated anti-tumor efficacy. Taken together, our data demonstrate that treatment with MVA-BN®-HER2 controls tumor growth through mechanisms including the induction of Th1-biased HER-2-specific immune responses and the control of tumor-mediated immunosuppression

Novel Serial Positive Enrichment Technology Enables Clinical Multiparameter Cell Sorting

A general obstacle for clinical cell preparations is limited purity, which causes variability in the quality and potency of cell products and might be responsible for negative side effects due to unwanted contaminants. Highly pure populations can be obtained best using positive selection techniques. However, in many cases target cell populations need to be segregated from other cells by combinations of multiple markers, which is still difficult to achieve – especially for clinical cell products. Therefore, we have generated low-affinity antibody-derived Fab-fragments, which stain like parental antibodies when multimerized via Strep-tag and Strep-Tactin, but can subsequently be removed entirely from the target cell population. Such reagents can be generated for virtually any antigen and can be used for sequential positive enrichment steps via paramagnetic beads. First protocols for multiparameter enrichment of two clinically relevant cell populations, CD4high/CD25high/CD45RAhigh ‘regulatory T cells’ and CD8high/CD62Lhigh/CD45RAneg ‘central memory T cells’, have been established to determine quality and efficacy parameters of this novel technology, which should have broad applicability for clinical cell sorting as well as basic research

A Pilot Study of IL-2Rα Blockade during Lymphopenia Depletes Regulatory T-cells and Correlates with Enhanced Immunity in Patients with Glioblastoma

Preclinical studies in mice have demonstrated that the prophylactic depletion of immunosuppressive regulatory T-cells (T(Regs)) through targeting the high affinity interleukin-2 (IL-2) receptor (IL-2Rα/CD25) can enhance anti-tumor immunotherapy. However, therapeutic approaches are complicated by the inadvertent inhibition of IL-2Rα expressing anti-tumor effector T-cells.To determine if changes in the cytokine milieu during lymphopenia may engender differential signaling requirements that would enable unarmed anti-IL-2Rα monoclonal antibody (MAbs) to selectively deplete T(Regs) while permitting vaccine-stimulated immune responses.A randomized placebo-controlled pilot study was undertaken to examine the ability of the anti-IL-2Rα MAb daclizumab, given at the time of epidermal growth factor receptor variant III (EGFRvIII) targeted peptide vaccination, to safely and selectively deplete T(Regs) in patients with glioblastoma (GBM) treated with lymphodepleting temozolomide (TMZ).Daclizumab treatment (n = 3) was well-tolerated with no symptoms of autoimmune toxicity and resulted in a significant reduction in the frequency of circulating CD4+Foxp3+ TRegs in comparison to saline controls (n = 3)( p = 0.0464). A significant (p<0.0001) inverse correlation between the frequency of TRegs and the level of EGFRvIII specific humoral responses suggests the depletion of TRegs may be linked to increased vaccine-stimulated humoral immunity. These data suggest this approach deserves further study.ClinicalTrials.gov NCT00626015

Class, Trust and Confessional Media in Austerity Britain

This article situates The Jeremy Kyle Show, a television talk show broadcast in the United Kingdom, in wider narratives of austerity politics in order to explore the reinforcement and legitimation through reality television of neoliberal measures for economic crisis management. In the first section, it is argued that technologies of confession – lie detectors, paternity tests, drug testing – are used on guests who are deemed, by virtue of class position, to be untrustworthy, undermining the very basis of therapeutic talk by deferring to scientific measurement of the body in order to derive truths. In the second section, it is argued that this measurement does not simply identify bodily truths but locates bodies that lack the discipline to contribute efficiently to the austerity agenda, providing a platform for shaming that amounts to an attack on the welfare state. This article introduces austerity television, and the austerity realism that it promotes, as an important area of study in the humanities and social sciences

Limitations to Intellectual Progress in Ecosystem Science

Are ecosystem scientists poised to make great leaps forward in developing understanding, and in applying it to real-world problems? The challenge is to deal simultaneously with the multidimensional complexity of time and space. An intellectual limitation is the false assumption that there will be simple, all-inclusive answers to complex, ecological questions, whereas the elegance of creative, innovative thought and approach is to discover ways to simplify questions or systems being studied to obtain fundamental, inclusive answers. Ecology must be an integrative science and will flourish from creative integration and synthesis. How are vision and creativity enhanced? Is the rate of breakthroughs in ecosystem science appropriate for a healthy, robust scientific field? Teams and team-building are critical components of successful ecosystem science, but efforts should be made to promote inter-disciplinary teams. There is a continuing need to attract the brightest and best into ecosystem science by utilizing the popularity of the ecosystem concept, the challenge of solving complex problems, and the awareness of how such solutions are of value to humanity. More undergraduate courses, textbooks, and scientific journals focused on ecosystem science are needed, however time limitations have become serious problems for scientists. Being busy is good, but if being busy leads to fragmentation of effort, loss of focus, superficial scholarship, and inability to meet commitments, then being busy represents a major intellectual limitation. The weak connection between ecosystem science and policy in the United States is frustrating, primarily because of fragmentation of approach and implementation. However, many opportunities exist for intellectual progress in ecosystem science