Combination immunotherapy and active-specific tumor cell vaccination augments anti-cancer immunity in a mouse model of gastric cancer

<p>Abstract</p> <p>Background</p> <p>Active-specific immunotherapy used as an adjuvant therapeutic strategy is rather unexplored for cancers with poorly characterized tumor antigens like gastric cancer. The aim of this study was to augment a therapeutic immune response to a low immunogenic tumor cell line derived from a spontaneous gastric tumor of a CEA424-SV40 large T antigen (CEA424-SV40 TAg) transgenic mouse.</p> <p>Methods</p> <p>Mice were treated with a lymphodepleting dose of cyclophosphamide prior to reconstitution with syngeneic spleen cells and vaccination with a whole tumor cell vaccine combined with GM-CSF (a treatment strategy abbreviated as LRAST). Anti-tumor activity to subcutaneous tumor challenge was examined in a prophylactic as well as a therapeutic setting and compared to corresponding controls.</p> <p>Results</p> <p>LRAST enhances tumor-specific T cell responses and efficiently inhibits growth of subsequent transplanted tumor cells. In addition, LRAST tended to slow down growth of established tumors. The improved anti-tumor immune response was accompanied by a transient decrease in the frequency and absolute number of CD4⁺CD25⁺FoxP3⁺T cells (Tregs).</p> <p>Conclusions</p> <p>Our data support the concept that whole tumor cell vaccination in a lymphodepleted and reconstituted host in combination with GM-CSF induces therapeutic tumor-specific T cells. However, the long-term efficacy of the treatment may be dampened by the recurrence of Tregs. Strategies to counteract suppressive immune mechanisms are required to further evaluate this therapeutic vaccination protocol.</p

Impact of entrainment and impingement on fish populations in the Hudson River Estuary. Volume II. Impingement impact analyses, evaluations of alternative screening devices, and critiques of utility testimony relating to density-dependent growth, the age-composition of the striped bass spawning stock, and the LMS real-time life cycle model

This volume includes a series of four exhibits relating to impacts of impingement on fish populations, together with a collection of critical evaluations of testimony prepared for the utilities by their consultants. The first exhibit is a quantitative evaluation of four sources of bias (collection efficiency, reimpingement, impingement on inoperative screens, and impingement survival) affecting estimates of the number of fish killed at Hudson River power plants. The two following exhibits contain, respectively, a detailed assessment of the impact of impingement on the Hudson River white perch population and estimates of conditional impingement mortality rates for seven Hudson River fish populations. The fourth exhibit is an evaluation of the engineering feasibility and potential biological effectiveness of several types of modified intake structures proposed as alternatives to cooling towers for reducing impingement impacts. The remainder of Volume II consists of critical evaluations of the utilities&#x27; empirical evidence for the existence of density-dependent growth in young-of-the-year striped bass and white perch, of their estimate of the age-composition of the striped bass spawning stock in the Hudson River, and of their use of the Lawler, Matusky, and Skelly (LMS) Real-Time Life Cycle Model to estimate the impact of entrainment and impingement on the Hudson River striped bass population

Efficacy of cytokine gene transfection may differ for autologous and allogeneic tumour cell vaccines

Whole tumour cells are a logical basis for generating immunity against the cancers they comprise or represent. A number of human trials have been initiated using cytokine-transfected whole tumour cells of autologous (patient-derived) or allogeneic [major histocompatibility complex (MHC)-disparate] origin as vaccines. Although precedent exists for the efficacy of autologous-transfected cell vaccines in animal models, little preclinical evidence confirms that these findings will extrapolate to allogeneic-transfected cell vaccines. In order to address this issue a murine melanoma cell line (K1735) was transfected to secrete interleukin (IL)-2, IL-4, IL-7 or granulocyte–macrophage colony-stimulating factor (GM-CSF); cytokines currently in use in trials. The efficacy of these cells as irradiated vaccines was tested head-to-head in syngeneic (C3H) mice and in MHC-disparate (C57BL/6) mice, the former being subsequently challenged with K1735 cells and the latter with naturally cross-reactive B16-F10 melanoma cells. Whilst the GM-CSF-secreting vaccine was the most effective at generating protection in C3H mice, little enhancement in protection above the wild-type vaccine was seen with any of the transfections for the allogeneic vaccines, even though the wild-type vaccine was more effective than the autologous B16-F10 vaccine. Anti-tumour cytotoxic T-lymphocyte (CTL) activity was detected in both models but did not correlate well with protection, whilst in vitro anti-tumour interferon-γ (IFN-γ) secretion tended to be higher following the GM-CSF-secreting vaccine. Cytokine transfection of vaccines generally increased anti-tumour CTL activity and IFN-γ secretion (T helper type 1 response). Further studies in other model systems are required to confirm this apparent lack of benefit of cytokine transduction over wild-type allogeneic vaccines, and to determine which in vitro assays will correlate best with protection in vivo