Blog
About

  • Record: found
  • Abstract: found
  • Article: found
Is Open Access

Cellular immunity induced by a recombinant adenovirus- human dendritic cell vaccine for melanoma

Read this article at

Bookmark
      There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

      Abstract

      BackgroundHuman Adenoviral vectors (HAdV) are immunogenic vectors which have been tested in many vaccination and gene therapy settings. Dendritic cells (DC) transduced by genetically engineered HAdV-5 (HAdV-5/DC), are investigational cancer vaccines being tested clinically. We have previously examined immune responses to HAdV-5 -encoded melanoma tumor antigens. Here, we determined whether the HAdV-5/DC also present immunogenic HAdV-5 vector-derived antigens, and characterized the cellular immune response to the viral as well as encoded melanoma tumor antigens.MethodsBoth CD4+ and CD8+ HAdV-5-specific T cell responses were examined in vitro, with cells from both 8 healthy donors (HD) and 2 melanoma patients. PBMC were stimulated weekly with HAdV-5/DC and responses were examined after each stimulation. We also tested HAdV-5 neutralizing antibody levels and natural killer (NK) cell and regulatory T cell (Treg) activation and expansion in vitro.ResultsHAdV-5/DC rapidly induced a high frequency of type 1 cytokine producing HAdV-5-specific CD8+ and CD4+ T cells. IFNγ and TNFα-producing T cells predominate. Those with pre-existing cellular memory to HAdV-5 had more robust responses to the HAdV-5 as well as tumor-associated antigens. NK cells are activated while Treg are only minimally and transiently expanded.ConclusionsThis study demonstrates that HAdV-5/DC promote strong type I cellular immunity to viral vector-derived antigens as well as to the encoded tumor antigens. The cytokine and chemokine milieu produced by HAdV-5/DC and the activated HAdV-5-specific T cells may enhance responses to encoded tumor antigens as well. These properties make HAdV-5/DC a cancer vaccine capable of activating type 1 virus and tumor antigen-specific immunity in a cooperative way.

      Related collections

      Most cited references 38

      • Record: found
      • Abstract: found
      • Article: not found

      The immune contexture in human tumours: impact on clinical outcome.

      Tumours grow within an intricate network of epithelial cells, vascular and lymphatic vessels, cytokines and chemokines, and infiltrating immune cells. Different types of infiltrating immune cells have different effects on tumour progression, which can vary according to cancer type. In this Opinion article we discuss how the context-specific nature of infiltrating immune cells can affect the prognosis of patients.
        Bookmark
        • Record: found
        • Abstract: found
        • Article: not found

        Tolerogenic dendritic cells.

        Dendritic cells (DCs) have several functions in innate and adaptive immunity. In addition, there is increasing evidence that DCs in situ induce antigen-specific unresponsiveness or tolerance in central lymphoid organs and in the periphery. In the thymus DCs generate tolerance by deleting self-reactive T cells. In peripheral lymphoid organs DCs also induce tolerance to antigens captured by receptors that mediate efficient uptake of proteins and dying cells. Uptake by these receptors leads to the constitutive presentation of antigens on major histocompatibility complex (MHC) class I and II products. In the steady state the targeting of DC antigen capture receptors with low doses of antigens leads to deletion of the corresponding T cells and unresponsiveness to antigenic rechallenge with strong adjuvants. In contrast, if a stimulus for DC maturation is coadministered with the antigen, the mice develop immunity, including interferon-gamma-secreting effector T cells and memory T cells. There is also new evidence that DCs can contribute to the expansion and differentiation of T cells that regulate or suppress other immune T cells. One possibility is that distinct developmental stages and subsets of DCs and T cells can account for the different pathways to peripheral tolerance, such as deletion or suppression. We suggest that several clinical situations, including autoimmunity and certain infectious diseases, can be influenced by the antigen-specific tolerogenic role of DCs.
          Bookmark
          • Record: found
          • Abstract: found
          • Article: not found

          Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step Study): a double-blind, randomised, placebo-controlled, test-of-concept trial.

          Observational data and non-human primate challenge studies suggest that cell-mediated immune responses might provide control of HIV replication. The Step Study directly assessed the efficacy of a cell-mediated immunity vaccine to protect against HIV-1 infection or change in early plasma HIV-1 levels. We undertook a double-blind, phase II, test-of-concept study at 34 sites in North America, the Caribbean, South America, and Australia. We randomly assigned 3000 HIV-1-seronegative participants by computer-generated assignments to receive three injections of MRKAd5 HIV-1 gag/pol/nef vaccine (n=1494) or placebo (n=1506). Randomisation was prestratified by sex, adenovirus type 5 (Ad5) antibody titre at baseline, and study site. Primary objective was a reduction in HIV-1 acquisition rates (tested every 6 months) or a decrease in HIV-1 viral-load setpoint (early plasma HIV-1 RNA measured 3 months after HIV-1 diagnosis). Analyses were per protocol and modified intention to treat. The study was stopped early because it unexpectedly met the prespecified futility boundaries at the first interim analysis. This study is registered with ClinicalTrials.gov, number NCT00095576. In a prespecified interim analysis in participants with baseline Ad5 antibody titre 200 or less, 24 (3%) of 741 vaccine recipients became HIV-1 infected versus 21 (3%) of 762 placebo recipients (hazard ratio [HR] 1.2 [95% CI 0.6-2.2]). All but one infection occurred in men. The corresponding geometric mean plasma HIV-1 RNA was comparable in infected male vaccine and placebo recipients (4.61 vs 4.41 log(10) copies per mL, one tailed p value for potential benefit 0.66). The vaccine elicited interferon-gamma ELISPOT responses in 75% (267) of the 25% random sample of all vaccine recipients (including both low and high Ad5 antibody titres) on whose specimens this testing was done (n=354). In exploratory analyses of all study volunteers, irrespective of baseline Ad5 antibody titre, the HR of HIV-1 infection between vaccine and placebo recipients was higher in Ad5 seropositive men (HR 2.3 [95% CI 1.2-4.3]) and uncircumcised men (3.8 [1.5-9.3]), but was not increased in Ad5 seronegative (1.0 [0.5-1.9]) or circumcised (1.0 [0.6-1.7]) men. This cell-mediated immunity vaccine did not prevent HIV-1 infection or reduce early viral level. Mechanisms for insufficient efficacy of the vaccine and the increased HIV-1 infection rates in subgroups of vaccine recipients are being explored.
            Bookmark

            Author and article information

            Affiliations
            [1 ]Department of Medicine, University of Pittsburgh Cancer Institute, 5117 Centre Avenue, Suite 1.27, Pittsburgh, PA 15213, USA
            [2 ]Department of Surgery, University of Pittsburgh Cancer Institute, 5117 Centre Avenue, Suite 1.27, Pittsburgh, PA 15213, USA
            [3 ]Department of Immunology, University of Pittsburgh Cancer Institute, 5117 Centre Avenue, Suite 1.27, Pittsburgh, PA 15213, USA
            [4 ]University of Pittsburgh Cancer Institute, 5117 Centre Avenue, Suite 1.27, Pittsburgh, PA 15213, USA
            Contributors
            Journal
            J Immunother Cancer
            J Immunother Cancer
            Journal for Immunotherapy of Cancer
            BioMed Central
            2051-1426
            2013
            18 November 2013
            : 1
            : 19
            4019908
            2051-1426-1-19
            10.1186/2051-1426-1-19
            Copyright © 2013 Naveh et al.; licensee BioMed Central Ltd.

            This is an open access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

            Categories
            Research Article

            Comments

            Comment on this article