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M. Van Nimwegen

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    ORAL 40 - Biology 1 (ID 154)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
    • Presentations: 1
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      ORAL40.03 - Combination Therapy with a CD40-Agonist and Dendritic Cell Immunotherapy Has Synergistic Effects in a Murine Mesothelioma Model (ID 2643)

      16:45 - 18:15  |  Author(s): M. Van Nimwegen

      • Abstract
      • Presentation
      • Slides

      The potential of immunotherapy in mesothelioma has recently been demonstrated in multiple (pre)clinical studies. The success of immunotherapy relies on the induction of an anti-tumor immune response which has to overcome the local immunosuppressive environment in established tumors. Tumor-associated macrophages (TAMs) are an important part of the suppressive environment in mesothelioma and reprogramming these TAMs towards a more pro-inflammatory phenotype using a CD40-agonist has shown promising results in multiple solid tumors. Dendritic cell (DC) immunotherapy has been shown to elicit anti-tumor T-cell responses and is currently being studied in mesothelioma patients at our institution. We hypothesize that the combination treatment with a CD40-agonist and DC therapy has synergistic effects and the aim of the current study is to investigate the efficacy of this combinatorial approach.

      Wildtype Balb/c mice were injected intraperitoneally (i.p.) with the AB1 murine mesothelioma cell line. Different treatment regimens were compared as follows: untreated control group (n=6), monotherapy with CD40-agonist (FGK4.5 monoclonal antibody, n=5), monotherapy with DC immunotherapy (n=5) and combination therapy of DC immunotherapy followed by treatment with the CD40-agonist (n=5). Three days after completion of the treatment regimens, blood was drawn and analyzed using flow cytometry to investigate peripheral immune activation. All mice were monitored and sacrificed when showing signs of severe illness. After sacrifice, tumors are investigated using flow cytometry to determine the local immunological composition.

      Blood analysis revealed that peripheral monocytes of the CD40-agonist group and the combination therapy group showed an increase in expression of MHC-II and PD-L1 compared to the mice in the control group and the DC immunotherapy group. In addition, the combination therapy induced a profound increase in effector CD8 T-cells and proliferating CD8 T-cells compared to the monotherapies. The interim survival analysis at day 40 post tumor cell injection demonstrates a 17% survival of the control group, 80% survival of the monotherapies and 100% survival of the combination therapy. The final survival analysis will be presented at the conference.

      Combination therapy of DC immunotherapy and a CD40-agonistic antibody induces synergistic immune activation in the peripheral blood of mesothelioma-bearing mice compared to the monotherapies. Although the final survival data are awaited, the presented data demonstrate the potential of the combination of cellular immunotherapy and targeting of the local tumor microenvironment in mesothelioma.

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