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  MA12 - New Frontiers from Pathology to Genomics (ID 138)

  • Event: WCLC 2019
  • Type: Mini Oral Session
  • Track: Mesothelioma
  • Presentations: 1
  • Now Available
  • Moderators:Prasad S Adusumilli, Francisco Perez Ochoa
  • Coordinates: 9/09/2019, 14:00 - 15:30, Melbourne (1991)

  • 30155

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    MA12.09 - Checkpoint Inhibitors Synergize with Dendritic Cell-Therapy in Pre-Clinical Models and Mesothelioma Patients (Now Available) (ID 2425)

    14:00 - 15:30  |  Author(s): Floris Dammeijer
    • Abstract
    • Presentation
    • Slides

    Background
    

    Malignant Pleural Mesothelioma (MPM) is a lethal, treatment resistant neoplasm. Checkpoint inhibitors (CI) have shown promising clinical effects in a minority of patients. It is hypothesized that low response rates to CI are correlated to low numbers of tumor-infiltrating T-cells in MPM patients. Dendritic cell (DC) therapy instigates an immune response and activates tumor-specific T-cells. DC therapy has proven to be effective in pre-clinical models and in a subset of MPM patients. Upregulation of PD-L1 and PD-1 co-inhibitory checkpoints may suppress DC-therapy induced anti-tumor immune response and limit clinical efficacy. To investigate this, we conducted a preclinical and clinical study to evaluate the clinical and immunological effects of DC therapy combined with CI.

    Method
    

    Immune competent CBA/J mice were orthotopically injected with a syngeneic mesothelioma cell line. Mice were treated with DC-therapy alone or in combination anti-PD-L1 antibodies at high tumor load when DC-monotherapy was found to be ineffective. Peripheral blood and tumors were obtained for flow cytometric analysis and survival was monitored.
    In a clinical setting, nine patients that received DC therapy were sequentially treated with CI. Progression free survival (PFS) was determined from start of CI, using the modified RECIST criteria.

    Result
    

    Tumors of mice treated with DC-therapy exhibited a three-fold increase in CD8+ T-cell infiltration which was paralleled by heightened expression of PD-L1 on tumor cells (r²=0.69, p=0.0015). Whereas both anti-PD-L1 and DC-monotherapies were ineffective in prolonging survival in our model, combination immunotherapy did (median OS: 24 vs 35 days, p=0.0063). Immune monitoring analyses demonstrated a synergistic increase in proliferation and activation of circulating T-cell following combination therapy. In the clinical trial 3 patients had partial response, 5 patients had stable disease and 1 patient had progressive disease. Median PFS was 5,2 months and median OS was 17,5 months. Currently 3 patients are still alive and two patients are still progression free. There were no grade 3/4 adverse events. PD-L1 expression in tumor biopsies was increased after DC therapy in two of the three responders to CI.

    Conclusion
    

    In a murine model the synergy between DC therapy and CI was proven and efficacy was driven by activation of CD4+ and CD8+ positive cells. In humans, CI after DC therapy is safe and feasible. Disease control was seen in 8 out of 9 patients treated with CI after DC therapy. DC therapy induces tumor-specific CD8+ T-cell proliferation which is correlated to PD-L1 expression on tumor cells and possibly synergizes with CI treatment.

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