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M. Sheaff



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    MA 19 - Mesothelioma: Bench to Bedside (ID 680)

    • Event: WCLC 2017
    • Type: Mini Oral
    • Track: Mesothelioma
    • Presentations: 1
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      MA 19.05 - Pegylated Arginine Deiminase Potentiates PD-1/PD-L1 Immune Checkpoint Blockade in Malignant Mesothelioma (ID 9207)

      11:30 - 11:35  |  Author(s): M. Sheaff

      • Abstract
      • Slides

      Background:
      Malignant pleural mesothelioma is a difficult to treat asbestos-driven cancer that is on the increase globally. The urea cycle and tumor suppressor enzyme argininosuccinate synthetase 1 (ASS1), involved in arginine synthesis, is downregulated in half of mesotheliomas which are then sensitive to arginine deprivation therapy. Trials of the arginine depletor pegylated arginine deiminase, ADI-PEG20, have confirmed single-agent and combination safety and efficacy in patients with mesothelioma. Here, we explored the immunometabolic consequences of ASS1 loss in mesothelioma uncovering a role for combining ADI-PEG20 with PD1/PD-L1 checkpoint blockade.

      Method:
      Three ASS1-negative and one ASS1-positive MPM cell lines were assessed for PD-L1 expression by real-time quantitative PCR, western blot and FACS analysis. Cell lines were manipulated for ASS1 overexpression (endogenous and genetic) and siRNA followed by gene expression analysis. Cell lines were cultured with and without ADI-PEG20 and assessed for PD-L1 expression and cytokine production by ELISA. An immunocompetent murine tumor model of ASS1 loss mimicking aggressive mesothelioma was treated with PBS control, ADI-PEG20, anti-PD-1 antibody, and ADI-PEG20 plus anti-PD-1 antibody. Tumors were harvested and analysed for immune cell subsets by FACS. Finally, human mesothelioma biopsies from trials of ADI-PEG20 were analyzed for ASS1 and PD-L1 and immune cell subsets.

      Result:
      PDL1 protein was absent in the three ASS1 negative MPM cell lines but was present in the ASS1 positive cell line. Transfection of ASS1 in the ASS1 negative MPM cell lines led to an increase in PD-L1 expression, which was reversible following ASS1 knockdown. Induction of PD-L1 expression by forced ASS1 overexpression was accompanied by an increase in interferon type I signaling. Similar results were obtained in a mesothelioma cell line developing resistance to ADI-PEG20 under long-term culture. Next, ADI-PEG20 treatment triggered release of interferon-alpha/beta which induced PD-L1 expression by 24hrs in the ASS1-negative MPM cell lines before declining by 48hrs. Analysis of MPM biopsies of patients progressing on ADI-PEG20 revealed upregulation of ASS1 and a concomitant increase in tumoral PD-L1 and CD3 positive T cells. ADI-PEG20 synergized with PD-1 blockade in the immunocompetent murine tumor model that was refractory to PD-1 inhibition.

      Conclusion:
      ASS1 and ADI-PEG20 modulate PDL1 expression via type I interferon signaling in malignant mesothelioma cell lines. Arginine deprivation with ADI-PEG20 combined with PD-1 blockade is synergistic and warrants further exploration in the clinic. A phase 1 trial of ADI-PEG20 combined with PD1 blockade is planned in patients with ASS1-negative cancers, including malignant mesothelioma.

      Information from this presentation has been removed upon request of the author.

      Information from this presentation has been removed upon request of the author.