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  • [Clin Cancer Res.] IDO1 Inhibition Synergizes with Radiation and PD-1 Blockade to Durably Increase Survival Against Advanced Glioblastoma.

    Northwestern University Feinberg School of Medicine / Derek A. Wainwright*

  • 출처
    Clin Cancer Res.
  • 등재일
    2018 Jun 1
  • 저널이슈번호
    24(11):2559-2573. doi: 10.1158/1078-0432.CCR-17-3573. Epub 2018 Mar 2.
  • 내용

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    Abstract
    Purpose: Glioblastoma is the most aggressive primary brain tumor in adults with a median survival of 15-20 months. Numerous approaches and novel therapeutics for treating glioblastoma have been investigated in the setting of phase III clinical trials, including a recent analysis of the immune checkpoint inhibitor, nivolumab (anti-PD-1), which failed to improve recurrent glioblastoma patient survival. However, rather than abandoning immune checkpoint inhibitor treatment for glioblastoma, which has shown promise in other types of cancer, ongoing studies are currently evaluating this therapeutic class when combined with other agents.Experimental Design: Here, we investigated immunocompetent orthotopic mouse models of glioblastoma treated with the potent CNS-penetrating IDO1 enzyme inhibitor, BGB-5777, combined with anti-PD1 mAb, as well as radiotherapy, based on our recent observation that tumor-infiltrating T cells directly increase immunosuppressive IDO1 levels in human glioblastoma, the previously described reinvigoration of immune cell functions after PD-1 blockade, as well as the proinflammatory effects of radiation.Results: Our results demonstrate a durable survival benefit from this novel three-agent treatment, but not for any single- or dual-agent combination. Unexpectedly, treatment efficacy required IDO1 enzyme inhibition in non-glioblastoma cells, rather than tumor cells. Timing of effector T-cell infiltration, animal subject age, and usage of systemic chemotherapy, all directly impacted therapy-mediated survival benefit.Conclusions: These data highlight a novel and clinically relevant immunotherapeutic approach with associated mechanistic considerations that have formed the basis of a newly initiated phase I/II trial for glioblastoma patients.

     


    Author information

    Ladomersky E1, Zhai L1, Lenzen A1, Lauing KL1, Qian J1, Scholtens DM2, Gritsina G3, Sun X4, Liu Y4, Yu F4, Gong W4, Liu Y4, Jiang B4, Tang T4, Patel R5, Platanias LC6,7, James CD1,7,8, Stupp R1,6,7,9, Lukas RV7,9, Binder DC10, Wainwright DA11,6,7,12.
    1
    Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
    2
    Department of Preventive Medicine-Biostatistics, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
    3
    Department of Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
    4
    BeiGene, Zhong-Guan-Cun Life Science Park, Changping District, Beijing, China.
    5
    Rosalind Franklin University of Medicine and Science, North Chicago, Illinois.
    6
    Department of Medicine-Division of Hematology and Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
    7
    Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois.
    8
    Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
    9
    Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
    10
    Department of Radiation Oncology, University of Colorado School of Medicine, Aurora, Colorado.
    11
    Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois. Derekwainwright@northwestern.edu.
    12
    Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago

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