IDO1 Inhibition Synergizes with Radiation and PD-1 Blockade to Durably Increase Survival Against Advanced Glioblastoma.

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. Clin Cancer Res; 24(11); 2559-73. ©2018 AACR.

• Authors: Erik Ladomersky, Lijie Zhai, Alicia Lenzen, Kristen L Lauing, Jun Qian, Denise M Scholtens, Galina Gritsina, Xuebing Sun, Ye Liu, Fenglong Yu, Wenfeng Gong, Yong Liu, Beibei Jiang, Tristin Tang, Ricky Patel, Leonidas C Platanias, C David James, Roger Stupp, Rimas V Lukas, David C Binder, Derek A Wainwright
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 24 Issue 11 Pg. 2559-2573 (06 01 2018) ISSN: 1557-3265 [Electronic] United States
• PMID: 29500275 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents, Immunological
• Enzyme Inhibitors
• IDO1 protein, mouse
• Indoleamine-Pyrrole 2,3,-Dioxygenase
• Programmed Cell Death 1 Receptor

Topics

• Animals
• Antineoplastic Agents, Immunological (administration & dosage, pharmacokinetics, pharmacology)
• Cell Line, Tumor
• Combined Modality Therapy
• Disease Models, Animal
• Drug Synergism
• Energy Metabolism (drug effects, radiation effects)
• Enzyme Activation (drug effects)
• Enzyme Inhibitors (administration & dosage, pharmacokinetics, pharmacology)
• Glioblastoma (metabolism, mortality, pathology, therapy)
• Humans
• Indoleamine-Pyrrole 2,3,-Dioxygenase (antagonists & inhibitors, genetics, metabolism)
• Male
• Mice
• Mice, Knockout
• Neoplasm Metastasis
• Neoplasm Staging
• Programmed Cell Death 1 Receptor (antagonists & inhibitors, metabolism)
• Radiation, Ionizing
• Survival Analysis
• T-Lymphocytes (drug effects, immunology, metabolism)
• Xenograft Model Antitumor Assays