TY - JOUR
T1 - IDO1 inhibition synergizes with radiation and PD-1 blockade to durably increase survival against advanced glioblastoma
AU - Ladomersky, Erik
AU - Zhai, Lijie
AU - Lenzen, Alicia
AU - Lauing, Kristen L.
AU - Qian, Jun
AU - Scholtens, Denise M.
AU - Gritsina, Galina
AU - Sun, Xuebing
AU - Liu, Ye
AU - Yu, Fenglong
AU - Gong, Wenfeng
AU - Liu, Yong
AU - Jiang, Beibei
AU - Tang, Tristin
AU - Patel, Ricky
AU - Platanias, Leonidas C.
AU - David James, C.
AU - Stupp, Roger
AU - Lukas, Rimas V.
AU - Binder, David C.
AU - Wainwright, Derek A.
N1 - Funding Information:
E. Ladomersky is supported by PHS grant number T32CA070085. D.A. Wainwright is supported by PHS grant number R00NS082381, R01NS097851 awarded by the NIH/NINDS, U.S. Department of Health and Human Services; a Robert H. Lurie Comprehensive Cancer Center – Zell Scholar Program of the Zell Family Foundation Gift; Wade F.B. Thompson/Cancer Research Institute (CRI) Clinic and Laboratory Investigation Program (CLIP) Investigator; the Curing Kids Cancer Foundation; the IDP Foundation of the Robert H. Lurie Comprehensive Cancer Center and the Lou and Jean Malnati Brain Tumor Institute at Northwestern Medicine. We thank the Northwestern University Center for Advanced Microscopy (generously supported by NCI CCSG P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center) and the Northwestern University Flow Cytometry Core Facility (generously supported by Cancer Center Support Grant, NCICA060553) for their technical support of microscope image acquisition and flow cytometry, respectively. We thank Mr. Michael Gallagher for his illustration expertise that led to the creation and rendering of Fig. 6D.
PY - 2018/6/1
Y1 - 2018/6/1
N2 - 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.
AB - 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.
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U2 - 10.1158/1078-0432.CCR-17-3573
DO - 10.1158/1078-0432.CCR-17-3573
M3 - Article
C2 - 29500275
AN - SCOPUS:85048128180
VL - 24
SP - 2559
EP - 2573
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 11
ER -