Durable therapeutic efficacy utilizing combinatorial blockade against IDO, CTLA-4, and PD-L1 in mice with brain tumors

Derek A. Wainwright, Alan L. Chang, Mahua Dey, Irina V. Balyasnikova, Chung Kwon Kim, Alex Tobias, Yu Cheng, Julius W. Kim, Jian Qiao, Lingjiao Zhang, Yu Han, Maciej S. Lesniak*

*Corresponding author for this work

Research output: Contribution to journalArticle

230 Citations (Scopus)

Abstract

Purpose: Glioblastoma (GBM) is the most common form of malignant glioma in adults. Although protected by both the blood-brain and blood-tumor barriers, GBMs are actively infiltrated by T cells. Previous work has shown that IDO, CTLA-4, and PD-L1 are dominant molecular participants in the suppression of GBM immunity. This includes IDO-mediated regulatory T-cell (Treg; CD4+CD25+FoxP3+) accumulation, the interaction of T-cell-expressed, CTLA-4, with dendritic cell-expressed, CD80, as well as the interaction of tumor- and/or macrophage-expressed, PD-L1, with T-cell-expressed, PD-1. The individual inhibition of each pathway has been shown to increase survival in the context of experimental GBM. However, the impact of simultaneously targeting all three pathways in brain tumors has been left unanswered. Experimental Design and Results: In this report, we demonstrate that, when dually challenged, IDO-deficient tumors provide a selectively competitive survival advantage against IDO-competent tumors. Next, we provide novel observations regarding tryptophan catabolic enzyme expression, before showing that the therapeutic inhibition of IDO, CTLA-4, and PD-L1 in a mouse model of well-established glioma maximally decreases tumor-infiltrating Tregs, coincident with a significant increase in T-cell-mediated long-term survival. In fact, 100% of mice bearing intracranial tumors were long-term survivors following triple combination therapy. The expression and/or frequency of T cell expressed CD44, CTLA-4, PD-1, and IFN-γ depended on timing after immunotherapeutic administration. Conclusions: Collectively, these data provide strong preclinical evidence that combinatorially targeting immunosuppression in malignant glioma is a strategy that has high potential value for future clinical trials in patients with GBM.

Original languageEnglish (US)
Pages (from-to)5290-5301
Number of pages12
JournalClinical Cancer Research
Volume20
Issue number20
DOIs
StatePublished - Oct 15 2014

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Brain Neoplasms
Glioblastoma
T-Lymphocytes
Glioma
Neoplasms
Survival
Therapeutics
Regulatory T-Lymphocytes
Blood-Brain Barrier
Tryptophan
Immunosuppression
Dendritic Cells
Survivors
Immunity
Research Design
Macrophages
Clinical Trials
Enzymes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Wainwright, Derek A. ; Chang, Alan L. ; Dey, Mahua ; Balyasnikova, Irina V. ; Kim, Chung Kwon ; Tobias, Alex ; Cheng, Yu ; Kim, Julius W. ; Qiao, Jian ; Zhang, Lingjiao ; Han, Yu ; Lesniak, Maciej S. / Durable therapeutic efficacy utilizing combinatorial blockade against IDO, CTLA-4, and PD-L1 in mice with brain tumors. In: Clinical Cancer Research. 2014 ; Vol. 20, No. 20. pp. 5290-5301.
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title = "Durable therapeutic efficacy utilizing combinatorial blockade against IDO, CTLA-4, and PD-L1 in mice with brain tumors",
abstract = "Purpose: Glioblastoma (GBM) is the most common form of malignant glioma in adults. Although protected by both the blood-brain and blood-tumor barriers, GBMs are actively infiltrated by T cells. Previous work has shown that IDO, CTLA-4, and PD-L1 are dominant molecular participants in the suppression of GBM immunity. This includes IDO-mediated regulatory T-cell (Treg; CD4+CD25+FoxP3+) accumulation, the interaction of T-cell-expressed, CTLA-4, with dendritic cell-expressed, CD80, as well as the interaction of tumor- and/or macrophage-expressed, PD-L1, with T-cell-expressed, PD-1. The individual inhibition of each pathway has been shown to increase survival in the context of experimental GBM. However, the impact of simultaneously targeting all three pathways in brain tumors has been left unanswered. Experimental Design and Results: In this report, we demonstrate that, when dually challenged, IDO-deficient tumors provide a selectively competitive survival advantage against IDO-competent tumors. Next, we provide novel observations regarding tryptophan catabolic enzyme expression, before showing that the therapeutic inhibition of IDO, CTLA-4, and PD-L1 in a mouse model of well-established glioma maximally decreases tumor-infiltrating Tregs, coincident with a significant increase in T-cell-mediated long-term survival. In fact, 100{\%} of mice bearing intracranial tumors were long-term survivors following triple combination therapy. The expression and/or frequency of T cell expressed CD44, CTLA-4, PD-1, and IFN-γ depended on timing after immunotherapeutic administration. Conclusions: Collectively, these data provide strong preclinical evidence that combinatorially targeting immunosuppression in malignant glioma is a strategy that has high potential value for future clinical trials in patients with GBM.",
author = "Wainwright, {Derek A.} and Chang, {Alan L.} and Mahua Dey and Balyasnikova, {Irina V.} and Kim, {Chung Kwon} and Alex Tobias and Yu Cheng and Kim, {Julius W.} and Jian Qiao and Lingjiao Zhang and Yu Han and Lesniak, {Maciej S.}",
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Durable therapeutic efficacy utilizing combinatorial blockade against IDO, CTLA-4, and PD-L1 in mice with brain tumors. / Wainwright, Derek A.; Chang, Alan L.; Dey, Mahua; Balyasnikova, Irina V.; Kim, Chung Kwon; Tobias, Alex; Cheng, Yu; Kim, Julius W.; Qiao, Jian; Zhang, Lingjiao; Han, Yu; Lesniak, Maciej S.

In: Clinical Cancer Research, Vol. 20, No. 20, 15.10.2014, p. 5290-5301.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Durable therapeutic efficacy utilizing combinatorial blockade against IDO, CTLA-4, and PD-L1 in mice with brain tumors

AU - Wainwright, Derek A.

AU - Chang, Alan L.

AU - Dey, Mahua

AU - Balyasnikova, Irina V.

AU - Kim, Chung Kwon

AU - Tobias, Alex

AU - Cheng, Yu

AU - Kim, Julius W.

AU - Qiao, Jian

AU - Zhang, Lingjiao

AU - Han, Yu

AU - Lesniak, Maciej S.

PY - 2014/10/15

Y1 - 2014/10/15

N2 - Purpose: Glioblastoma (GBM) is the most common form of malignant glioma in adults. Although protected by both the blood-brain and blood-tumor barriers, GBMs are actively infiltrated by T cells. Previous work has shown that IDO, CTLA-4, and PD-L1 are dominant molecular participants in the suppression of GBM immunity. This includes IDO-mediated regulatory T-cell (Treg; CD4+CD25+FoxP3+) accumulation, the interaction of T-cell-expressed, CTLA-4, with dendritic cell-expressed, CD80, as well as the interaction of tumor- and/or macrophage-expressed, PD-L1, with T-cell-expressed, PD-1. The individual inhibition of each pathway has been shown to increase survival in the context of experimental GBM. However, the impact of simultaneously targeting all three pathways in brain tumors has been left unanswered. Experimental Design and Results: In this report, we demonstrate that, when dually challenged, IDO-deficient tumors provide a selectively competitive survival advantage against IDO-competent tumors. Next, we provide novel observations regarding tryptophan catabolic enzyme expression, before showing that the therapeutic inhibition of IDO, CTLA-4, and PD-L1 in a mouse model of well-established glioma maximally decreases tumor-infiltrating Tregs, coincident with a significant increase in T-cell-mediated long-term survival. In fact, 100% of mice bearing intracranial tumors were long-term survivors following triple combination therapy. The expression and/or frequency of T cell expressed CD44, CTLA-4, PD-1, and IFN-γ depended on timing after immunotherapeutic administration. Conclusions: Collectively, these data provide strong preclinical evidence that combinatorially targeting immunosuppression in malignant glioma is a strategy that has high potential value for future clinical trials in patients with GBM.

AB - Purpose: Glioblastoma (GBM) is the most common form of malignant glioma in adults. Although protected by both the blood-brain and blood-tumor barriers, GBMs are actively infiltrated by T cells. Previous work has shown that IDO, CTLA-4, and PD-L1 are dominant molecular participants in the suppression of GBM immunity. This includes IDO-mediated regulatory T-cell (Treg; CD4+CD25+FoxP3+) accumulation, the interaction of T-cell-expressed, CTLA-4, with dendritic cell-expressed, CD80, as well as the interaction of tumor- and/or macrophage-expressed, PD-L1, with T-cell-expressed, PD-1. The individual inhibition of each pathway has been shown to increase survival in the context of experimental GBM. However, the impact of simultaneously targeting all three pathways in brain tumors has been left unanswered. Experimental Design and Results: In this report, we demonstrate that, when dually challenged, IDO-deficient tumors provide a selectively competitive survival advantage against IDO-competent tumors. Next, we provide novel observations regarding tryptophan catabolic enzyme expression, before showing that the therapeutic inhibition of IDO, CTLA-4, and PD-L1 in a mouse model of well-established glioma maximally decreases tumor-infiltrating Tregs, coincident with a significant increase in T-cell-mediated long-term survival. In fact, 100% of mice bearing intracranial tumors were long-term survivors following triple combination therapy. The expression and/or frequency of T cell expressed CD44, CTLA-4, PD-1, and IFN-γ depended on timing after immunotherapeutic administration. Conclusions: Collectively, these data provide strong preclinical evidence that combinatorially targeting immunosuppression in malignant glioma is a strategy that has high potential value for future clinical trials in patients with GBM.

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