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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

Clinical cancer research, 2014-10, Vol.20 (20), p.5290-5301 [Periódico revisado por pares]

United States

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Título:
Durable therapeutic efficacy utilizing combinatorial blockade against IDO, CTLA-4, and PD-L1 in mice with brain tumors
Autor: 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
Assuntos: Animals ; Antibodies, Monoclonal - administration & dosage ; Antibodies, Monoclonal - pharmacology ; Antineoplastic Agents - administration & dosage ; Antineoplastic Agents - pharmacology ; B7-H1 Antigen - antagonists & inhibitors ; Brain Neoplasms - drug therapy ; Brain Neoplasms - genetics ; Brain Neoplasms - immunology ; Brain Neoplasms - metabolism ; Brain Neoplasms - mortality ; Brain Neoplasms - pathology ; Cell Line, Tumor ; CTLA-4 Antigen - antagonists & inhibitors ; Dacarbazine - administration & dosage ; Dacarbazine - analogs & derivatives ; Dacarbazine - pharmacology ; Disease Models, Animal ; Drug Therapy, Combination ; Glioma - drug therapy ; Glioma - genetics ; Glioma - immunology ; Glioma - metabolism ; Indoleamine-Pyrrole 2,3,-Dioxygenase - antagonists & inhibitors ; Mice ; Mice, Knockout ; T-Lymphocytes, Regulatory - drug effects ; T-Lymphocytes, Regulatory - immunology ; Temozolomide
É parte de: Clinical cancer research, 2014-10, Vol.20 (20), p.5290-5301
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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Descrição: 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. 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. 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.
Editor: United States
Idioma: Inglês

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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

United States

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