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Durable therapeutic efficacy utilizing combinatorial blockade against IDO, CTLA-4, and PD-L1 in mice with brain
Derek A Wainwright1, Alan L Chang1, Mahua Dey1
1The Brain Tumor Center, The University of Chicago Pritzker School of Medicine, Chicago, Illinois.
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.
Insights
Triple therapy targeting IDO, CTLA-4, and PD-L1 eradicated glioblastoma in mice. This combination therapy significantly reduced regulatory T-cells and increased long-term survival in a preclinical glioma model.
Area of Science:
- Neuro-oncology
- Immunology
- Cancer Research
Background:
- Glioblastoma (GBM) is a prevalent and aggressive adult brain tumor.
- Despite T-cell infiltration, GBM exhibits immune suppression mediated by IDO, CTLA-4, and PD-L1.
- Individual inhibition of these pathways improves survival in experimental GBM.
Purpose of the Study:
- To investigate the impact of simultaneously targeting IDO, CTLA-4, and PD-L1 in brain tumors.
- To evaluate the efficacy of combination immunotherapy in a preclinical glioma model.
Main Methods:
- Utilized a mouse model of well-established glioma.
- Administered therapeutic inhibition of IDO, CTLA-4, and PD-L1.
- Assessed tumor-infiltrating regulatory T-cells (Tregs) and T-cell-mediated survival.
Main Results:
- Dual challenge with IDO-deficient tumors conferred a survival advantage.
- Triple combination therapy maximally decreased tumor-infiltrating Tregs.
- 100% of mice with intracranial tumors achieved long-term survival after triple therapy.
- Expression of CD44, CTLA-4, PD-1, and IFN-γ in T cells varied with immunotherapy timing.
Conclusions:
- Combination targeting of immunosuppression pathways shows high potential for GBM treatment.
- These findings provide strong preclinical support for clinical trials in GBM patients.
