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

Al's Comment:

 This may be one of the most important articles of the year. It is only in mice, but 100% of the mice were long term survivors. I would love to see this tried in people.


Posted on: 04/03/2014

Clin Cancer Res. 2014 Apr 1. [Epub ahead of print]
Durable therapeutic efficacy utilizing combinatorial blockade against IDO, CTLA-4 and PD-L1 in mice with brain tumors.
Wainwright DA1, Chang AL, Dey M, Balyasnikova IV, Kim C, Tobias AL, Cheng Y, Kim J, Zhang L, Qiao J, Han Y, Lesniak MS.
Author information
Glioblastoma (GBM) is the most common form of malignant glioma in adults. Although protected by both the blood brain- and blood tumor-barriers, T cells actively infiltrate GBM. 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, co-incident 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-gamma depended on timing after immunotherapeutic administration.
Collectively, these data provide strong pre-clinical evidence that combinatorially-targeting immunosuppression in malignant glioma is a strategy that has high potential value for future clinical trials in patients with GBM.
PMID: 24691018 [PubMed - as supplied by publisher]


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