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, 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 blood tumor-barriers, GBMs are actively infiltrated by T cells. 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 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.

Advances in Experimental Targeted Therapy and Immunotherapy for Patients with Glioblastoma Multiforme

“…The effectiveness of combined CTLA-4 with PD-L1 and indoleamine-2,3-dioxygenase 1 blockade was studied in mouse model of GBM. It was shown that 100% of mice (n=5) survived on the triple combination therapy for a long time (126). A more recent study with a murine model of GBM showed that anti-CTLA-4 plus anti-PD-1 therapy was able to cure 75% of the animals (12 out of 16), even with advanced and late-stage tumors (127).…”

Preclinical efficacy of immune-checkpoint monotherapy does not recapitulate corresponding biomarkers-based clinical predictions in glioblastoma

“…To this end, we decided to experimentally test the efficacy of ICIs targeting all three immune checkpoints, i.e., CTLA4, PD1 or IDO1 in orthotopic GL261 glioma-bearing mice. In one case, we administered pharmacological IDO1 inhibitors, i.e., 1-Methyl-DL-tryptophan (1-DL-MT, a mixture of levorotary/L and dextrorotary/D stereoisomers of 1-MT) or 1-Methyl-D-tryptophan (i.e., 1-D-MT) 12 ( Fig. 6A).…”

“…2,11 It has been reported that IDO1 can be upregulated during gliomagenesis thereby making it an attractive target for GBM immunotherapy. 12 On the other hand, studies on neuronal autoimmune disorders have shown that the CNS particularly exploits the PD1-axis for maintaining immune-tolerance. 2 Hence, anti-PD1 Ab is currently being prioritized for GBM immunotherapy.…”

TIGIT and PD-1 dual checkpoint blockade enhances antitumor immunity and survival in GBM

“…Studies of anti-PD-1 treatment with other checkpoint inhibitors, such as anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and anti-T cell immunoglobulin and mucin domain 3 (TIM-3), have demonstrated promising results in a murine GBM model, and various combinations are currently being tested in clinical trials. 11 , 12 …”