IDO1 Inhibition Synergizes with Radiation and PD-1 Blockade to Durably Increase Survival Against Advanced Glioblastoma

Abstract

Glioblastoma is the most aggressive primary brain tumor in adults with a median survival of 15-20 months. Numerous approaches and novel therapeutics for treating glioblastoma have been investigated in the setting of phase III clinical trials, including a recent analysis of the immune checkpoint inhibitor, nivolumab (anti-PD-1), which failed to improve recurrent glioblastoma patient survival. However, rather than abandoning immune checkpoint inhibitor treatment for glioblastoma, which has shown promise in other types of cancer, ongoing studies are currently evaluating this therapeutic class when combined with other agents. Here, we investigated immunocompetent orthotopic mouse models of glioblastoma treated with the potent CNS-penetrating IDO1 enzyme inhibitor, BGB-5777, combined with anti-PD1 mAb, as well as radiotherapy, based on our recent observation that tumor-infiltrating T cells directly increase immunosuppressive IDO1 levels in human glioblastoma, the previously described reinvigoration of immune cell functions after PD-1 blockade, as well as the proinflammatory effects of radiation. Our results demonstrate a durable survival benefit from this novel three-agent treatment, but not for any single- or dual-agent combination. Unexpectedly, treatment efficacy required IDO1 enzyme inhibition in non-glioblastoma cells, rather than tumor cells. Timing of effector T-cell infiltration, animal subject age, and usage of systemic chemotherapy, all directly impacted therapy-mediated survival benefit. These data highlight a novel and clinically relevant immunotherapeutic approach with associated mechanistic considerations that have formed the basis of a newly initiated phase I/II trial for glioblastoma patients. .

Targeting the tumor microenvironment and T cell metabolism for effective cancer immunotherapy

“…High levels of IDO expression in the TME is correlated with poor prognosis and promotes resistance to CTLA-4 blockade [47] and CD19-CAR-T cells [48]. A recent study evidenced the beneficial role of IDO1 inhibitors in long-term survival in combination with radiotherapy and PD-1 blockade in a mouse model of glioblastoma [49]. Similarly, studies performed in the murine B16.SIY melanoma model showed improved tumor control when combining anti-PD-L1 or anti-CTLA-4 with the IDO inhibitor INCB23843 [50].…”

RNA-seq for identification of therapeutically targetable determinants of immune activation in human glioblastoma

“…Immunologically, GBM is characterized by a highly suppressive tumor microenvironment [12], and for most patients, there is scant intratumoral infiltration of effector T cells [27,28]. Well-described barriers to infiltration and/or activation of effector T cells in the GBM tumor microenvironment include immunosuppressive microglial cells and tumor-associated (M2) macrophages [29,30], upregulation of immune checkpoints on functionally exhausted cytotoxic T lymphocytes and other immune cells [31], the presence of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) [32,33], and increased expression and secretion of immune inhibitory molecules by tumor and other cells [2,14]. With each of these immunosuppressive mechanisms involving modulation of different signaling pathways and gene expression levels, as well as the unprecedented number of targeted and immunomodulatory therapies in development or already approved across oncology [34], prioritization of individual targets and combinations of targets for preclinical and clinical evaluation in GBM is a significant challenge.…”

“…However, despite promise in preclinical and early phase studies [2,3], single agent programmed death 1 (PD-1) inhibition is ineffective for recurrent GBM in the absence of a rare, markedly hypermutated tumor [4–6]. This is due, in part, to the relative paucity of intratumoral T cells in GBM compared to cancers with carcinogen-induced mutational signatures and high tumor mutational burden (TMB) [7–11].…”

Targeting Aryl Hydrocarbon Receptor with small molecule, 1′H-indole-3′-carbonyl-thiazole-4-carboxylic acid methyl ester blocked human glioma cell invasion via MYH9

“…The majority of endogenous AHR ligands are tryptophan metabolites, and the most abundant tryptophan metabolite in glioma is kynurenine, which is produced by enzymes 2,3-dioxygenase (IDO/TDO), binds to AHR and inhibits cytotoxic immune cells activity against glioma cells [6], forming a pathway of Tryptophan-Kynurenine-AHR-Impairment of Immunity. To block this pathway, inhibitors for the IDO/TDO were developed and mixed clinical trial results have been posted [7,8], not meeting expectations. An alternative route is to directly target AHR using small-molecule ligands.…”