Synergistic antitumor effect with indoleamine 2,3-dioxygenase inhibition and temozolomide in a murine glioma model

Abstract

M alignant glioma is the most common brain tumor in adults; it has an aggressive lethal nature and a median survival of only 14 months, despite the standard established therapy of maximum resection followed by radiation and chemotherapy. Several immunotherapies, such as dendritic cell therapy, have been evaluated as new adjuvant approaches. However, the efficacy of immunotherapy for patients with malignant glioma is limited for several reasons, including the anatomical isolation of the central nervous system by the blood-brain barrier, the absence of a lymphatic drainage system, and the ability of glioma cells to escape recognition by the immune system. Recent studies suggest that indoleamine 2,3-dioxygenase (IDO), the initial rate-limiting enzyme in tryptophan (Trp) metabolism, may be involved in such tumor-induced escape from immunosurveillance, showing an immunosuppressive function.14,27 IDO is expressed in various human cancers such as malignant melanoma, ovarabbreviatioNs FACS = fluorescence-activated cell sorter; GAPDH = glyceraldehyde-3-phosphate dehydrogenase; IDO = indoleamine 2,3-dioxygenase; IDO-KD = IDO-knockdown; INF-g = interferon-g; PBS = phosphate-buffered saline; RT-PCR = real-time polymerase chain reaction; SEM = standard error of the mean; shRNA = short hairpin RNA; TMZ = temozolomide; Treg = regulatory T cell; Trp = tryptophan; 1-MT = 1-methyl-l-tryptophan. Thus, IDO may be a therapeutic target for malignant cancer. The authors have recently shown that IDO expression is markedly increased in human glioblastoma and secondary glioblastoma with malignant change, suggesting that IDO targeting may also have therapeutic potential for patients with glioma. The aim of this study was to investigate the antitumor effect of IDO inhibition and to examine the synergistic function of IDO inhibitor and temozolomide (TMZ) in a murine glioma model. methods Murine glioma GL261 cells and human glioma U87 cells were included in this study. The authors used 3 mouse models to study glioma cell growth: 1) a subcutaneous ectopic model, 2) a syngeneic intracranial orthotopic model, and 3) an allogenic intracranial orthotopic model. IDO inhibition was achieved via knockdown of IDO in GL261 cells using short hairpin RNA (shRNA) and through oral administration of the IDO inhibitor, 1-methyl-l-tryptophan (1-MT). Tumor volume in the subcutaneous model and survival time in the intracranial model were evaluated. results In the subcutaneous model, oral administration of 1-MT significantly suppressed tumor growth, and synergistic antitumor effects of 1-MT and TMZ were observed (p < 0.01). Mice containing intracranially inoculated IDO knockdown cells had a significantly longer survival period as compared with control mice (p < 0.01). coNclusioNs These results suggest that IDO expression is implicated in immunosuppression and tumor progression in glioma cells. Therefore, combining IDO inhibition with standard TMZ treatment could be an encouraging therapeutic strategy for patients with malignant glioma.

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

“…Studies were excluded because of following reasons: (1) not sufficient survival data reported, (2) letters, reviews, commentary, perspectives, case reports, conference abstracts, editorials or expert opinion, (3) studies reporting xenograft results in immunodeficient or humanized mice. Overall these search criteria helped short-list 15 research articles 12,15,16,[50][51][52][53][54][55][56][57][58][59][60][61] mentioned in Box S1.…”

The Kynurenine Pathway: A Primary Resistance Mechanism in Patients with Glioblastoma

“…Hanihara et al reported 1MT significantly suppressed tumor growth in a murine glioma model. 1MT also had synergistic effects with temozolomide (193). Li et al showed that mice bearing intracranial GL 261 glioblastoma tumors that were treated with 1MT added to radiation therapy plus temozolomide and cytoxan, survived longer than mice treated with chemotherapy and radiation therapy alone (194).…”

The Burden of Oncology Promises not Kept in Glioblastoma

“…Indoleamine 2,3-dioxygenase (IDO) is another checkpoint molecule expressed by glioblastoma to suppress immune function [18]. Preclinical models showed that strategies involving IDO inhibition were active [19,20], in fact, Phase I clinical trials with indoximod, an IDO inhibitor started (NCT02052648).…”