The rationale of indoleamine 2,3-dioxygenase inhibition for cancer therapy.
TL;DR: Current available data on the role of IDO in cancer and the current results obtained with IDO inhibition are reviewed, both in animal models and in phase 1 and 2 clinical trials in humans.
About: This article is published in European Journal of Cancer.The article was published on 2017-05-01. It has received 222 citations till now. The article focuses on the topics: Immune tolerance.
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TL;DR: Novel insights are discussed into the roles of Treg cells in cancer, which can hopefully be used to develop Treg cell-targeted therapies and facilitate immune precision medicine.
Abstract: Regulatory T (Treg) cells, an immunosuppressive subset of CD4+ T cells characterized by the expression of the master transcription factor forkhead box protein P3 (FOXP3), are a component of the immune system with essential roles in maintaining self-tolerance. In addition, Treg cells can suppress anticancer immunity, thereby hindering protective immunosurveillance of neoplasia and hampering effective antitumour immune responses in tumour-bearing hosts, thus promoting tumour development and progression. Identification of the factors that are specifically expressed in Treg cells and/or that influence Treg cell homeostasis and function is important to understanding cancer pathogenesis and to identifying therapeutic targets. Immune-checkpoint inhibitors (ICIs) have provided a paradigm shift in the treatment of cancer. Most immune-checkpoint molecules are expressed in Treg cells, but the effects of ICIs on Treg cells, and thus the contributions of these cells to treatment responses, remain unclear. Notably, evidence indicates that ICIs targeting programmed cell death 1 (PD-1) might enhance the immunosuppressive function of Treg cells, whereas cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitors might deplete these cells. Thus, although manipulation of Treg cells is a promising anticancer therapeutic strategy, approaches to controlling these cells require further research. Herein, we discuss novel insights into the roles of Treg cells in cancer, which can hopefully be used to develop Treg cell-targeted therapies and facilitate immune precision medicine. Regulatory T (Treg) cells are implicated in cancer immune evasion and escape and thus contribute to tumour development and progression. In this Review, the authors provide an overview of the phenotypes and roles of Treg cells in the context of cancer and outline potential strategies to target this cell type in anticancer immunotherapy.
717 citations
TL;DR: Smart clinical trials testing rational immunotherapy combinations that include robust biomarker evaluations will accelerate clinical progress, moving us closer to effective immunotherapy for almost all patients with breast cancer.
Abstract: Immunotherapy is revolutionizing the management of multiple solid tumors, and early data have revealed the clinical activity of PD-1/PD-L1 antagonists in small numbers of metastatic breast cancer patients. Clinical activity appears more likely if the tumor is triple negative, PD-L1+, and/or harbors higher levels of TILs. Responses to atezolizumab and pembrolizumab appear to be durable in metastatic triple negative breast cancer (TNBC), suggesting these agents may transform the lives of responding patients. Current clinical efforts are focused on developing immunotherapy combinations that convert non-responders to responders, deepen those responses that do occur, and surmount acquired resistance to immunotherapy. Identifying biomarkers that can predict the potential for response to single agent immunotherapy, identify the best immunotherapy combinations for a particular patient, and guide salvage immunotherapy in patients with progressive disease are high priorities for clinical development. Smart clinical trials testing rational immunotherapy combinations that include robust biomarker evaluations will accelerate clinical progress, moving us closer to effective immunotherapy for almost all breast cancer patients.
474 citations
Cites background from "The rationale of indoleamine 2,3-di..."
...Like PD-L1, IDO is upregulated by IFNg-secreting T cells in the TME as a means of immune escape, and these two pathways are potentially redundant pathways of immune suppression in breast cancers that have TILs....
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...Together, these forces establish a formidable network of immune suppression within the breast TME....
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...Integrating indoleamine 2,3-dioxygenase inhibitors and immune checkpoint blockade Indoleamine2,3-dioxygenase (IDO) is an enzyme that converts tryptophan to kynurenine, thereby suppressing immunity in the TME (75)....
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...Integrating indoleamine 2,3-dioxygenase inhibitors and immune checkpoint blockade Indoleamine2,3-dioxygenase (IDO) is an enzyme that converts tryptophan to kynurenine, thereby suppressing immunity in the TME (75)....
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...HER-2þ breast cancers and TNBCs are also more likely to express the programmed death ligand-1 (PD-L1) in the TME than luminal breast cancers (15, 16)....
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TL;DR: Pioneers of this new drug class provide a bench-to-bedside review on preclinical validation of IDO1 as a cancer therapeutic target and on the discovery and development of a set of mechanistically distinct compounds that were first to be evaluated as IDO inhibitors in clinical trials.
Abstract: Small-molecule inhibitors of indoleamine 2,3-dioxygenase-1 (IDO1) are emerging at the vanguard of experimental agents in oncology. Here, pioneers of this new drug class provide a bench-to-bedside review on preclinical validation of IDO1 as a cancer therapeutic target and on the discovery and development of a set of mechanistically distinct compounds, indoximod, epacadostat, and navoximod, that were first to be evaluated as IDO inhibitors in clinical trials. As immunometabolic adjuvants to widen therapeutic windows, IDO inhibitors may leverage not only immuno-oncology modalities but also chemotherapy and radiotherapy as standards of care in the oncology clinic. Cancer Res; 77(24); 6795-811. ©2017 AACR.
400 citations
Journal Article•
TL;DR: In this paper, the authors showed that enzymatically active Tryptophan 2,3-dioxygenase (TDO) is expressed in a significant proportion of human tumors and developed a TDO inhibitor which, upon systemic treatment, restored the ability of mice to reject TDO-expressing tumors.
Abstract: Tryptophan catabolism mediated by indoleamine 2,3-dioxygenase (IDO1) is an important mechanism of peripheral immune tolerance contributing to tumoral immune resistance, and IDO1 inhibition is an active area of drug development. Tryptophan 2,3-dioxygenase (TDO) is an unrelated hepatic enzyme that also degrades tryptophan along the kynurenine pathway. Here, we show that enzymatically active TDO is expressed in a significant proportion of human tumors. In a preclinical model, TDO expression by tumors prevented their rejection by immunized mice. We developed a TDO inhibitor, which, upon systemic treatment, restored the ability of mice to reject TDO-expressing tumors. Our results describe a mechanism of tumoral immune resistance based on TDO expression and establish proof-of-concept for the use of TDO inhibitors in cancer therapy.
395 citations
TL;DR: Systematic metabolite profiling across cancer cell lines uncovers patterns associated with genetic and epigenetic features and reveals dysregulated metabolic states that can be exploited for anticancer therapy.
Abstract: Despite considerable efforts to identify cancer metabolic alterations that might unveil druggable vulnerabilities, systematic characterizations of metabolism as it relates to functional genomic features and associated dependencies remain uncommon. To further understand the metabolic diversity of cancer, we profiled 225 metabolites in 928 cell lines from more than 20 cancer types in the Cancer Cell Line Encyclopedia (CCLE) using liquid chromatography–mass spectrometry (LC-MS). This resource enables unbiased association analysis linking the cancer metabolome to genetic alterations, epigenetic features and gene dependencies. Additionally, by screening barcoded cell lines, we demonstrated that aberrant ASNS hypermethylation sensitizes subsets of gastric and hepatic cancers to asparaginase therapy. Finally, our analysis revealed distinct synthesis and secretion patterns of kynurenine, an immune-suppressive metabolite, in model cancer cell lines. Together, these findings and related methodology provide comprehensive resources that will help clarify the landscape of cancer metabolism. Systematic metabolite profiling across cancer cell lines uncovers patterns associated with genetic and epigenetic features and reveals dysregulated metabolic states that can be exploited for anticancer therapy
318 citations
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Harvard University1, Vanderbilt University2, Netherlands Cancer Institute3, University of Colorado Denver4, Institut Gustave Roussy5, University of Duisburg-Essen6, University of Mannheim7, University of Utah8, VU University Amsterdam9, Mount Sinai Hospital10, Washington University in St. Louis11, University Hospital Southampton NHS Foundation Trust12, University of Paris13, Technische Universität München14, Loyola University Chicago15, Memorial Sloan Kettering Cancer Center16, University of South Florida17, Medarex18, Bristol-Myers Squibb19
TL;DR: Ipilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone, improved overall survival in patients with previously treated metastatic melanoma.
Abstract: Background An improvement in overall survival among patients with metastatic melanoma has been an elusive goal. In this phase 3 study, ipilimumab — which blocks cytotoxic T-lymphocyte–associated antigen 4 to potentiate an antitumor T-cell response — administered with or without a glycoprotein 100 (gp100) peptide vaccine was compared with gp100 alone in patients with previously treated metastatic melanoma. Methods A total of 676 HLA-A*0201–positive patients with unresectable stage III or IV melanoma, whose disease had progressed while they were receiving therapy for metastatic disease, were randomly assigned, in a 3:1:1 ratio, to receive ipilimumab plus gp100 (403 patients), ipilimumab alone (137), or gp100 alone (136). Ipilimumab, at a dose of 3 mg per kilogram of body weight, was administered with or without gp100 every 3 weeks for up to four treatments (induction). Eligible patients could receive reinduction therapy. The primary end point was overall survival. Results The median overall survival was 10.0 months among patients receiving ipilimumab plus gp100, as compared with 6.4 months among patients receiving gp100 alone (hazard ratio for death, 0.68; P<0.001). The median overall survival with ipilimumab alone was 10.1 months (hazard ratio for death in the comparison with gp100 alone, 0.66; P = 0.003). No difference in overall survival was detected between the ipilimumab groups (hazard ratio with ipilimumab plus gp100, 1.04; P = 0.76). Grade 3 or 4 immune-related adverse events occurred in 10 to 15% of patients treated with ipilimumab and in 3% treated with gp100 alone. There were 14 deaths related to the study drugs (2.1%), and 7 were associated with immune-related adverse events. Conclusions Ipilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone, improved overall survival in patients with previously treated metastatic melanoma. Adverse events can be severe, long-lasting, or both, but most are reversible with appropriate treatment. (Funded by Medarex and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00094653.)
13,081 citations
TL;DR: Nivolumab was associated with even greater efficacy than docetaxel across all end points in subgroups defined according to prespecified levels of tumor-membrane expression (≥1, ≥5%, and ≥10%) of the PD-1 ligand.
Abstract: BackgroundNivolumab, a fully human IgG4 programmed death 1 (PD-1) immune-checkpoint–inhibitor antibody, disrupts PD-1–mediated signaling and may restore antitumor immunity. MethodsIn this randomized, open-label, international phase 3 study, we assigned patients with nonsquamous non–small-cell lung cancer (NSCLC) that had progressed during or after platinum-based doublet chemotherapy to receive nivolumab at a dose of 3 mg per kilogram of body weight every 2 weeks or docetaxel at a dose of 75 mg per square meter of body-surface area every 3 weeks. The primary end point was overall survival. ResultsOverall survival was longer with nivolumab than with docetaxel. The median overall survival was 12.2 months (95% confidence interval [CI], 9.7 to 15.0) among 292 patients in the nivolumab group and 9.4 months (95% CI, 8.1 to 10.7) among 290 patients in the docetaxel group (hazard ratio for death, 0.73; 96% CI, 0.59 to 0.89; P=0.002). At 1 year, the overall survival rate was 51% (95% CI, 45 to 56) with nivolumab ve...
7,474 citations
The Royal Marsden NHS Foundation Trust1, European Institute of Oncology2, University of Colorado Denver3, Aix-Marseille University4, Baylor University5, University of Michigan6, University of Zurich7, Cross Cancer Institute8, Peter MacCallum Cancer Centre9, Netherlands Cancer Institute10, Hospital General Universitario Gregorio Marañón11, Memorial Sloan Kettering Cancer Center12, Huntsman Cancer Institute13, Yale University14, University of Melbourne15, University of Sydney16, Cornell University17, Ludwig Institute for Cancer Research18, University of Utah19, Yale Cancer Center20, Odense University Hospital21, Bristol-Myers Squibb22, Harvard University23
TL;DR: Among previously untreated patients with metastatic melanoma, nivolumab alone or combined with ipilimumab resulted in significantly longer progression-free survival than ipILimumab alone, and in patients with PD-L1-negative tumors, the combination of PD-1 and CTLA-4 blockade was more effective than either agent alone.
Abstract: The median progression-free survival was 11.5 months (95% confidence interval [CI], 8.9 to 16.7) with nivolumab plus ipilimumab, as compared with 2.9 months (95% CI, 2.8 to 3.4) with ipilimumab (hazard ratio for death or disease progression, 0.42; 99.5% CI, 0.31 to 0.57; P<0.001), and 6.9 months (95% CI, 4.3 to 9.5) with nivolumab (hazard ratio for the comparison with ipilimumab, 0.57; 99.5% CI, 0.43 to 0.76; P<0.001). In patients with tumors positive for the PD-1 ligand (PD-L1), the median progression-free survival was 14.0 months in the nivolumab-plus-ipilimumab group and in the nivolumab group, but in patients with PD-L1–negative tumors, progression-free survival was longer with the combination therapy than with nivolumab alone (11.2 months [95% CI, 8.0 to not reached] vs. 5.3 months [95% CI, 2.8 to 7.1]). Treatment-related adverse events of grade 3 or 4 occurred in 16.3% of the patients in the nivolumab group, 55.0% of those in the nivolumab-plus-ipilimumab group, and 27.3% of those in the ipilimumab group. CONCLUSIONS Among previously untreated patients with metastatic melanoma, nivolumab alone or combined with ipilimumab resulted in significantly longer progression-free survival than ipilimumab alone. In patients with PD-L1–negative tumors, the combination of PD-1 and CTLA-4 blockade was more effective than either agent alone. (Funded by Bristol-Myers Squibb; CheckMate 067 ClinicalTrials.gov number, NCT01844505.)
6,318 citations
Memorial Sloan Kettering Cancer Center1, Institut Gustave Roussy2, Harvard University3, Roswell Park Cancer Institute4, Johns Hopkins University5, Stanford University6, University of Washington7, Vanderbilt University8, Fox Chase Cancer Center9, Macquarie University10, Aarhus University11, University of Helsinki12, The Royal Marsden NHS Foundation Trust13, University of Duisburg-Essen14, Niigata University15, Swansea University16, University of British Columbia17, Bristol-Myers Squibb18, University of Texas MD Anderson Cancer Center19
TL;DR: Overall survival was longer and fewer grade 3 or 4 adverse events occurred with nivolumab than with everolimus among patients with previously treated advanced renal-cell carcinoma.
Abstract: BackgroundNivolumab, a programmed death 1 (PD-1) checkpoint inhibitor, was associated with encouraging overall survival in uncontrolled studies involving previously treated patients with advanced renal-cell carcinoma. This randomized, open-label, phase 3 study compared nivolumab with everolimus in patients with renal-cell carcinoma who had received previous treatment. MethodsA total of 821 patients with advanced clear-cell renal-cell carcinoma for which they had received previous treatment with one or two regimens of antiangiogenic therapy were randomly assigned (in a 1:1 ratio) to receive 3 mg of nivolumab per kilogram of body weight intravenously every 2 weeks or a 10-mg everolimus tablet orally once daily. The primary end point was overall survival. The secondary end points included the objective response rate and safety. ResultsThe median overall survival was 25.0 months (95% confidence interval [CI], 21.8 to not estimable) with nivolumab and 19.6 months (95% CI, 17.6 to 23.1) with everolimus. The haz...
4,643 citations
TL;DR: The anti-PD-1 antibody pembrolizumab prolonged progression-free survival and overall survival and had less high-grade toxicity than did ipilimumab in patients with advanced melanoma.
Abstract: Background The immune checkpoint inhibitor ipilimumab is the standard-of-care treatment for patients with advanced melanoma. Pembrolizumab inhibits the programmed cell death 1 (PD-1) immune checkpoint and has antitumor activity in patients with advanced melanoma. Methods In this randomized, controlled, phase 3 study, we assigned 834 patients with advanced melanoma in a 1:1:1 ratio to receive pembrolizumab (at a dose of 10 mg per kilogram of body weight) every 2 weeks or every 3 weeks or four doses of ipilimumab (at 3 mg per kilogram) every 3 weeks. Primary end points were progressionfree and overall survival. Results The estimated 6-month progression-free-survival rates were 47.3% for pembrolizumab every 2 weeks, 46.4% for pembrolizumab every 3 weeks, and 26.5% for ipilimumab (hazard ratio for disease progression, 0.58; P<0.001 for both pembrolizumab regimens versus ipilimumab; 95% confidence intervals [CIs], 0.46 to 0.72 and 0.47 to 0.72, respectively). Estimated 12-month survival rates were 74.1%, 68.4%, and 58.2%, respectively (hazard ratio for death for pembrolizumab every 2 weeks, 0.63; 95% CI, 0.47 to 0.83; P = 0.0005; hazard ratio for pembrolizumab every 3 weeks, 0.69; 95% CI, 0.52 to 0.90; P = 0.0036). The response rate was improved with pembrolizumab administered every 2 weeks (33.7%) and every 3 weeks (32.9%), as compared with ipilimumab (11.9%) (P<0.001 for both comparisons). Responses were ongoing in 89.4%, 96.7%, and 87.9% of patients, respectively, after a median follow-up of 7.9 months. Efficacy was similar in the two pembrolizumab groups. Rates of treatment-related adverse events of grade 3 to 5 severity were lower in the pembrolizumab groups (13.3% and 10.1%) than in the ipilimumab group (19.9%). Conclusions The anti–PD-1 antibody pembrolizumab prolonged progression-free survival and overall survival and had less high-grade toxicity than did ipilimumab in patients with advanced melanoma. (Funded by Merck Sharp & Dohme; KEYNOTE-006 ClinicalTrials .gov number, NCT01866319.)
4,612 citations