Discovery of IDO1 Inhibitors: From Bench to Bedside

Prendergast, George C.; Malachowski, William P.; DuHadaway, James B.; Muller, Alexander J.

doi:10.1158/0008-5472.can-17-2285

Cited by 459 publications

(425 citation statements)

References 141 publications

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“…It has been previously shown that tryptophan depletion by cancer cell-expressed IDO1 could lead to the T cell anergy and activation of immunosuppressive Tregs and MDSCs. 46,47 Currently, drugs targeting IDO1 pathway are in clinical trials to reverse the tumor-induced immunosuppression. 47 In accordance with our data, a recent report demonstrated that restoration of p53 activity via nutlin-3a was able to induce ICD and promote CD8 T cell-dependent anti-tumor immunity in mice bearing EL4 tumor.…”

Section: Discussionmentioning

confidence: 99%

“…46,47 Currently, drugs targeting IDO1 pathway are in clinical trials to reverse the tumor-induced immunosuppression. 47 In accordance with our data, a recent report demonstrated that restoration of p53 activity via nutlin-3a was able to induce ICD and promote CD8 T cell-dependent anti-tumor immunity in mice bearing EL4 tumor. 31 In that study, activated p53 was able to eliminate immunosuppressive MDSCs.…”

Section: Discussionmentioning

confidence: 99%

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Combination with SGT-53 overcomes tumor resistance to a checkpoint inhibitor

et al. 2018

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The tumor suppressor p53 responds to genotoxic and oncogenic stresses by inducing cell cycle arrest and apoptosis. Recent studies suggest that p53 also participates in the regulation of cellular immune responses. Here, we have investigated the potential of p53 gene therapy to augment immune checkpoint inhibition by combining an anti-programmed cell death protein 1 (PD1) antibody with SGT-53, our investigational nanomedicine carrying a plasmid encoding human wild-type p53. In three syngeneic mouse tumor models examined including a breast cancer, a non-small cell lung carcinoma, and a glioblastoma, SGT-53 sensitized otherwise refractory tumors to anti-PD1 antibody. The involvement of p53 in enhancing anti-PD1 immunotherapy appears to be multifaceted, since SGT-53 treatment increased tumor immunogenicity, enhanced both innate and adaptive immune responses, and reduced tumor-induced immunosuppression in a 4T1 breast tumor model. In addition, SGT-53 alleviates a fatal xenogeneic hypersensitivity associated with the anti-PD1 antibody in this model. Our data suggest that restoring p53 function by SGT-53 is able to boost anti-tumor immunity to augment anti-PD1 therapy by sensitizing tumors otherwise insensitive to anti-PD1 immunotherapy while reducing immune-related adverse events.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Combination with SGT-53 overcomes tumor resistance to a checkpoint inhibitor

et al. 2018

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“…226 Finally, several studies aim at testing the safety and therapeutic potential of peptide-based vaccines targeting one single TAA including not only viral antigens like HPV p16, E6 and E7, 227-229 but also shared TAAs like HER2, NY-ESO-1, survivin and telomerase reverse transcriptase (TERT), 161,230-252 as well as TAAs involved in the establishment of immunosuppression, such as PD-L1 and indoleamine 2,3-dioxygenase 1 (IDO1). 253-256 …”

Section: Ongoing Clinical Trialsmentioning

confidence: 99%

Trial watch: Peptide-based vaccines in anticancer therapy

et al. 2018

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Peptide-based anticancer vaccination aims at stimulating an immune response against one or multiple tumor-associated antigens (TAAs) following immunization with purified, recombinant or synthetically engineered epitopes. Despite high expectations, the peptide-based vaccines that have been explored in the clinic so far had limited therapeutic activity, largely due to cancer cell-intrinsic alterations that minimize antigenicity and/or changes in the tumor microenvironment that foster immunosuppression. Several strategies have been developed to overcome such limitations, including the use of immunostimulatory adjuvants, the co-treatment with cytotoxic anticancer therapies that enable the coordinated release of damage-associated molecular patterns, and the concomitant blockade of immune checkpoints. Personalized peptide-based vaccines are also being explored for therapeutic activity in the clinic. Here, we review recent preclinical and clinical progress in the use of peptide-based vaccines as anticancer therapeutics.Abbreviations: CMP: carbohydrate-mimetic peptide; CMV: cytomegalovirus; DC: dendritic cell; FDA: Food and Drug Administration; HPV: human papillomavirus; MDS: myelodysplastic syndrome; MHP: melanoma helper vaccine; NSCLC: non-small cell lung carcinoma; ODD: orphan drug designation; PPV: personalized peptide vaccination; SLP: synthetic long peptide; TAA: tumor-associated antigen; TNA: tumor neoantigen

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“…The concept of IDO1 as an immunosuppressive actor was extended by later discoveries that it was a common pathophysiological mediator of tumoral immune escape [25]. As a classical pharmacological target, IDO was ripe for development of small molecule inhibitors [26] with medicinal chemistry groups at New Link Genetics i and Incyte ii ultimately advancing several mechanistically distinct compounds to clinical trials [27]. Efforts to elucidate IDO1 regulatory and effector pathways discussed below have illuminated its major function as a inflammatory modifier in cancer ( Figure 2) .…”

Section: Ido1 Modifies Inflammation and Immunitymentioning

confidence: 99%

“…Careful examination of the phenotype of Ido1 –/– mice suggests that IDOi may not be free of side-effects but may be much less toxic than immune checkpoint drugs or traditional or targeted chemotherapy [108]. A detailed review on the preclinical discovery and development of the first IDOi to be translated to clinic – indoximod, epacadastat and navoximod – will appear elsewhere [27]. There also have been several excellent comprehensive reviews with detailed surveys of medicinal chemistry, pharmacological and biological considerations [8, 59, 74, 109–112].…”

Section: Therapeutic Approaches To Block Ido Functionmentioning

confidence: 99%

Inflammatory Reprogramming with IDO1 Inhibitors: Turning Immunologically Unresponsive ‘Cold’ Tumors ‘Hot’

Prendergast¹,

Mondal²,

Dey³

et al. 2018

Trends in Cancer

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We discuss how small molecule inhibitors of the tryptophan catabolic enzyme indoleamine 2,3-dioxygenase (IDOi) represent a vanguard of new immunometabolic adjuvants to safely enhance the efficacy of cancer immunotherapy, radiotherapy or 'immunogenic' chemotherapy by leveraging responses to tumor neoantigens. IDO activation in cancer supports inflammatory processes that IDOi can re-program to help clear tumors by blunting tumor neovascularization and restoring immunosurveillance. Studies of regulatory and effector pathways illuminate IDO as an inflammatory modifier. Recent work suggests that coordinate targeting of the Trp catabolic enzymes TDO and IDO2 may also safely broaden efficacy. Understanding IDOi as adjuvants to turn immunologically 'cold' tumors 'hot' can seed new concepts in how to improve the efficacy of cancer therapy while limiting its collateral damage.

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Discovery of IDO1 Inhibitors: From Bench to Bedside

Cited by 459 publications

References 141 publications

Combination with SGT-53 overcomes tumor resistance to a checkpoint inhibitor

Combination with SGT-53 overcomes tumor resistance to a checkpoint inhibitor

Trial watch: Peptide-based vaccines in anticancer therapy

Inflammatory Reprogramming with IDO1 Inhibitors: Turning Immunologically Unresponsive ‘Cold’ Tumors ‘Hot’

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