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Cited by 413Cancer Immunotherapy and BiomarkersTryptophan and brain disordersImmunotherapy and Immune Responses

Reimagining IDO Pathway Inhibition in Cancer Immunotherapy via Downstream Focus on the Tryptophan–Kynurenine–Aryl Hydrocarbon Axis

Open access
Labadie, Brian W., Bao, Riyue, Luke, Jason J.·2019·Clinical Cancer Research
DOI 10.1158/1078-0432.ccr-18-2882PMC PMC6397695

Published version of a preprint

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Abstract

Significant progress has been made in cancer immunotherapy with checkpoint inhibitors targeting programmed cell death protein 1 (PD-1)–programmed death-ligand 1 signaling pathways. Tumors from patients showing sustained treatment response predominately demonstrate a T cell–inflamed tumor microenvironment prior to, or early on, treatment. Not all tumors with this phenotype respond, however, and one mediator of immunosuppression in T cell–inflamed tumors is the tryptophan–kynurenine–aryl hydrocarbon receptor (Trp–Kyn–AhR) pathway. Multiple mechanisms of immunosuppression may be mediated by this pathway including depletion of tryptophan, direct immunosuppression of Kyn, and activity of Kyn-bound AhR. Indoleamine 2,3-dioxygenase 1 (IDO1), a principle enzyme in Trp catabolism, is the target of small-molecule inhibitors in clinical development in combination with PD-1 checkpoint inhibitors. Despite promising results in early-phase clinical trials in a range of tumor types, a phase III study of the IDO1-selective inhibitor epacadostat in combination with pembrolizumab showed no difference between the epacadostat-treated group versus placebo in patients with metastatic melanoma. This has led to a diminution of interest in IDO1 inhibitors; however, other approaches to inhibit this pathway continue to be considered. Novel Trp–Kyn–AhR pathway inhibitors, such as Kyn-degrading enzymes, direct AhR antagonists, and tryptophan mimetics are advancing in early-stage or preclinical development. Despite uncertainty surrounding IDO1 inhibition, ample preclinical evidence supports continued development of Trp–Kyn–AhR pathway inhibitors to augment immune-checkpoint and other cancer therapies.

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Crossref · 10.1158/1078-0432.ccr-18-2882

Cites

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Claims the paper makes

0 of 107 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Across 30 human solid tumors from TCGA, IDO1 gene expression was strongly correlated with PD1 expression across increasing IFNγ responsive gene expression from non-T cell-inflamed to highly T cell-inflamed tumors.

    “Indeed, across 30 human solid tumors from The Cancer Genome Atlas (TCGA) database, we have observed that the gene expression of IDO1 was strongly correlated with the expression of PD1 across increasing level of IFNγ responsive gene expression from non-T cell-inflamed to highly T cell-inflamed tumors (Figure 4A).”
    Quote in the paperSubstantial claim
  • Interpretationreasoning

    Ample preclinical evidence supports continued development of Trp-Kyn-AhR pathway inhibitors to augment immune-checkpoint and other cancer therapies.

    “Despite uncertainty surrounding IDO1 inhibition, ample preclinical evidence supports continued development of Trp-Kyn-AhR pathway inhibitors to augment immune-checkpoint and other cancer therapies.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Preclinical evidence of Trp-Kyn-AhR pathway inhibition predicts clinical benefit in human cancer patients.
  • Premisecitation

    Barriers downstream of initial T cell priming limit meaningful tumor elimination.

    “This finding led to the prediction that important barriers downstream of initial T cell priming must exist that limit meaningful tumor elimination (2).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [2] Gajewski, 2000, Monitoring specific T-cell responses to melanoma vaccines: ELISPOT, tetramers, and beyond, Clin Diagn Lab Immunol source

      Not checked in the free run.

  • Premisecitation

    The Trp-Kyn-AhR pathway is one mediator of immunosuppression in T cell-inflamed tumors.

    “one mediator of immunosuppression in T cell-inflamed tumors is the tryptophan-kynurenine-aryl hydrocarbon receptor (Trp-Kyn-AhR) pathway.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [14] Lanitis, 2017, Mechanisms regulating T-cell infiltration and activity in solid tumors, Ann Oncol source

      Not checked in the free run.

    • cites [15] Gajewski, 2006, Immune resistance orchestrated by the tumor microenvironment, Immunol Rev source

      Not checked in the free run.

  • Premisecitation

    Tumors in patients who have sustained responses to checkpoint inhibitors mostly show a T cell-inflamed microenvironment before or early in treatment.

    “Tumors from patients showing sustained treatment response predominately demonstrate a T cell-inflamed tumor microenvironment prior to, or early on, treatment.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [5] Gajewski, 2010, Gene signature in melanoma associated with clinical activity: a potential clue to unlock cancer immunotherapy, Cancer J source

      Not checked in the free run.

    • cites [6] Harlin, 2009, Chemokine expression in melanoma metastases associated with CD8+ T-cell recruitment, Cancer Res source

      Not checked in the free run.

    • cites [7] Spranger, 2013, Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8(+) T cells, Sci Transl Med source

      Not checked in the free run.

  • May combine two claims. 38
  • Classified as probably not a substantial claim. 10

  • May combine two claims.

    Findingown data

    Expression of IDO2, TDO2, KYNU, AHR, and GCN2 does not appear to correlate with PD1 expression or demonstrate IFNγ responsiveness as strongly as IDO1.

    “In contrast, expression of IDO2, TDO2, KYNU, AHR and GCN2 (alias EIF2AK4) does not appear to correlate with PD1 expression or demonstrate IFNγ responsiveness on a transcriptional level as strongly as IDO1 (Figure 4B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Cancer vaccines produced antigen presentation and cytotoxic T cell infiltration, but tumor regression occurred only in a small subset of patients.

    “Despite clinical trial evidence that cancer vaccines led to efficient antigen presentation with subsequent priming and infiltration of cytotoxic T cells into tumors, regression of tumors only occurred in a small subset of patients (1).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] Rosenberg, 2005, Tumor progression can occur despite the induction of very high levels of self/tumor antigen-specific CD8+ T cells in patients with melanoma, J Immunol source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Immune evasion occurs through multiple mechanisms including immuno-editing, decreased antigen presentation, and local immunosuppression in the tumor microenvironment.

    “It is now appreciated that evasion of immune mediated elimination occurs through multiple mechanisms, including immuno-editing, decreased antigen presentation, and importantly, local immunosuppression in the tumor microenvironment (3,4).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [3] Hanahan, 2011, Hallmarks of cancer: the next generation, Cell source

      Not checked in the free run.

    • cites [4] Becker, 2013, Immune-suppressive properties of the tumor microenvironment, Cancer Immunol Immunother source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Non-T cell-inflamed tumors have a low inflammatory signature and absence of tumor infiltrating lymphocytes.

    “In contrast, a non-T cell-inflamed tumor is observed to have a low inflammatory signature and the absence of tumor infiltrating lymphocytes (5–7).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [5] Gajewski, 2010, Gene signature in melanoma associated with clinical activity: a potential clue to unlock cancer immunotherapy, Cancer J source

      Not checked in the free run.

    • cites [6] Harlin, 2009, Chemokine expression in melanoma metastases associated with CD8+ T-cell recruitment, Cancer Res source

      Not checked in the free run.

    • cites [7] Spranger, 2013, Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8(+) T cells, Sci Transl Med source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    The Trp-Kyn-AhR pathway can mediate immunosuppression through tryptophan depletion, direct effects of Kyn, and Kyn-bound AhR activity.

    “Multiple mechanisms of immunosuppression may be mediated by this pathway including depletion of tryptophan, direct immunosuppression of Kyn and activity of Kyn-bound AhR.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Patients more likely to benefit from checkpoint immunotherapy include those with high somatic mutation density, elevated PD-L1 expression, and/or IFNγ transcriptional profiles.

    “Patients more likely to benefit from checkpoint immunotherapy include those with tumors demonstrating a high density of somatic mutations, elevated PD-L1 expression and/or are enriched with IFNγ transcriptional profiles (8–13).”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [8] Ayers, 2017, IFN-gamma-related mRNA profile predicts clinical response to PD-1 blockade, J Clin Invest source

      Not checked in the free run.

    • cites [9] Ji, 2012, An immune-active tumor microenvironment favors clinical response to ipilimumab. Cancer Immunology, Immunotherapy

      Not checked in the free run.

    • cites [10] Le, 2017, Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade, Science source

      Not checked in the free run.

    • cites [11] Ribas, 2016, Association of pembrolizumab with tumor response and survival among patients with advanced melanoma, JAMA source

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    • cites [12] Tang, 2018, PD-L1 on host cells is essential for PD-L1 blockade-mediated tumor regression, J Clin Invest source

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    • cites [13] Garon, 2015, Pembrolizumab for the treatment of non–small-cell lung cancer, N Engl J Med source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisenone given

    IDO1 is a principal enzyme in tryptophan catabolism and is the target of small molecule inhibitors being developed with PD-1 checkpoint inhibitors.

    “Indoleamine 2,3-dioxygenase 1 (IDO1), a principle enzyme in Trp catabolism, is the target of small molecule inhibitors in clinical development in combination with PD-1 checkpoint inhibitors.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    T cell-inflamed tumors are characterized by tumor infiltrating lymphocytes, a type-I/II IFN transcriptional profile, and high expression of immunosuppressive mechanisms.

    “T cell-inflamed tumors are characterized by tumor infiltrating lymphocytes, a type-I/II interferon (IFN) transcriptional profile, and high degree of expression of immunosuppressive mechanisms.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [5] Gajewski, 2010, Gene signature in melanoma associated with clinical activity: a potential clue to unlock cancer immunotherapy, Cancer J source

      Not checked in the free run.

    • cites [6] Harlin, 2009, Chemokine expression in melanoma metastases associated with CD8+ T-cell recruitment, Cancer Res source

      Not checked in the free run.

    • cites [7] Spranger, 2013, Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8(+) T cells, Sci Transl Med source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Novel Trp-Kyn-AhR pathway inhibitors such as Kyn degrading enzymes, direct AhR antagonists, and tryptophan mimetics are advancing in early-stage or preclinical development.

    “Novel Trp-Kyn-AhR pathway inhibitors such as Kyn degrading enzymes, direct AhR antagonists and tryptophan mimetics are advancing in early stage or pre-clinical development.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    A subset of T cell-inflamed tumors do not respond to checkpoint immunotherapy, suggesting that immunosuppressive mechanisms other than PD-1/L1 limit immune-mediated tumor regression.

    “However, a subset of tumors identified as having a T cell-inflamed tumor phenotype do not respond to checkpoint immunotherapy, suggesting other immunosuppressive mechanisms contribute to limiting immune-mediated tumor regression besides the PD-1/L1 axis.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [14] Lanitis, 2017, Mechanisms regulating T-cell infiltration and activity in solid tumors, Ann Oncol source

      Not checked in the free run.

    • cites [15] Gajewski, 2006, Immune resistance orchestrated by the tumor microenvironment, Immunol Rev source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Patient characteristics appeared relatively similar between ECHO-202 and ECHO-301 across performance status 0 (77 vs 76%), M1c staging (55 vs 61%), elevated lactate dehydrogenase (37 vs 32%), and no prior therapy (71 vs 89%).

    “the patient characteristics appeared to be relatively similar from the early (ECHO-202) to late phase (ECHO-301) melanoma studies across multiple variables including but not limited to performance status of zero (77 vs 76%), M1c staging (55 vs 61%), elevated lactate dehydrogenase (37 vs 32%) and no prior therapy (71 vs 89%), respectively (55,56).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [55] Long, 2018, Epacadostat (E) plus pembrolizumab (P) versus pembrolizumab alone in patients (pts) with unresectable or metastatic melanoma: results of the phase 3 ECHO-301/KEYNOTE-252 study

      Not checked in the free run.

    • cites [56] Hamid, 2017, Epacadostat plus pembrolizumab in patients with advanced melanoma: phase 1 and 2 efficacy and safety results from ECHO-202/KEYNOTE-037, Ann Oncol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Low tryptophan levels suppress mTORC pathways and activate GCN2 kinase, leading to cell cycle arrest and anergy of infiltrating T cells via eIF-2-dependent pathways.

    “T cells are exquisitely sensitive to local depletion of tryptophan in which low tryptophan levels suppress mTORC pathways and activate general control nondepressible 2 (GCN2) kinase leading to cell cycle arrest and anergy of infiltrating T cells via eIF-2-dependent pathways (Figure 1) (29–31).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [29] Munn, 1999, Inhibition of T cell proliferation by macrophage tryptophan catabolism, J Exp Med source

      Not checked in the free run.

    • cites [30] Munn, 2005, GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase, Immunity source

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    • cites [31] Eleftheriadis, 2015, Indoleamine 2,3-dioxygenase depletes tryptophan, activates general control non-derepressible 2 kinase and down-regulates key enzymes involved in fatty acid synthesis in primary human CD4+ T cells, Immunology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Accumulation of kynurenines induces effector T cell arrest and binding to AhR, resulting in nuclear translocation and promotion of FoxP3 transcripts and IL-10, producing regulatory T cell populations.

    “Accumulation of kynurenines induce effector T cell arrest and lead to binding of AhR. This results in nuclear translocation and promotion of FoxP3 transcripts and IL-10, eventually producing regulatory T cell populations (18,34–37).”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [18] Gutierrez-Vazquez, 2018, Regulation of the immune response by the aryl hydrocarbon receptor, Immunity source

      Not checked in the free run.

    • cites [34] Mellor, 2004, Specific subsets of murine dendritic cells acquire potent T cell regulatory functions following CTLA4-mediated induction of indoleamine 2,3 dioxygenase, Int Immunol source

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    • cites [35] Veldhoen, 2009, Natural agonists for aryl hydrocarbon receptor in culture medium are essential for optimal differentiation of Th17 T cells, J Exp Med source

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    • cites [36] Mezrich, 2010, An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells, J Immunol source

      Not checked in the free run.

    • cites [37] Gandhi, 2010, Activation of the aryl hydrocarbon receptor induces human type 1 regulatory T cell-like and Foxp3(+) regulatory T cells, Nat Immunol source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    In ECHO-301, IDO1 expression was not an inclusion criterion, while PD-L1 expression was a randomization stratification factor.

    “In ECHO-301 IDO1 expression was not an inclusion criterion (though PD-L1 expression was a randomization stratification factor) with only PD-L1 status as a surrogate from the early phase studies.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    IDO1 knockout mice show no clinical phenotype, unlike the inflammatory phenotype observed in CTLA-4 and PD-1 knockouts.

    “IDO1 knockout mice demonstrate no clinical phenotype, in contrast to the inflammatory phenotype observed for knockouts of the immune checkpoints CTLA-4 and PD-1, and thus IDO1 inhibitors have predominantly been used in combination with other treatment modalities (43,44).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [43] Vacchelli, 2014, Trial watch: IDO inhibitors in cancer therapy, Oncoimmunology source

      Not checked in the free run.

    • cites [44] Hunt, Structure, in vitro biology and in vivo pharmacodynamic characterization of a novel clinical IDO1 inhibitor [abstract]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In ECHO-301, the overall response rate was 34.2% with epacadostat plus pembrolizumab versus 31.5% with placebo plus pembrolizumab; treatment-related adverse events occurred in 79.3% versus 81.0%, and Grade >3 events in 21.8% versus 17.0%.

    “The overall response rate was 34.2% versus 31.5% in the epacadostat plus pembrolizumab and placebo plus pembrolizumab groups respectively. Treatment related adverse events occurred in 79.3% of patients receiving epacadostat plus pembrolizumab versus 81.0% receiving placebo plus pembrolizumab and Grade >3 treatment-related adverse events occurred in 21.8% versus 17.0%, respectively (55).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [55] Long, 2018, Epacadostat (E) plus pembrolizumab (P) versus pembrolizumab alone in patients (pts) with unresectable or metastatic melanoma: results of the phase 3 ECHO-301/KEYNOTE-252 study

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Kynurenines are potent agonists of AhR, a ligand-gated transcription factor expressed in many immune cells that mediates immunomodulatory effects.

    “Kynurenines act as potent agonists of AhR, a ligand-gated transcription factor that is expressed in many immune cells and mediates a wide range of immunomodulatory effects (26,27).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [26] Kewley, 2004, The mammalian basic helix-loop-helix/PAS family of transcriptional regulators, Int J Biochem Cell Biol source

      Not checked in the free run.

    • cites [27] Cheong, 2018, Targeting the IDO1/TDO2-KYN-AhR pathway for cancer immunotherapy - challenges and opportunities, Trends Pharmacol Sci source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    The early phase trial was conducted at a select number of sites in the United States, while the late phase study was predominantly international with lesser accrual in the United States.

    “One of these would be to note that the early phase trial was conducted at a select number of sites in the United States while the late phase study was predominately international (Australia, Europe, Asia, South America) with a lesser accrual in the United States.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    IDO1 is expressed by stromal cells in the tumor microenvironment and induced by IFNγ as a result of CD8+ T cell infiltration and activation of other immunosuppressive pathways.

    “In tumors, IDO1 is expressed by stromal cells of the TME and is induced by IFNγ as a result of CD8+ T cell infiltration and activation of other immunosuppressive pathways (7,23,24).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [7] Spranger, 2013, Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8(+) T cells, Sci Transl Med source

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    • cites [23] Ryan, 2007, Interferon-γ does not break, but promotes the immunosuppressive capacity of adult human mesenchymal stem cells, Clin Exp Immunol source

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    • cites [24] Vigneron, 2015, Expression profile of the human IDO1 protein, a cancer drug target involved in tumoral immune resistance, Oncoimmunology source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Initial peripheral blood Kyn suppression data for selective-IDO1 inhibitors showed approximately 50% reduction, suggesting other enzymes such as TDO contribute to systemic kynurenine.

    “Initial peripheral blood Kyn suppression data demonstrated approximately 50% reduction suggesting other enzymes contribute to the production of systemic kynurenine, such as TDO.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    AhR suppresses innate immunogenicity of antigen presenting cells and promotes IL-10 production by natural killer cells.

    “AhR suppresses innate immunogenicity of antigen presenting cells and promotes IL-10 production by natural killer cells (Figure 2) (39–41).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [39] Nguyen, 2010, Aryl hydrocarbon receptor negatively regulates dendritic cell immunogenicity via a kynurenine-dependent mechanism, Proc Natl Acad Sci U S A source

      Not checked in the free run.

    • cites [40] Wagage, 2014, The aryl hydrocarbon receptor promotes IL-10 production by NK cells, J Immunol source

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    • cites [41] Yamada, 2016, Constitutive aryl hydrocarbon receptor signaling constrains type I interferon-mediated antiviral innate defense, Nat Immunol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    BMS-986205 demonstrates higher potency based on IC50 in IDO1-expressing cell lines relative to epacadostat.

    “Relative to epacadostat, BMS-986205 demonstrates higher potency based on IC50 in IDO1 expressing cell lines.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Intra-tumoral injection of engineered E. coli strains that metabolize kynurenine demonstrated reduction in in vivo kynurenine levels and generation of antitumor response.

    “Intra-tumoral injection of engineered E. coli strains that metabolize kynurenine have demonstrated reduction in in vivo kynurenine levels and generation of antitumor response (75).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [75] Giannakis, 35, 2017, Metabolomic correlates of response in nivolumab-treated renal cell carcinoma and melanoma patients, J Clin Oncol

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationnone given

    Dual inhibition of IDO1 and TDO, and/or use of recombinant enzymes that degrade kynurenine, might achieve greater reduction of kynurenine within tumors.

    “Comprehensive inhibition of kynurenine production by dual IDO1/TDO inhibitors and/or degradation of Kyn molecules by recombinant kynurenine degrading enzymes may provide more robust intra-tumoral Kyn reduction.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Indoximod is the D-enantiomer of 1-methyl-tryptophan and inhibits the IDO pathway as a tryptophan mimetic.

    “Indoximod, the D-enantiomer of 1-methyl-tryptophan, has demonstrated inhibition of the IDO pathway as a tryptophan mimetic.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    The immunosuppressive effect of the Trp-Kyn-AhR pathway is believed to be mediated by Trp depletion, Kyn cytotoxicity-mediated T cell cycle arrest, and activation of immune-tolerogenic AhR.

    “The immunosuppressive effect of this pathway is believed to be mediated by Trp depletion, T cell cycle arrest mediated by Kyn cytotoxicity and activation of immune-tolerogenic AhR.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Dual IDO/TDO inhibitors such as RG70099 decrease serum Kyn levels by approximately 90%.

    “Dual IDO/TDO inhibitors such as RG70099 decrease serum Kyn levels by approximately 90%.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Preclinical studies of recombinant PEG-KYNase in established tumor models demonstrated inhibition of tumor growth and increase in tumor infiltrating effector T cells as monotherapy.

    “Preclinical studies of a recombinant PEG-KYNase in established tumor models have demonstrated inhibition of tumor growth and increase in tumor infiltrating effector T cells as monotherapy.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [73] Triplett, 2018, Reversal of indoleamine 2,3-dioxygenase-mediated cancer immune suppression by systemic kynurenine depletion with a therapeutic enzyme, Nat Biotechnol source

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    • cites [74] West, Metabolic modulation of the tumor microenvironment using Synthetic Biotic™ Medicines [abstract]

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  • May combine two claims.

    Premisecitation

    In an AhR-dependent manner, indoximod stimulates CD4+ T cell differentiation to Th17 helper T cells, inhibits FoxP3 T regulatory cells, and downregulates IDO expression in dendritic cells.

    “In an AhR-dependent manner, indoximod was shown to stimulate CD4+ T cell differentiation to Th17+ helper T cells, inhibit FoxP3 T regulatory cells and downregulate expression of IDO in dendritic cells (66).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [66] Brincks, Indoximod modulates AhR-driven transcription of genes that control immune function [abstract]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Analysis of 39 paired pre- versus on-treatment tumor samples from the Phase I trial of BMS-986205 plus nivolumab demonstrated decreased Kyn levels (mostly near zero on-treatment) and increased percentage of proliferating CD8+ T cells.

    “analysis of 39 paired pre- vs on-treatment tumor samples across various tumor types from the Phase I trial of BMS-986205 plus nivolumab demonstrated decreased Kyn levels (and mostly near zero levels on-treatment) and increased the percentage of proliferating CD8+ T cells (65).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [65] Luke, 2017, Preliminary antitumor and immunomodulatory activity of BMS-986205, an optimized indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor, in combination with nivolumab in patients with advanced cancers, J Immunother Cancer

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Indoximod limits IDO-mediated immunosuppression by at least two mechanisms: serving as an artificial Trp-sufficiency signal that prevents GCN2 activation and mTORC1 inhibition, and modulating AhR-dependent transcriptional activity.

    “Indoximod limits IDO-mediated immunosuppression by at least two mechanisms including 1) serving as an artificial Trp-sufficiency signal that prevents activation of GCN2 and inhibition of mTORC1 and 2) modulation of AhR-dependent transcriptional activity (66).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [66] Brincks, Indoximod modulates AhR-driven transcription of genes that control immune function [abstract]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    An early phase study of epacadostat with nivolumab used 300 mg, and published modeling implies a higher likelihood of IDO1 inhibition at this dose.

    “It is somewhat notable that an early phase study of epacadostat with nivolumab was simultaneously pursued using 300 mg of epacadostat (61) and published modeling implies a higher likelihood of IDO1 inhibition at this dose (60).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [60] Mitchell, 2018, Epacadostat plus pembrolizumab in patients with advanced solid tumors: phase I results from a multicenter, open-label phase I/II trial (ECHO-202/KEYNOTE-037), J Clin Oncol source

      Not checked in the free run.

    • cites [61] Daud, 2018, Epacadostat plus nivolumab for advanced melanoma: updated phase 2 results of the ECHO-204 study, J Clin Oncol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In murine models, complete IDO/TDO inhibition results in significant alteration of Trp metabolism, raising concern over potential neurologic toxicity (seizures).

    “It is worth pointing out however that in murine models, complete IDO/TDO inhibition results in significant alteration of Trp metabolism which has raised concern over potential neurologic toxicity (seizures) from dual IDO1/TDO inhibition (71).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [71] Kanai, 2009, Tryptophan 2,3-dioxygenase is a key modulator of physiological neurogenesis and anxiety-related behavior in mice, Mol Brain source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    BMS-986205 is an irreversible IDO1 inhibitor whose pivotal studies have been predominately scaled back after epacadostat's late-stage failure, though a randomized bladder cancer study is still planned.

    “Pivotal studies of BMS-986205, an irreversible IDO1 inhibitor developed by Flexus Biosciences and Bristol Meyers Squib, have been predominately scaled back in wake of epacadostat’s late-stage trial failure though a randomized study in bladder cancer is still planned.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Analysis of tumor and immune cells by immunohistochemistry revealed differences in IDO1 and TDO expression among tumor types, suggesting potential advantage with dual IDO/TDO inhibitors in certain tumors.

    “Analysis of tumor and immune cells by immunohistochemistry revealed differences in the expression of IDO1 and TDO among tumor types, suggesting the potential for a possible advantage with dual IDO and TDO inhibitors in certain tumors (69).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [69] Gyulveszi, RG70099: a novel, highly potent dual IDO1/TDO inhibitor to reverse metabolic suppression of immune cells in the tumor micro-environment [abstract] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A single-arm phase 2 trial of indoximod plus anti-PD1 in advanced melanoma achieved an ORR of 56% and CR in 19% with low rates of high-grade immune-related adverse events.

    “Data from a single-arm phase 2 trial of indoximod plus anti-PD1 in advanced melanoma achieved an ORR of 56% and CR in 19% with low rates of high-grade immune-related adverse events (68).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [68] Zakharia, 2018, Phase 2 trial of the IDO pathway inhibitor indoximod plus checkpoint inhibition for the treatment of patients with advanced melanoma, J Clin Oncol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Recent studies have cast doubt on Trp-depletion mechanisms and highlighted potent immunosuppressive activity of intra-tumoral Kyn and AhR signaling.

    “Recent studies have cast doubt on the Trp-depletion mechanisms (32,33) and highlighted the potent immunosuppressive activity of intra-tumoral Kyn and AhR signaling.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [32] Sonner, 2016, The stress kinase GCN2 does not mediate suppression of antitumor T cell responses by tryptophan catabolism in experimental melanomas, Oncoimmunology source

      Not checked in the free run.

    • cites [33] Badawy, 2016, The end of the road for the tryptophan depletion concept in pregnancy and infection, Clin Sci source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Even though epacadostat did not work in unselected melanoma patients, there is still a strong rationale for combining Trp-Kyn-AhR pathway targeting with immunotherapy.

    “Despite the failed experience of epacadostat in unselected melanoma patients, a strong translational rationale still exists for targeting of the Trp-Kyn-AhR pathway in conjunction with immunotherapy.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Epacadostat failed in unselected melanoma patients.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    The Trp-Kyn-AhR pathway and PD-1-PD-L1 signaling are each linked to the IFNγ response.

    “the Trp-Kyn-AhR pathway and PD-1–PD-L1 signaling are both associated with IFNγ response”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    New agents from the dual IDO1/TDO, kynurenine-degrading enzyme, and AhR inhibitor classes are moving toward phase I trials, and preclinical experiments have yielded encouraging results.

    “Novel agents in each of these classes are approaching phase I studies and pre-clinical experiments have shown promising results (72–75).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [72] Zhang, A novel approach to targeting the IDO/TDO pathway through degradation of the immunosuppressive metabolite kynurenine [abstract]

      Not checked in the free run.

    • cites [73] Triplett, 2018, Reversal of indoleamine 2,3-dioxygenase-mediated cancer immune suppression by systemic kynurenine depletion with a therapeutic enzyme, Nat Biotechnol source

      Not checked in the free run.

    • cites [74] West, Metabolic modulation of the tumor microenvironment using Synthetic Biotic™ Medicines [abstract]

      Not checked in the free run.

    • cites [75] Giannakis, 35, 2017, Metabolomic correlates of response in nivolumab-treated renal cell carcinoma and melanoma patients, J Clin Oncol

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Despite uncertainty about selective IDO1 inhibition, substantial preclinical evidence justifies continuing development of Trp-Kyn-AhR pathway inhibitors to enhance immune-checkpoint and other cancer treatments.

    “Despite uncertainty surrounding selective-IDO1 inhibition, ample preclinical evidence supports continued development of Trp-Kyn-AhR pathway inhibitors to augment immune-checkpoint and other cancer therapies.”
    Quote in the paperSubstantial claim
41 of 41

  • The paper relies on this without support.

    Preclinical evidence of Trp-Kyn-AhR pathway inhibition predicts clinical benefit in human cancer patients.

    “Despite uncertainty surrounding IDO1 inhibition, ample preclinical evidence supports continued development of Trp-Kyn-AhR pathway inhibitors to augment immune-checkpoint and other cancer therapies.”

  • The paper relies on this without support.

    Intra-tumoral Kyn levels are a more valid pharmacodynamic measure than peripheral blood Kyn for the Trp-Kyn-AhR pathway.

    “it is unclear if serum kynurenine is a surrogate for intra-tumoral Kyn.”

  • The paper relies on this without support.

    Epacadostat failed in unselected melanoma patients.

    “Despite the failed experience of epacadostat in unselected melanoma patients”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Cites

Flagged first, then by citations

Research works printed but not linked: 7

  1. Gajewski, 2010, Gene signature in melanoma associated with clinical activity: a potential clue to unlock cancer immunotherapy, Cancer J, 16, 399, 10.1097/PPO.0b013e3181eacbd8 · DOI · Paper page
  2. Hunt, Structure, in vitro biology and in vivo pharmacodynamic characterization of a novel clinical IDO1 inhibitor [abstract]
  3. Luke, 2017, Preliminary antitumor and immunomodulatory activity of BMS-986205, an optimized indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor, in combination with nivolumab in patients with advanced cancers, J Immunother Cancer, 5, 89
  4. Wise, Pre-clinical development of next generation inhibitors of the enzymes indoleamine 2,3-dioxygenase 1 and tryptophan 2,3-dioxygenase as cancer immunotherapies [abstract]
  5. Zhang, A novel approach to targeting the IDO/TDO pathway through degradation of the immunosuppressive metabolite kynurenine [abstract]
  6. Mie, 2017, In vitro and in vivo characterization of KHK2455, a highly potent and selective indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor with a novel mechanism of action, J Immunother Cancer, 5, P149
  7. Sahebjam, 2017, KHK2455, a long-acting selective IDO-1 inhibitor, in combination with mogamulizumab, an anti-CCR4 monoclonal antibody, in patients with advanced solid tumors: preliminary safety report and pharmacodynamic activity from a first-in-human study, J Immunother Cancer, 5, P148

Cited by

Sorted by citations

Authors
Labadie, B. W., Bao, R., & Luke, J. J.
Affiliations
University of Chicago (US)
Corresponding author
Luke, Jason J.
ORCID
Venue
Clinical Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2019-03-01
Volume
25
Issue
5
Pages
1462-1471
ISSN
  • 1078-0432 (ISSN-L)
  • 1557-3265
DOI
10.1158/1078-0432.ccr-18-2882
PMC
PMC6397695
OpenAlex
W2899358783
Semantic Scholar
643b705397c16ce89e7fae073aec25c081fe29d9
Cited by
413
References
78
Citations by year
2026: 52 · 2025: 43 · 2024: 42 · 2023: 50 · 2022: 67 · 2021: 65 · 2020: 68 · 2019: 25 · 2018: 1
FWCI
4.21
Type
journal article
Language
en
Open access
Locations
  • Clinical Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Department of Defense (W81XWH-17-1-0265)
  • National Cancer Institute (P30CA014599-43S)
  • Institute for Translational Medicine/CTSA (NIH UL1 RR024999)
Topics
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords
IDO1 inhibition, epacadostat, pembrolizumab, PD-1 inhibitors, cancer immunotherapy, tryptophan catabolism, aryl hydrocarbon receptor antagonist, immunosuppressive tumor microenvironment, metastatic melanoma, combination therapy
MeSH terms
Enzyme Inhibitors, Humans, Immunotherapy, Kynurenine, Models, Biological, Neoplasms, Tryptophan, Signal Transduction, Receptors, Aryl Hydrocarbon, Computational Biology, Gene Expression Profiling, Cell Line, Tumor, Indoleamine-Pyrrole 2,3,-Dioxygenase, Immunomodulation, Transcriptome

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

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