IDO/TDO dual inhibitor / Lumos Pharma - LARVOL DELTA

[VIRTUAL] Metabolomic adaptations and correlates of survival to immune checkpoint blockade (AACR-II 2020) - "To investigate the generalizability of our results, we also performed metabolomics and serum specimens from a large randomized Phase 3 trial (CheckMate 025) with 743 RCC patients, among which 394 received nivolumab and 349 received everolimus. We identified increased tryptophan to kynurenine conversion in response to PD1 blockade in a subset of melanoma and RCC patients. By using independent cohorts, we showed that Kyn/Trp temporal alterations robustly correlated with overall survival of patients receiving nivolumab. Our findings illustrate that checkpoint blockade in combination with IDO/TDO inhibitors might only benefit a selected group of patients with checkpoint-inhibition-triggered kynurenine pathway activation."

Checkpoint inhibition • IO biomarker • Genito-urinary Cancer • Melanoma • Oncology • Renal Cell Carcinoma • Solid Tumor • IDO1 • PD-L1 • TMB

Targeting the IDO/TDO pathway through degradation of the immunosuppressive metabolite kynurenine (AACR 2018) - "Kynase demonstrated superior tumor growth inhibition and survival benefit relative to a leading IDO1 inhibitor epacadostat in these models. The effects of Kynase on a number of immune cell types, both in vitro and in vivo, are being investigated. Human Kynase has also shown a favorable PK profile and kynurenine degradation in non-human primates, and Kynase variants are now moving toward development candidate selection for treatment of cancers where both IDO/TDO pathways play a significant immunosuppressive role."

Oncology

The aryl hydrocarbon receptor as driver of cancer immunity (AACR 2018) - "The Aryl Hydrocarbon Receptor (AHR) has been identified as a driver of cancer progression and cancer immunity in the tryptophan-IDO/TDO-kynurenine-AHR pathway...Preliminary data suggest that AHR+ myeloid cells mediate suppression of tumor immunity. These results collectively suggest that the AHR may be targeted for immunotherapy of several cancers and that HP163 may represent a novel approach to cancer therapy."

IO Biomarker • PD(L)-1 Biomarker • Oncology

Role of indoleamine 2,3-dioxygenase in testicular immune-privilege. (PubMed, Sci Rep) - "Here we assessed the in vivo role of IDO/TDO in experimental autoimmune orchitis (EAO), a model of autoimmune testicular inflammation and immunologically impaired spermatogenesis...Finally, in vivo inhibition of IDO with 1-methyl-tryptophan increased severity of the disease, demonstrating down regulation of IDO-based tolerance when testicular immune regulation was disrupted. We present evidence that an IDO-based mechanism is involved in testicular immune privilege."

IO Biomarker • Journal • Immunology • Infertility • Inflammation • Mood Disorders • Oncology • Sexual Disorders

Blockade of the AHR restricts a Treg-macrophage suppressive axis induced by L-Kynurenine. (PubMed, Nat Commun) - "Selective AHR blockade delays progression in IDO/TDO-overexpressing tumors, and its efficacy is improved in combination with PD-1 blockade. Our findings suggest that blocking the AHR pathway in IDO/TDO expressing tumors would overcome the limitation of single IDO or TDO targeting agents and constitutes a personalized approach to immunotherapy, particularly in combination with immune checkpoint inhibitors."

Journal • Immune Modulation • Inflammation • Oncology

Synthesis and in vivo antitumor evaluation of an orally active potent phosphonamidate derivative targeting IDO1/IDO2/TDO. (PubMed, Biochem Pharmacol) - "Based on the promising enzyme inhibitory activity toward IDO/TDO, compound F04 was evaluated of its antitumor effects in two tumor models. Further evaluation of mechanism demonstrated compound F04 with the remarkable capacity of reducing kynurenine level in plasma/TME and restoring anti-tumor immune response. F04 could be further developed as a potential immunotherapeutic agent combined with immune checkpoint inhibitors or chemotherapeutic drugs for cancer treatment."

Journal • Preclinical • Immune Modulation • Inflammation • Lung Cancer • Oncology • Solid Tumor • Thoracic Cancer

Resistance Exercise Modulates Kynurenine Pathway in Pancreatic Cancer Patients. (PubMed, Int J Sports Med) - "IL-6 levels decreased over the first three months for both intervention groups as well as the Control group (Supervised: p < 0.01, Home-based: p < 0.010, Control group: p < 0.01). Supervised resistance exercise might positively regulate the Kynurenine pathway and downregulate the kynurenine/tryptophan (indicative of IDO/TDO enzyme) levels, hence modulating the immune system."

Clinical • Journal • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Solid Tumor • IL6

Indoximod opposes the immunosuppressive effects mediated by IDO and TDO via modulation of AhR function and activation of mTORC1. (PubMed, Oncotarget) - "These indoximod-driven effects on CD8 and CD4 T cells were independent from the activity of IDO/TDO and from the presence of exogenous Kyn, though they do oppose the effects of Kyn produced by these Trp catabolizing enzymes. Indoximod can also downregulate expression of IDO protein in vivo in murine lymph node dendritic cells and in vitro in human monocyte-derived dendritic cells via a mechanism that involves signaling through the AhR. Together, these data improve the understanding of how indoximod influences the effects of IDO, beyond and distinct from direct enzymatic inhibition of the enzyme."

IO Biomarker • Journal

Indoximod: An Immunometabolic Adjuvant That Empowers T Cell Activity in Cancer. (PubMed, Front Oncol) - "Exploding interest in immunometabolism as a source of new cancer therapeutics has been driven in large part by studies of tryptophan catabolism mediated by IDO/TDO enzymes. We also review the potential advantages indoximod offers compared to selective IDO1-specific blockade, which preclinical studies and the clinical study ECHO-301 suggest may be bypassed readily by tumors. Indoximod lies at a leading edge of broad-spectrum immunometabolic agents that may act to improve responses to many anticancer modalities, in a manner analogous to vaccine adjuvants that act to boost immunity in settings of infectious disease. "

Clinical • Journal • Review • Biosimilar • Immune Modulation • Inflammation • Oncology

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 (SITC 2017) - "...In vitro dose-dependent potency and selectivity were analyzed in IDO/TDO expressing 293T cells...KHK2455 is an IDO1 inhibitor with a novel MOA that potently and selectively inhibits kyn production in preclinical models, and demonstrates synergistic inhibition of tumor growth in a mouse tumor model with anti-CTLA-4 antibody. Together, these data support the clinical evaluation of KHK2455 in a phase I study."

Checkpoint inhibition • Oncology

[VIRTUAL] Metabolomic adaptations and correlates of survival to immune checkpoint blockade (AACR 2020) - "To investigate the generalizability of our results, we also performed metabolomics and serum specimens from a large randomized Phase 3 trial (CheckMate 025) with 743 RCC patients, among which 394 received nivolumab and 349 received everolimus. We identified increased tryptophan to kynurenine conversion in response to PD1 blockade in a subset of melanoma and RCC patients. By using independent cohorts, we showed that Kyn/Trp temporal alterations robustly correlated with overall survival of patients receiving nivolumab. Our findings illustrate that checkpoint blockade in combination with IDO/TDO inhibitors might only benefit a selected group of patients with checkpoint-inhibition-triggered kynurenine pathway activation."

Checkpoint inhibition • IO Biomarker • Genito-urinary Cancer • Melanoma • Oncology • Renal Cell Carcinoma • Solid Tumor • Urothelial Cancer • IDO1 • PD-L1 • TMB

"Many thanks to @IDontDoGiddy for the pic!" (@PeterHotez)

Metabolomic adaptations and correlates of survival to immune checkpoint blockade. (PubMed, Nat Commun) - "Here, in order to investigate the metabolic alterations in response to immune checkpoint blockade, we comprehensively profile serum metabolites in advanced melanoma and renal cell carcinoma patients treated with nivolumab, an antibody against programmed cell death protein 1 (PD1). We identify serum kynurenine/tryptophan ratio increases as an adaptive resistance mechanism associated with worse overall survival. This advocates for patient stratification and metabolic monitoring in immunotherapy clinical trials including those combining PD1 blockade with indoleamine 2,3-dioxygenase/tryptophan 2,3-dioxygenase   (IDO/TDO) inhibitors."

Checkpoint inhibition • Journal

Blockade of IDO/TDO downstream effectors restricts a Treg-macrophage suppressive axis and resistance to anti-PD-1 therapy (SITC 2019) - "In summary, our findings demonstrate that targeting the Kyn pathway through AHR inhibition could overcome key suppressive mechanisms and sensitize otherwise immune resistant tumors to PD-1 blockade."

IO Biomarker • PD(L)-1 Biomarker

"@choo_ek @EstOdek @marynmck @DrJenGunter @drjessigold @karenerrichetti @bethlinas @peakpilot @17frosted @andrearchbeir @justineldees @Darcy_ID_doc @DocSaimaAslam @EpiEllie @Laurie_Garrett @PeterHotez @CarlosdelRio7 @IDontDoGiddy @AmericanCancer @DanaFarber @KRBurgio @TheWanKasia" (@chngin_the_wrld)

"#WhyIDontDoTheMowing" (@CArnold_GI)

Reporter imaging of Trp-IDO/TDO-Kyn-AHR pathway activity (CRI-CIMT-EATI-AACR 2019) - "Two AHR activating molecules (kynurenine and the AHR agonist FICZ) were observed to increase luciferase expression, in B16-DRE and 4T1-DRE reporter cells, whereas an AHR inhibitor (CH223191) reduced reporter activity. Coupled with a constitutive reporter in the same cells, it is possible to quantitatively monitor AHR transcriptional activity using this dual reporter system. The dual reporter system is expected to: i) quantify the kinetics of engagement with the AHR upon treatment with different agonists/antagonists and monitor the correlation with phenotypic changes in different components of the TME, including cancer cells, macrophage and T cells ; ii) monitor the dynamic activation of the AHR pathway in vivo during tumor progression and targeted treatment in IDO/TDO-expressing cancer models ; iv) evaluate the in vivo dynamics of AHR activation after response to immune-based therapeutic interventions (PD-1/CTLA-4 blockade, T cell therapy) in the same models ; v)..."

IO Biomarker • PD(L)-1 Biomarker

Role of IDO and TDO in Cancers and Related Diseases and the Therapeutic Implications. (PubMed, J Cancer) - "In the present review, we depict the structure of IDO and TDO and explicate their functions in various diseases to facilitate a better understanding of them and to indicate new therapeutic plans to target them. Moreover, we summarize the inhibitors of IDO/TDO that are currently under development and their efficacy in the treatment of cancer and other diseases."

Journal • Review

Blockade of IDO/TDO downstream effectors restricts cancer immune suppression (AAI 2019) - "Treatment of B16-IDO-bearing mice with an AHR-specific antagonist (CH-223191) leads to an increase of MHC II in TAMs, of activation markers in CD8 T cells and reduced frequency of T-regs. AHR inhibition delays progression of tumors with an active IDO/TDO/Kyn pathway (B16-IDO and B16-TDO), and efficacy is further improved when ICB is used in combination. In summary, our findings demonstrate that targeting the Kyn pathway through AHR inhibition could overcome key suppressive mechanisms and sensitize tumors to ICB"

IO Biomarker • PD(L)-1 Biomarker

Blockade of IDO/TDO downstream effectors restricts cancer immune suppression (AAI 2019) - No abstract available.

Discovery and optimization of imidazoisoindole-based IDO/TDO dual inhibitors (ACS-Sp 2019) - "Next, activity against IDO was gained through further modification of the same element to arrive at potent dual IDO/TDO inhibitors. Finally, through optimization of compound physical properties, potent and orally bio-available dual inhibitors were identified."

IO Biomarker

Discovery and optimization of imidazoisoindole-based IDO/TDO dual inhibitors (ACS-Sp 2019) - "Next, activity against IDO was gained through further modification of the same element to arrive at potent dual IDO/TDO inhibitors. Finally, through optimization of compound physical properties, potent and orally bio-available dual inhibitors were identified."

IO Biomarker