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DRUG:

indoximod (NLG8189)

i
Other names: NLG8189, 1-MT, D-1MT, NSC-721782, NLG-001, NSC-721782, NLG 8189, NLG-8189, D1MT, 1-methyl-D-tryptophan, NLG 001, NLG001, D 1MT
Company:
Lumos Pharma
Drug class:
IDO inhibitor
3ms
Synergistic Photothermal Tumor Immunotherapy by 1-MT Based on Zeolitic Imidazolate Framework-8 with pH-High Sensitivity. (PubMed, Int J Nanomedicine)
The PCMZ NPs, possessing good photothermal conversion capabilities due to join of PDA, effectively overcome two main challenges in immunotherapy: insufficient stimulation of the immune response and evasion of the immune system. This provides a robust platform against invasive cancer and recurrent tumors.
Journal
|
ANXA5 (Annexin A5)
|
indoximod (NLG8189)
3ms
An injectable composite hydrogel containing polydopamine-coated curcumin nanoparticles and indoximod for the enhanced combinational chemo-photothermal-immunotherapy of breast tumors. (PubMed, Colloids Surf B Biointerfaces)
After intratumoral injection of PCur/IND@Gel, significant apoptosis in 4T1 tumors was induced, dendritic cells in lymph nodes were highly activated, potent CD8+ and CD4+ antitumor immune responses were elicited and regulative T cells in tumors were significantly reduced, which notably inhibited the tumor growth and prolonged the survive time of 4T1 tumor-bearing mice. Therefore, this injectable nanocomposite hydrogel is a promising drug co-delivery platform for chemo-photothermal-immunotherapy of breast tumors.
Journal
|
CD8 (cluster of differentiation 8) • CD4 (CD4 Molecule)
|
indoximod (NLG8189)
4ms
Indoleamine 2,3-Dioxygenase Inhibitor Suppresses Colon Cancer Cell Migration, Invasion, and Epithelial-Mesenchymal Transition. (PubMed, Anticancer Res)
IDO1 inhibition reduced the invasion and migration ability of IDO1-expressing DLD-1 colon cancer cells, which was accompanied by altered expression of EMT-related proteins. IDO1 could be a potential target for the treatment of advanced CRC.
Journal • IO biomarker
|
CDH1 (Cadherin 1) • VIM (Vimentin) • DLD (Dihydrolipoamide Dehydrogenase) • SNAI2 (Snail Family Transcriptional Repressor 2)
|
indoximod (NLG8189)
8ms
Gut microbiota composition is associated with the efficacy of Delta-24-RGDOX in malignant gliomas. (PubMed, Mol Ther Oncol)
To test this hypothesis, we evaluated the changes in gut microbiota in two mouse cohorts: (1) GSC-005 glioblastoma-bearing mice treated orally with indoximod, an immunotherapeutic agent, or with Delta-24-RGDOX by intratumoral injection and (2) a mouse cohort harboring GL261-5 tumors used to mechanistically evaluate the importance of CD4+ T cells in relation to viroimmunotherapy efficacy. The CD4+ T cell depletion was associated with gut dysbiosis, lower mouse survival, and lower antitumor efficacy of the therapy. These findings suggest that microbiota modulation along the gut-glioma axis contributes to the clinical efficacy and patient survival of viroimmunotherapy treated animals.
Journal • IO biomarker
|
CD4 (CD4 Molecule) • TNFSF4 (TNF Superfamily Member 4)
|
indoximod (NLG8189) • DNX-2440
9ms
A metal-organic framework (MOF) built on surface-modified Cu nanoparticles eliminates tumors via multiple cascading synergistic therapeutic effects. (PubMed, J Colloid Interface Sci)
Herein, we report the synthesis of ultrafine Cu nanoparticles loaded with a drug combination of cisplatin (Pt) and 1-methyl-d-tryptophan (1-MT) and externally coated with 5,10,15,20-tetrakis(4-carboxyphenyl)porphyrin (TCPP) photosensitizer, polydopamine (PDA) and CaO2 of MIL-101(Fe) as a new nanoplatform (Cu@MIL-101@PMTPC). CaO2 on the outer layer generated oxygen (O2) and hydrogen peroxide (H2O2) to ameliorate hypoxia in the tumor microenvironment, enhance the PDT effect, and provide a continuous supply of H2O2 for the Fenton-like reaction. Thus, this nanocarrier platform exhibited a powerful chemodynamic, photodynamic, and immunochemotherapeutic cascade, providing a new strategy for cancer treatment.
Journal • IO biomarker
|
CD8 (cluster of differentiation 8) • IFNG (Interferon, gamma) • TNFA (Tumor Necrosis Factor-Alpha) • CD4 (CD4 Molecule)
|
CD8 expression • IFNG expression
|
cisplatin • indoximod (NLG8189)
10ms
Alleviation of Rheumatoid Arthritis by Inducing IDO Expression with Trichinella spiralis Recombinant Protein 43. (PubMed, J Immunol Res)
Then, we randomized BALB/c mice (8 weeks old) into six groups, including control, phosphate buffer saline (PBS), BCII, BCII + heat inactivated Tsp43 (HiTsp43), BCII + Tsp43, and BCII + Tsp43 + 1-methyl-troptophan (1-MT) groups...These results suggested that Tsp43 played an important role in the treatment of arthritis by inhibiting the proliferation of CD4T cells and inducing CD4T cells apoptosis through the high expression of IDO. The purpose of this experiment was to provide a new idea for the treatment of RA and lay a foundation for the development of parasite-derived drugs for the treatment of RA.
Journal
|
TNFA (Tumor Necrosis Factor-Alpha) • IDO1 (Indoleamine 2,3-dioxygenase 1) • IL1B (Interleukin 1, beta)
|
IDO1 expression
|
indoximod (NLG8189)
11ms
Assessment of an Anticancer Effect of the Simultaneous Administration of MM-129 and Indoximod in the Colorectal Cancer Model. (PubMed, Cancers (Basel))
Additionally, the expression of protein kinase B (AKT) and indoleamine 2,3-dioxygenase-(1IDO1) was disrupted under the applied compound combination. (4) Simultaneous targeting of ongoing cell signaling that promotes tumor progression, along with inhibition of the kynurenine pathway enzyme IDO1, results in the enhancement of the antitumor effect of the tested compounds against the colon cancer cells.
Preclinical • Journal • IO biomarker
|
IDO1 (Indoleamine 2,3-dioxygenase 1)
|
indoximod (NLG8189)
11ms
Trial completion date • Trial primary completion date
|
Imbruvica (ibrutinib) • temozolomide • cyclophosphamide • etoposide IV • indoximod (NLG8189)
1year
Chemo-immunotherapy Using Ibrutinib Plus Indoximod for Patients With Pediatric Brain Cancer (clinicaltrials.gov)
P1, N=37, Recruiting, Theodore S. Johnson | Phase classification: P1b --> P1
Phase classification
|
Imbruvica (ibrutinib) • temozolomide • cyclophosphamide • etoposide IV • indoximod (NLG8189)
1year
Effect of radiation fractionation on IDO1 via the NF-κB/COX2 axis in non-small cell lung cancer. (PubMed, Int Immunopharmacol)
Furthermore, the IDO1 inhibitor, D-1-methyl-tryptophan (D-1MT), exerted RT-related tumor-killing effects in the NSCLC cell lines and mouse models...Furthermore, an unappreciated mechanism may exist, where a larger fraction size might be superior to conventional sizes in cancer treatment. This study may provide a rationale for future research in using IDO1 as a biomarker to personalize RT dose fractionation and COX2 inhibitor to decrease radiation immune suppression from CRT.
Journal • IO biomarker
|
IDO1 (Indoleamine 2,3-dioxygenase 1)
|
IDO1 expression
|
indoximod (NLG8189)
1year
Treatment Response in First-Line Metastatic Pancreatic Ductal Adenocarcinoma Is Stratified By a Composite Index of Tumor Proliferation and CD8 T-Cell Infiltration. (PubMed, Clin Cancer Res)
Patients with treatment-naïve metastatic PDA were enrolled in a Phase II trial (NCT02077881) investigating gemcitabine plus nab-paclitaxel in combination with indoximod, an orally administered small-molecule inhibitor of the IDO pathway. A composite of decreased tumor proliferation in response to treatment and increased CD8 T-cell infiltration in metastatic lesions identified responders and associated with a favorable survival outcome. Our findings suggest that inhibiting cancer cell proliferation alone in PDA is insufficient to produce tumor responses and support a role for tumor-extrinsic mechanisms, such as CD8+ T cells, which combine with the cancer cell proliferation index to define treatment outcomes.
Journal • Metastases
|
CD8 (cluster of differentiation 8)
|
gemcitabine • albumin-bound paclitaxel • indoximod (NLG8189)
1year
Indoximod-based chemo-immunotherapy for pediatric brain tumors: a first-in-children phase 1 trial. (PubMed, Neuro Oncol)
Indoximod was well tolerated and could be safely combined with chemotherapy and radiation. Encouraging preliminary evidence of efficacy supports advancing to Phase 2/3 trials for pediatric brain tumors.
P1 data • Journal
|
CD8 (cluster of differentiation 8)
|
temozolomide • indoximod (NLG8189)
1year
Tryptophan Modulation in Cancer-Associated Cachexia Mouse Models. (PubMed, Int J Mol Sci)
While treatment with 1-MT did not show benefits in terms of muscle wasting and atrophy in our experimental setting, muscle functionality was not affected and central nuclei fibers appeared, being a feature of regeneration. Therefore, tryptophan metabolism pathway is a promising target for inflammation modulation in cancer-associated cachexia.
Preclinical • Journal
|
CD8 (cluster of differentiation 8) • IL2RA (Interleukin 2 receptor, alpha) • IL7R (Interleukin 7 Receptor) • CCR2 (C-C Motif Chemokine Receptor 2) • FBXO32 (F-Box Protein 32)
|
IL2RA expression
|
indoximod (NLG8189)
over1year
IDO1 inhibition sensitizes metastatic lung tumors to hypoxia/ER stress targeting agent-induced cell death (AACR 2023)
Similarly, when WT 4T1 tumor-bearing mice were administered GSK2656157 together with the IDO1 inhibitors Epacadostat, Indoximod or Navoximod, the attenuated neovascularization and elevated regional hypoxia in lung metastases elicited by IDO1 inhibition was accompanied by an increased level of tumor cell death. Co-administration of the hypoxia-activated prodrug Evofosfamide with Epacadostat likewise resulted in elevated metastatic tumor cell death. This contrasts with results obtained with the non-targeted cytotoxic agent Carboplatin that elicited comparable levels of metastatic tumor cell death regardless of Epacadostat co-administration. Altogether, these data establish the potential to benefit treatment in tumor settings where IDO1 inhibition enhances intra-tumoral hypoxia through neovascular regression by facilitating the ability of hypoxia-targeting agents to effectively eliminate tumor cells in a more targeted manner than can be achieved with conventional chemotherapy.
Metastases
|
IFNG (Interferon, gamma) • IL6 (Interleukin 6)
|
carboplatin • epacadostat (INCB024360) • indoximod (NLG8189) • evofosfamide (IMGS-101) • navoximod (NLG919)
almost2years
Enhancement of radiation therapy by indoleamine 2,3 dioxygenase 1 inhibition through multimodal mechanisms. (PubMed, BMC Cancer)
The combination of 1-MT and radiation suppressed colon cancer cells in vitro and in vivo via multiple mechanisms.
Journal • IO biomarker
|
CD8 (cluster of differentiation 8) • IDO1 (Indoleamine 2,3-dioxygenase 1) • FOXP3 (Forkhead Box P3)
|
IDO1 expression
|
indoximod (NLG8189)
almost2years
IDO-1 inhibitor INCB24360 elicits distant metastasis of basal extruded cancer cells in pancreatic ductal adenocarcinoma. (PubMed, Acta Pharmacol Sin)
Ido-1 deletion in KPIC cells deprived its tumorigenicity in immunocompetent mice, decreased cellular proliferation and macropinocytic ability, and increased immunogenicity. KPIC organoids with IFN-γ-induced basal extrusion did not accelerate distant metastasis, whereas inhibition IFN-γ-induced IDO-1 with INB24360 but not 1-MT in KPIC organoids elicited liver metastasis of subcutaneous KPIC organoid tumors, suggesting that lower IDO-1 activity accelerated distant metastasis, whereas IDO-1 was indispensable for tumorigenicity of PDAC cells and supports the survival of extruding cells.
Journal • IO biomarker
|
IFNG (Interferon, gamma) • VIM (Vimentin)
|
IDO1 expression • VIM expression
|
indoximod (NLG8189)
almost2years
Interleukin-6 and indoleamine-2,3-dioxygenase as potential adjuvant targets for Papillomavirus-related tumors immunotherapy. (PubMed, Front Immunol)
C57BL/6 wild-type (WT) and transgenic IL-6 mice were engrafted with HPV16-E6/E7-expressing TC-1 cells and treated with 1-methyl-tryptophan isoforms (D-1MT and DL-1MT), capable to inhibit IDO...The outcome of the combined therapy was associated with an increased frequency of activated dendritic cells and decreased frequencies of intratumoral polymorphonuclear myeloid-derived suppressor cells and T regulatory cells. In conclusion, the present study demonstrated that IL-6 and IDO negatively contribute to the activation of immune cells, particularly dendritic cells, reducing gDE7 vaccine-induced protective immune responses and, therefore, opening perspectives for the use of combined strategies based on inhibition of IL-6 and IDO as immunometabolic adjuvants for immunotherapies against HPV-related tumors.
Journal • IO biomarker
|
IL6 (Interleukin 6)
|
IDO1 expression • IL6 expression
|
indoximod (NLG8189)
2years
Engineered DBCO+PD-1 Nanovesicles Carrying 1-MT for Cancer-Targeted Immunotherapy. (PubMed, ACS Biomater Sci Eng)
Results have shown that PD-1@1-MT NVs obviously attenuated tumor growth, promoting IFN-γ production, increasing the T cells infiltration in tumors and spleens, and improving the survival period of tumor-bearing mice compared to monotherapy. Therefore, we propose a promising delivery strategy of the combination of DBCO+PD-1 NVs and 1-MT for specific and effective cancer-targeted immunotherapy.
Journal
|
CD8 (cluster of differentiation 8) • IFNG (Interferon, gamma)
|
indoximod (NLG8189)
over2years
IDO Inhibitor and Gallic Acid Cross-Linked Small Molecule Drug Synergistic Treatment of Melanoma. (PubMed, Front Oncol)
In this study, we synthesized a molecule GA-1MT (GM) composed of indoleamine 2,3-dioxygenase (IDO) inhibitor (1-methyl-d-tryptophan, 1MT) called NLG8189 and gallic acid (GA) and verified its therapeutic effect on B16F10 melanoma cells and an orthotopic tumor-bearing mouse model...In vivo experiments showed that GM could effectively inhibit the expression of tyrosinase, regulate the proportion of CD4 T cells, CD8 T cells, and regulatory T cells (T cells) in tumors, and significantly suppress melanoma growth. The newly synthesized drug GM could more effectively inhibit melanoma than GA and 1MT alone or in combination.
Journal • IO biomarker
|
CD8 (cluster of differentiation 8) • CD4 (CD4 Molecule)
|
indoximod (NLG8189)
over2years
Polymeric indoximod based prodrug nanoparticles with doxorubicin entrapment for inducing immunogenic cell death and improving the immunotherapy of breast cancer. (PubMed, J Mater Chem B)
Moreover, significant reductions in vascular endothelial growth factor (VEGF), MMP9, and CD31 (a vascular marker) expression levels were observed after DOX-IND nanoparticle treatment. This resulted in obvious tumor regression in a murine breast cancer model compared to reference formulations, indicating that the codelivery of DOX and IND is a potent potential strategy for breast cancer chemoimmunotherapy.
Journal • IO biomarker
|
CD8 (cluster of differentiation 8) • CD31 (Platelet and endothelial cell adhesion molecule 1) • MMP9 (Matrix metallopeptidase 9)
|
CD31 expression
|
doxorubicin hydrochloride • indoximod (NLG8189)
over2years
TUMOR-SUPPRESSIVE ACTIVITY OF RADIOTHERAPY AND INDOLEAMINE 2,3 DIOXYGENASE 1 BLOCKADE VIA DIRECT TUMOR CELL GROWTH INHIBITION AND PRONOUNCED ANTITUMOR IMMUNITY (DDW 2022)
Leukopenia was induced by radiation, whereas 1-MT-specific adverse event was not observed. Taken together, the combination of radiation and 1-MT suppressed colon cancer cells in vitro and in vivo via multiple mechanisms, and is thus considered as a promising treatment option for colon cancer in the clinical setting.
IO biomarker
|
CD8 (cluster of differentiation 8) • IDO1 (Indoleamine 2,3-dioxygenase 1) • FOXP3 (Forkhead Box P3)
|
IDO1 expression • IDO1 overexpression
|
indoximod (NLG8189)
almost3years
Characterizing the distributions of IDO-1 expressing macrophages/microglia in human and murine brains and evaluating the immunological and physiological roles of IDO-1 in RAW264.7/BV-2 cells. (PubMed, PLoS One)
Inhibiting IDO-1 with 1-MT or INCB24360 increased IL-1β secretion and suppressed NLRP3 expression in RAW264.7/BV-2 cells. Our data collectively show that IDO-1 expression in perivascular and meninges macrophages/microglia increases cellular phagocytic capacity and might suppress overactivation of inflammatory reaction.
Preclinical • Journal • IO biomarker
|
IDO1 (Indoleamine 2,3-dioxygenase 1) • IL1B (Interleukin 1, beta) • NLRP3 (NLR Family Pyrin Domain Containing 3)
|
IDO1 expression
|
indoximod (NLG8189)
3years
Analysis of Interleukin-1 Signaling Alterations of Colon Adenocarcinoma Identified Implications for Immunotherapy. (PubMed, Front Immunol)
IL-1-MT may be an independent predictor of a good prognosis in COAD patients receiving ICIs, with significantly longer OS in IL-1-MT COAD patients. Additionally, IL-1-MT was associated with significantly increased immunogenicity, activated immune cell and inflammatory mediator levels and immune response-related scores.
Journal • Tumor Mutational Burden • IO biomarker
|
TMB (Tumor Mutational Burden) • CD8 (cluster of differentiation 8) • CD4 (CD4 Molecule)
|
indoximod (NLG8189)
3years
D-MT prompts the anti-tumor effect of oxaliplatin by inhibiting IDO expression in a mouse model of colon cancer. (PubMed, Int Immunopharmacol)
Herein, an IDO inhibitor, D-MT (indoximod, 1-Methyl-D-tryptophan), was combined with oxaliplatin to treat colon cancer in mice. More importantly, the combination treatment increased the ratios of CD4 T, CD8 T and NK cells from the spleen in tumor-bearing mice, and prompted T cell infiltration in tumor tissues. This study provided a new therapeutic strategy for colon cancer treatment in the clinic, especially for patients with oxaliplatin resistance.
Preclinical • Journal
|
IDO1 (Indoleamine 2,3-dioxygenase 1) • CD4 (CD4 Molecule)
|
IDO1 expression
|
oxaliplatin • indoximod (NLG8189)
3years
Necrostatin-1 Prevents Ferroptosis in a RIPK1- and IDO-Independent Manner in Hepatocellular Carcinoma. (PubMed, Antioxidants (Basel))
The present study examined whether necrostatin-1 could interrupt ferroptosis induced by system xc- inhibitors (sulfasalazine and erastin) and a glutathione peroxidase 4 inhibitor (RSL3) in Huh7 and SK-HEP-1 cells...Necrostatin-1, ferrostatin-1, and deferoxamine repressed sulfasalazine-provoked membrane permeabilization, as detected by 7-aminoactinomycin D staining and lipid peroxidation measured using a C11-BODIPY probe. However, other RIPK1 inhibitors (necrostatin-1s and GSK2982772) and an IDO inhibitor (1-methyl-D-tryptophan) did not recover the decrease in cell viability induced by sulfasalazine. Necrostatin-1 potentiated sulfasalazine-induced expression of xCT, a catalytic subunit of system xc- in these cells. These results demonstrated that necrostatin-1 blocked ferroptosis through a mechanism independent from RIPK1 and IDO inhibition in Huh7 and SK-HEP-1 cells, indicating that its antioxidant activity should be considered when using necrostatin-1 as a RIPK1 inhibitor.
Journal • IO biomarker
|
GPX4 (Glutathione Peroxidase 4) • CDK7 (Cyclin Dependent Kinase 7) • RIPK1 (Receptor Interacting Serine/Threonine Kinase 1)
|
erastin • indoximod (NLG8189) • RSL3
over3years
Immunogenic camptothesome nanovesicles comprising sphingomyelin-derived camptothecin bilayers for safe and synergistic cancer immunochemotherapy. (PubMed, Nat Nanotechnol)
In addition, camptothesomes improve the pharmacokinetics and lactone stability of camptothecin, avoid systemic toxicities, penetrate deeply into the tumour and outperform the antitumour efficacy of Onivyde. Camptothesome co-load the indoleamine 2,3-dioxygenase inhibitor indoximod into its interior using the lipid-bilayer-crossing capability of the immunogenic cell death inducer doxorubicin, eliminating clinically relevant advanced orthotopic CT26-Luc tumours and late-stage B16-F10-Luc2 melanoma, and achieving complete metastasis remission when combined with ICB and folate targeting. The sphingomyelin-derived nanotherapeutic platform and doxorubicin-enabled transmembrane transporting technology are generalizable to various therapeutics, paving the way for transformation of the cancer immunochemotherapy paradigm.
Journal
|
GZMB (Granzyme B)
|
doxorubicin hydrochloride • indoximod (NLG8189) • Onivyde (nanoliposomal irinotecan)
over3years
IDO Inhibition Facilitates Antitumor Immunity of Vγ9Vδ2 T Cells in Triple-Negative Breast Cancer. (PubMed, Front Oncol)
However, Vγ9Vδ2 T cells combined with IDO1 inhibitor 1-Methyl-L-tryptophan (1-MT) or Lindrostat showed substantial inhibitory effects on MDA-MB-231 tumor cells. Finally, we found that IDO1 inhibitor promoted T cell's cytotoxicity by enhancing perforin production. These results converged to suggest the potential application of Vγ9Vδ2 T cells treated with IDO1 inhibitor for TNBC therapy.
Journal
|
CD8 (cluster of differentiation 8)
|
PD-L1 expression • PD-L1 overexpression
|
indoximod (NLG8189)
over3years
The efficacy of indoximod upon stimulation with pro-inflammatory cytokines in triple-negative breast cancer cells. (PubMed, Immunopharmacol Immunotoxicol)
Indoximod exhibited a therapeutic potential in TNBC cells and pro-inflammatory cytokines could affect the effectiveness of indoximod. However, further studies are required to identify the role of the IDO-associated signaling pathways, the molecular mechanisms of indoximod induced apoptotic cell death, and the relationship between IDO inhibition by IDO inhibitors and pro-inflammatory cytokine levels.
Clinical • Journal • PD(L)-1 Biomarker • IO biomarker
|
PD-L1 (Programmed death ligand 1) • IFNG (Interferon, gamma) • TNFA (Tumor Necrosis Factor-Alpha)
|
PD-L1 expression • IDO1 expression
|
indoximod (NLG8189)
over3years
STING agonist and IDO inhibitor combination therapy inhibits tumor progression in murine models of colorectal cancer. (PubMed, Cell Immunol)
Our findings demonstrated that STING agonist diABZI combined with IDO inhibitor 1-MT significantly inhibited tumor growth, even better than the three-drug combination, promoted the recruitment of CD8 T cells and dendritic cells, and decreased the infiltration of myeloid-derived suppressor cells. We conclude that diABZI combined with 1-MT is a promising option for CRC.
Preclinical • Journal • Combination therapy
|
CD8 (cluster of differentiation 8) • STING (stimulator of interferon response cGAMP interactor 1)
|
indoximod (NLG8189)
over3years
Phase II trial of the IDO pathway inhibitor indoximod plus pembrolizumab for the treatment of patients with advanced melanoma. (PubMed, J Immunother Cancer)
In this study, the combination of indoximod and (P) was well tolerated and showed antitumor efficacy that is worth further evaluation in selected patients with advanced melanoma.
Clinical • P2 data • Journal
|
PD-L1 (Programmed death ligand 1)
|
PD-L1 negative
|
Keytruda (pembrolizumab) • Opdivo (nivolumab) • Yervoy (ipilimumab) • indoximod (NLG8189)
over3years
IDO1-Targeted Therapy Does Not Control Disease Development in the Eµ-TCL1 Mouse Model of Chronic Lymphocytic Leukemia. (PubMed, Cancers (Basel))
To explore the potential of IDO1 as a therapeutic target for CLL, we treated mice after adoptive transfer of Eµ-TCL1 leukemia cells with the IDO1 modulator 1-methyl-D-tryptophan (1-MT) which resulted in a minor reduction in leukemia development which disappeared over time. Similarly, treatment of leukemic mice with the clinically investigated IDO1 inhibitor epacadostat reduced the frequency of Tregs and initially delayed CLL development slightly, an effect that was, however, lost at later time points. In sum, despite the observed upregulation of IDO1 in CLL, its inhibition is not sufficient to control leukemia development in the Eµ-TCL1 adoptive transfer model.
Preclinical • Journal
|
IDO1 (Indoleamine 2,3-dioxygenase 1)
|
IDO1 expression
|
epacadostat (INCB024360) • indoximod (NLG8189)
over3years
Co-delivery of anionic epitope/CpG vaccine and IDO inhibitor by self-assembled cationic liposomes for combination melanoma immunotherapy. (PubMed, J Mater Chem B)
In this work, cationic polymer-lipid hybrid nanovesicle (P/LNV)-based liposomes are designed to simultaneously deliver tumor vaccines composed of anionic antigen epitopes, toll-like receptor-9 agonist (TLR9), CpG (AE/CpG), and indoleamine-2,3-dioxygenase (IDO) inhibitor, 1-methyl-tryptophan (1-MT), to increase the immunogenicity of peptide antigens and meanwhile block the immune checkpoint...Mechanistically, the co-delivery system could elicit a strong cancer-specific T-cell response, as characterized by the remarkably increased infiltration of CD8+ T cells in the tumor and draining lymph nodes. Altogether, cationic liposomes delivered with tumor vaccines and IDO inhibitor provide a promising platform for cancer immunotherapy by provoking antitumor T-cell immunity and simultaneously reversing the immunosuppressive tumor microenvironment.
Journal
|
CD8 (cluster of differentiation 8) • CD86 (CD86 Molecule)
|
indoximod (NLG8189)
over3years
[VIRTUAL] Gut microbiome changes are associated with the efficacy of Delta-24-RGDOX viroimmunotherapy against malignant glioma (AACR 2021)
Then mice were treated with intratumoral injections of control (PBS) or a combination of Delta-24-RGDOX and Indoximod, an inhibitor of the immune modulator IDO. Importantly, increase in Bifidobacterium and Lactobacillus was associated with a better response to the therapy, likely strengthening antitumor immunity and raising efficacy in viroimmunotherapy-treated mice. This reveals the benefits of gut microbiome therapeutics in positively influencing the final clinical outcome of viroimmunotherapy.
Clinical • Oncolytic virus
|
CD4 (CD4 Molecule)
|
indoximod (NLG8189) • DNX-2440
over3years
[VIRTUAL] The indoleamine 2,3 dioxygenase-1 pathway drives intratumoral B cell maintenance (AACR 2021)
Surprisingly, we found that D-1MT enhanced anti-tumor effects of the BRAF inhibitor, vemurafenib, in a preclinical model of BRAF mutant melanoma, suggesting that targeting B cells in this setting may be beneficial. Together, our data reveal a novel paradigm for the IDO1 pathway in regulating TIL-B cells, and uncovered IDO1 as a potential targetable mechanism of resistance to BRAF inhibition in melanoma.
Clinical • IO biomarker
|
IDO1 (Indoleamine 2,3-dioxygenase 1)
|
BRAF mutation • IDO1 expression
|
Zelboraf (vemurafenib) • indoximod (NLG8189)
almost4years
Smart Nanovesicle Mediated Immunogenic Cell Death through Tumor Microenvironment Modulation for Effective Photodynamic Immunotherapy. (PubMed, ACS Nano)
After coencapsulation of a photosensitizer, 2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-a (HPPH) and an indoleamine 2,3-dioxygenase inhibitor, indoximod (IND), pRNVs/HPPH/IND at a single low dose elicited significant antitumor efficacy and abscopal effect following laser irradiation in a B16F10 melanoma tumor model...This study exploited nanocarrier to induce ICD for host's immunity activation. The "all-in-one" smart nanovesicles allows to design multifunctional materials to strengthen cancer immunotherapy efficacy.
Journal
|
CD8 (cluster of differentiation 8)
|
indoximod (NLG8189)
4years
Effect of Taxane Chemotherapy With or Without Indoximod in Metastatic Breast Cancer: A Randomized Clinical Trial. (PubMed, JAMA Oncol)
A taxane (paclitaxel [80 mg/m2] weekly 3 weeks on, 1 week off, or docetaxel [75 mg/m2] every 3 weeks) plus placebo or indoximod (1200 mg) orally twice daily as first-line treatment. This randomized clinical trial found that, among patients with ERBB2-negative metastatic breast cancer, addition of indoximod to a taxane did not improve PFS compared with a taxane alone. ClinicalTrials.gov Identifier: NCT01792050.
Clinical • Journal
|
HER-2 (Human epidermal growth factor receptor 2) • IDO1 (Indoleamine 2,3-dioxygenase 1)
|
HER-2 negative • IDO1 expression
|
paclitaxel • docetaxel • indoximod (NLG8189)
4years
Liposomal Delivery of Mitoxantrone and a Cholesteryl Indoximod Prodrug Provides Effective Chemo-Immunotherapy in Multiple Solid Tumors. (PubMed, ACS Nano)
Moreover, the growth inhibitory effect of MTO was enhanced by IND co-delivery in EMT6 and 4T1 tumors. All considered, our data support the use of encapsulated MTO delivery for chemo-immunotherapy, with the possibility to boost the immune response by co-delivery of an IDO-1 pathway inhibitor.
Journal
|
IDO1 (Indoleamine 2,3-dioxygenase 1) • GZMB (Granzyme B) • FOXP3 (Forkhead Box P3)
|
IDO1 expression • FOXP3 expression
|
mitoxantrone • indoximod (NLG8189)
over4years
Indigo301: A Study of Indoximod or Placebo Plus Pembrolizumab or Nivolumab for Subjects With Unresectable or Metastatic Melanoma (clinicaltrials.gov)
P2, N=21, Terminated, NewLink Genetics Corporation | Trial completion date: Jan 2021 --> Nov 2019 | Active, not recruiting --> Terminated; Sponsor termination, not related to efficacy, safety or feasibility.
Clinical • Trial completion date • Trial termination
|
BRAF (B-raf proto-oncogene)
|
BRAF mutation • BRAF V600
|
Keytruda (pembrolizumab) • Opdivo (nivolumab) • indoximod (NLG8189)
5years
Results of a phase II double-blinded, randomized, placebo-controlled clinical trial of Indoximod, an Indoleamine-2,3-dioxygenase 1 (IDO1) inhibitor, in combination with Taxane chemotherapy in metastatic breast cancer (MBC) (SABCS 2019)
The combination of indoximod with a taxane in 1st line HER2- MBC was safe and did not result in added toxicity. In an unselected population, no improvement in clinical outcomes was observed for the combination over taxane alone. However, higher tumor IDO expression may select for MBC pts who benefit more from indoximod and should be investigated as a predictive biomarker in future studies.Demographics and tumor featuresIndoximodPlaceboOverallParameterStatistic(N=85)(N=79)(N=164)Age (years)n8579164median (min, max)58 (29,76)57 (29,85)58 (29,85)GenderMalen (%)1 (1.2)2 (2.5)3 (1.8)Femalen (%)84 (98.8)77 (97.5)161 (98.2)RaceWhiten (%)71 (83.5)66 (83.5)137 (83.5)African Americann (%)12 (14.1)10 (12.7)22 (13.4)Asiann (%)1 (1.2)01 (0.6)Othern (%)1 (1.2)3 (3.8)4 (2.4)ECOG status0n (%)41 (48.8)43 (54.4)84 (51.5)1n (%)44 (52.2)36 (44.3)80 (46.6)Hormone Receptor StatusNegativen (%)23 (27.1)23 (29.1)46 (28.0)Positiven (%)62 (72.9)56 (70.9)118 (72.0)Choice of TaxaneDocetaxeln (%)62 (72.9)59 (74.7)121 (73.8)Paclitaxeln (%)23 (27.1)20 (25.3)43 (26.2)
Clinical • P2 data • Combination therapy • IO biomarker
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HER-2 (Human epidermal growth factor receptor 2) • IDO1 (Indoleamine 2,3-dioxygenase 1)
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paclitaxel • docetaxel • indoximod (NLG8189)