indoximod (NLG8189)

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.

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.

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.

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.

P1, N=37, Recruiting, Theodore S. Johnson

P1, N=37, Recruiting, Theodore S. Johnson | Phase classification: P1b --> P1

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.

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.

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.

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.

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.

The combination of 1-MT and radiation suppressed colon cancer cells in vitro and in vivo via multiple mechanisms.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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)