At present, despite 5-fluorouracil (5-FU), as a clinical first-line FOLFIRINOX chemo-drug, has achieved significant therapeutic effects...Therefore, a metal matrix protease-2 (MMP-2) and endogenous GSH dual-responsive liposomal-based nanovesicle, co-loading with 5-FU (anti-cancer drug) and NLG919 (IDO1 inhibitor), was constructed (named as ENP919@5-FU)...Moreover, the combination of ENP919@5-FU and PD-L1 antibody (αPD-L1) showed a synergistic anti-tumor effect on the PDAC model with abdominal cavity metastasis. Collectively, ENP919@5-FU nanovesicle, as a PDAC treatment strategy, showed excellent antitumor efficacy by remodeling tumor microenvironment to circulate tumor chemoimmunotherapy amplification, which has promising potential in a precision medicine approach.

The production of ROS, consumption of GSH, and photothermal properties of MGNH make it possible for CDT/PTT activated ferroptosis, and synergistically disrupt and reprogram tumor growth and immunosuppressive tumor microenvironment with NLG919 and Mn2+-mediated activation of cGAS-STING pathway, achieving CDT/PTT/immunotherapy activated by ferroptosis. Meanwhile, ultra-small structural properties of MGNH facilitate subsequent metabolic clearance by the body, allowing for the minimization of potential biotoxicity associated with its prolonged retention.

When treating HeLa cells with PRGD/NLG919 nanosheets followed by laser irradiation, a more robust adaptive immune response occurred, leading to a substantial proliferation of CD3+CD8+ T cells and CD3+CD4+ T cells compared to control groups. Our pH-responsive targeted PRGD/NLG919 nanosheets therefore represent a promising nanosystem for combination therapy, offering effective PDT and an enhanced host immune response.

P2, N=60, Recruiting, IO Biotech | N=30 --> 60

Lastly, IDO1 and PDL1-specific CD4+ T cell clones from melanoma patients treated with IO102-IO103 vaccine could selectively target cells differentially expressing IDO1 or PDL1.Our data collectively show that cells expressing IDO1 and PD-L1 represent distinct populations in the TME thus targetable by the IDO1-PD-L1 vaccination approach...These data are supported by ex vivo functional assays using target specific T cells from vaccinated patients. Altogether, our data support the use of a dual antigen approach to reduce the immunosuppression and enhance anti-tumor effect.

To simultaneously tackle these issues, a MnO2-containing albumin nanoplatform co-delivering IR780, NLG919, and a paclitaxel (PTX) dimer is designed to boost photodynamic immunotherapy. More importantly, alleviating hypoxia reshapes the immunosuppressive TME via down-regulating the intratumoral infiltration of M2-type TAMs and the PD-L1 expression of tumor cells to enhance the infiltration and efficacy of CTLs in combination with immune checkpoint inhibitor NLG919, consequently eradicating primary tumors and almost completely preventing tumor relapse and metastasis. This study sets an example of enhanced immunotherapy for breast cancers through dual ICD induction and simultaneous immunosuppression modulation via both hypoxia relief and ICB, providing a strategy for the treatment of other hypoxic and immunosuppressive cancers.

P2, N=30, Recruiting, IO Biotech | Trial completion date: Aug 2028 --> Jan 2027 | Trial primary completion date: Sep 2025 --> Apr 2025

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.

P3, N=407, Active, not recruiting, IO Biotech | Recruiting --> Active, not recruiting

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

P2, N=30, Recruiting, IO Biotech | Not yet recruiting --> Recruiting

Meanwhile, the combination could block cisplatin-induced neurotoxicity and not interfere with chemotherapy. Taken together, the study investigated the promising therapeutic potential of combined navoximod with cisplatin to mitigate tumoral immune resistance via alleviating IDO1 CAFs-secreted immune-suppression and CIN-caused cisplatin resistance, providing a paradigm for combined chemo-immunotherapy to prolong survival in patients with OSCC.

However, studies using IDO/TDO inhibitors against cancer have not yet shown that this type of treatment can be successful...This strategy may be beneficial in the treatment of aggressive breast cancer, particularly in patients with triple-negative breast cancer. A major challenge to this strategy, when searching for an effective treatment for tumors, especially tumors like breast carcinoma that often metastasize to the brain, is finding KMO inhibitors that adequately cross the blood-brain barrier.

Moreover, tryptophan facilitated the expression of M1 polarization markers, whereas inhibitors of tryptophan metabolic enzymes, such as NLG919, LM10, and Ro 61-8048, inhibited the expression of M1 polarization markers. In conclusion, this study identified a dual role for macrophage tryptophan metabolism in breast cancer; on the one hand, it promotes macrophage M1 polarization, while on the other hand, it serves as a promising predictor for the effectiveness of immunotherapy in breast cancer.

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.

In brief, a nanozyme therapeutic agent (PNDPL) is constructed, which mainly consists of PtBi nanozymes, lactate oxidase (LOX) and the indoleamine 2,3-dioxygenase (IDO) inhibitor NLG919...Therefore, the combination of lactate depletion-induced starvation therapy and PTT, along with the blocking of IDO-mediated immune escape, effectively inhibits tumor growth and reverses immunosuppressive microenvironment, thus preventing tumor metastasis. This study represents the first investigation into the synergistic antitumor effects by lactate metabolism regulation and IDO-related immunotherapy.

Furthermore, RCIS can be used as a nanocarrier to form RNCIS nanoparticles (NPs) by loading NLG919, which blocks the indoleamine 2,3-dioxygenase-1...RNCIS exhibits chemodynamic, photodynamic, and photothermal activated immunotherapy by inhibiting indoleamine 2,3-dioxygenase-1. This can enhance the recruitment of cytotoxic T lymphocyte and M1 polarization of macrophage, leading to higher synergetic photo-immune therapeutic efficacy.

P2, N=30, Not yet recruiting, IO Biotech | N=60 --> 30 | Trial completion date: Mar 2029 --> Aug 2028 | Trial primary completion date: Feb 2025 --> Sep 2025

P2, N=15, Recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Not yet recruiting --> Recruiting

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.

To simultaneously tackle these pivotal problems, we herein create an albumin-based nanoplatform co-delivering IR780, NLG919 dimer and a hypoxia-activated prodrug tirapazamine (TPZ) as the dual enhancer for synergistic cancer therapy. Eventually, enriched intratumoral GSH triggers the activation of NLG919 to mitigate the immunosuppressive TME via specific indoleamine 2,3-dioxygenase 1 (IDO-1) inhibition, consequently promoting the intratumoral infiltration of CTLs and the killing of both primary and distant tumors, while the resultant memory T cells allows nearly 100% suppression of tumor recurrence and metastasis. This nanoplatform sets up an example for dully enhanced photodynamic immunotherapy of breast cancer via hypoxia-activated chemotherapy, and paves a solid way for the treatment of other hypoxic and immunosuppressive malignant 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.

Treatment with IO102-IO103 plus nivolumab in anti-PD-1 naïve metastatic melanoma shows high clinical activity and is well tolerated ( Kjeldsen, Nat Med 2021). Enrollment is ongoing. Additional clinical and biomarker data from trial patients are planned to be presented at the meeting.

We proved that the mechanism of the combined therapy could inhibit the activity of IDO1, blocking amino acid tryptophan (Trp) conversion to kynurenine (Kyn) through the kynurenine pathway (KP), which further inhibited the aryl hydrocarbon receptor (AhR) expression. Our study underscored the combination of cisplatin and NLG-919 as a potent therapeutic way for reversal of cisplatin resistance.

P3, N=380, Recruiting, IO Biotech | Trial completion date: May 2027 --> Sep 2027 | Trial primary completion date: Apr 2025 --> Jul 2025

P1, N=30, Recruiting, Mamta Parikh | Not yet recruiting --> Recruiting

P2, N=43, Recruiting, Memorial Sloan Kettering Cancer Center

The study also illustrated the mechanism of a novel cyanide release metabolism from the fused imidazo[5,1-a]isoindole ring. Such biotransformation should be kept in mind when working with imidazole containing new chemical entities (NCE) in drug discovery and development.

Mechanistically, we further discovered that our combination strategy entirely reprogramed the TME through single-cell RNA sequencing. All these results collectively indicated that the combination of Navoximod with HSV-1 could boost the viral replication and reshape TME for tumor eradication through the hydrogel reservoir.

In addition, NLG919 inhibits tryptophan metabolism and enhances CD8 T cell activity, ultimately activating anti-tumor immunity and enhancing the anti-tumor effects of platinum-based drugs. NP-Pt-IDOi were shown to have superior anti-cancer activity in vitro and in vivo in mouse models of osteosarcoma, providing a new clinical paradigm for combining chemotherapy with immunotherapy for osteosarcoma.

P2; Trial primary completion date: Apr 2023 --> Apr 2024

Herein, a kind of tumor cascade-targeted responsive liposome (NLG919@Lip-pep1) is developed by conjugating polypeptide inhibitor of PD-1 signal pathway (AUNP-12), which is also a targeted peptide that conjugated with liposome carrier through matrix metalloproteinase-2 (MMP-2) cleavable peptide (GPLGVRGD). The exposure of secondary targeting module II VRGDC-NLG919@Lip mediated tumor cells targeting, and further relieved the immunosuppressive microenvironment. Overall, this study offers a potentially appealing paradigm of a high efficiency, low toxicity, and simple intelligent responsive drug delivery system for targeted drug delivery in breast cancer, which can effectively rescue and activate the body's anti-tumor immune response and furthermore achieve effective treatment of metastatic breast cancer.

P1, N=30, Not yet recruiting, Mamta Parikh

In addition, NLG919 was further loaded into a gel to form (M13@Pd/NLG gel) for down-regulating the expression of tryptophan metabolic enzyme indoleamine 2,3-dioxygenase 1 (IDO1). Both in vitro and in vivo studies showed that the M13 bacteriophage served not only as a cargo-loaded device but also as a self-immune adjuvant, which induced the immunogenic death of tumor cells effectively and down-regulated IDO1 expression. Such a bioactive gel system constructed by natural living materials could reverse immunosuppression and significantly improve the anti-breast cancer response.

Herein, a cancer treatment approach that combines photothermal therapy (PTT) and nitric oxide (NO) gas therapy for tumor extracellular matrix (ECM) degradation, along with NLG919, an indoleamine 2,3-dioxygenase (IDO) inhibitor that reduces tryptophan catabolism to kynurenine, and DMXAA, a stimulator of interferon gene (STING) agonist that stimulates antigen cross-presentation, is proposed to overcome this issue...Additional unification of IDO inhibition during PTT supplements the immunotherapy by reducing the T cell apoptosis and immune suppressive cell infiltration to TME. NO-GEL with the STING agonist and IDO inhibitor is an effective therapeutic combination to counter possible limitations during solid tumor immunotherapy.

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.