indoximod (NLG8189) / Lumos Pharma - LARVOL DELTA

Interim outcome analysis and pharmacodynamic evidence of immune activation in ependymoma patients treated with indoximod-based chemo-immunotherapy (NCT04049669) (SNO 2026) - P2 | No abstract available

Clinical • PK/PD data • Ependymoma • Oncology • Solid Tumor

Chronic Sleep Deprivation Accelerates Ejaculation by Shifting Brain Tryptophan Metabolism Toward the Kynurenine Pathway in Male Rats. (PubMed, Andrology) - "This work provides new insights into the pathophysiological mechanism of acquired premature ejaculation (APE) caused by sleep deprivation and suggests prospective treatment strategies by identifying a critical role for brain IDO1."

IO biomarker • Journal • Preclinical • Oncology • Sexual Disorders • IL6 • TNFA

Therapeutic remodeling of the tuberculosis granuloma with 1-methyl-D-tryptophan enhances CD8+ T cell-macrophage interactions. (PubMed, Proc Natl Acad Sci U S A) - "D-1MT enhanced CD8+ T cell infiltration throughout the granuloma, with particularly pronounced effects in the myeloid core, where we observed significantly enhanced spatial interactions between macrophages and CD8+ T cells, but not CD4+ T cells. Our results demonstrate that: i) effective intragranulomatous Mtb control is associated with the close spatial proximity between CD8+ T cells and macrophages, a feature less abundant in uncontrolled pulmonary TB; ii) IDO1 induction blocks CD8+ T cell infiltration and reduces T cell activation and proliferation; and iii) therapeutic strategies, including D-1MT, that improve intragranulomatous killing hold strong translational potential."

IO biomarker • Journal • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis • CD4 • CD8 • IDO1

Trial of NLG802 Indoximod Prodrug Plus Temozolomide for Patients With Progressive Pediatric Brain Cancer (clinicaltrials.gov) - P1 | N=30 | Not yet recruiting | Sponsor: Lumos Pharma

New P1 trial • Brain Cancer • Oncology • Pediatrics • Solid Tumor

Interleukin-6 Downregulates T Helper 17 Cytokines via Indoleamine 2,3-Dioxygenase 1 at the Maternal-Fetal Interface. (PubMed, Am J Reprod Immunol) - "During normal pregnancy, IL-6 alone or the combination of IL-6 and TGF-β at the maternal-fetal interface may inhibit Th17 cytokine production by upregulating IDO1 expression, thereby maintaining pregnancy stability."

IO biomarker • Journal • IDO1 • IL17A • IL22 • IL6 • TGFB1

METTL3-Activated IDO1-Kynurenine Pathway in Insulin-Producing Cells Enhances Graft Survival and Attenuates Endogenous Islet Apoptosis in Diabetic Mice. (PubMed, FASEB J) - "A four-group rescue experiment (WT-IPCs, WT-IPCs+Kyn, Mettl3-OE-IPCs, Mettl3-OE-IPCs+1-MT) evaluated the causal contribution of Kyn...Rescue experiments show that Kyn is both sufficient and necessary for these effects. These findings suggest that the METTL3-IDO1-Kyn pathway may be a potential target for improving cell replacement therapy for diabetes."

IO biomarker • Journal • Preclinical • Diabetes • Metabolic Disorders • Transplantation • Type 1 Diabetes Mellitus • BAX • BCL2 • CD4 • CD8 • IDO1 • IL2RA • METTL3

NIR-Programmable Stealth 2D Black Phosphorus Nanobiointerfaces for Deep Tumor Penetration and Photoimmunotherapy. (PubMed, ACS Nano) - "By coloading Mn2+ and Indoximod, PTPBP@Mn2+/Indoximod enables synergistic photoimmunotherapy by inducing immunogenic cell death (ICD), activating the cGAS-STING pathway, and inhibiting the indoleamine 2,3-dioxygenase (IDO) pathway. In orthotopic breast cancer models, this strategy potently inhibits primary and metastatic tumors and establishes long-term immunological memory. By integrating "stealth-by-design" corona management and precise spatiotemporally activated charge conversion, this work facilitates the rational development of high-efficiency nanotherapeutics for cancer and broader disease applications."

Journal • Breast Cancer • Oncology • Solid Tumor

Co-delivery of endoplasmic reticulum-targeted photosensitizer and Ido-1 inhibitor potentiates immunotherapeutic efficacy in triple-negative breast cancer. (PubMed, Mater Today Bio) - "To address this, a multifunctional nanoparticle, TPI@RPB, was constructed with RGD-PEG-BSA as the carrier for tumor-targeted delivery, while co-loading the self-synthesized endoplasmic reticulum (ER) target photosensitizer TSE-Ppa and Indoleamine 2,3-dioxygenase 1 (IDO-1) inhibitor 1-MT...In vivo, TPI@RPB not only demonstrates active tumor targeting but also significant antitumor efficacy with a favorable safety profile; specifically, tumor weight reduced to 13.70%, intratumoral CD8+ T-cell infiltration increased 1.92-fold, Treg cells decreased to 51.7%, and splenic effector-memory T cells increased 4.70-fold of control, with no observable systemic toxicity. These results suggest that ER-targeted PDT combined with IDO-1 blockade effectively remodels the tumor microenvironment and elicits durable antitumor immunity in TNBC."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CD4 • CD8

Dysregulated Kynurenine metabolism promotes hepatic encephalopathy via neuroinflammation (EASL 2026) - "IDO, an enzyme that metabolizes Tryptophan into Kynurenine, was chemically inhibited by 1-MT in vitro and in vivo... The transcriptomic and metabolomic profiling of the HE model mice and patients identified kynurenine as a novel immunometabolic factor that is increased early in the development of HE. Kynurenine could be a novel biomarker and therapeutic target of HE."

CNS Disorders • Fibrosis • Hepatic Encephalopathy • Hepatology • Inflammation

Indoleamine 2,3-dioxygenase 1 (IDO1) promoted the activation of inflammatory response in the brain tissue of Alzheimer's disease mice by regulating NF-κB pathway. (PubMed, Neurosci Lett) - "Interfering with IDO1 can inhibit the NF-κB pathway, reduce the release of inflammatory factors, and improve brain tissue damage in AD mice."

IO biomarker • Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Inflammation • FAP • GFAP • IDO1 • IL1B • IL6 • TNFA

Combinatory Effects of Indoximod and Melatonin Alleviate Myeloid Derived Suppressor Cells Driven Triple Negative Breast Cancer Progression and Metastasis. (PubMed, J Pineal Res) - "Importantly, the accumulation of myeloid-derived suppressor cells (MDSCs), a key driver of tumor progression and metastasis, decreased in the primary tumor, metastatic liver, and lung of mice treated with indoximod and melatonin combination. Our findings revealed that melatonin enhances the immunotherapeutic efficacy of indoximod in TNBC."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • IL10 • IL1B • TNFA

Mechanism of recombinant Trichinella spiralis antigen p53 alleviating experimental colitis via the IDO-AhR Axis. (PubMed, Int Immunopharmacol) - "This study demonstrates that rTs p53 promotes Trp catabolism toward Kyn by activating the IDO-AhR signaling axis in DCs. This mechanism regulates the Treg/Th17 balance, suppresses intestinal inflammatory responses, and ultimately mitigates experimental colitis. These findings provide a novel perspective for clarifying the mechanisms of parasite-derived immunomodulatory molecules and offer experimental evidence for the development of IDO-AhR-targeted therapeutic strategies against IBD."

Journal • Gastroenterology • Gastrointestinal Disorder • Immunology • Infectious Disease • Inflammation • Inflammatory Bowel Disease • CD4 • MPO

Meloxicam-1-d-MT Dual-Drug Hydrogel Serves as an Immunomodulator to Reverse Tumor Postoperative Recurrence and Metastasis. (PubMed, ACS Appl Mater Interfaces) - "Here, we design and construct an in situ injectable therapeutic hydrogel encapsulating 1-methyl-d-tryptophan (1-d-MT), a small-molecule competitive inhibitor of indoleamine 2,3-dioxygenase, and meloxicam, a selective inhibitor of cyclooxygenase-2 (Ge1MT/Mel hydrogel) to prevent postoperative tumor metastasis and relapse. Importantly, the Ge1MT/Mel hydrogel markedly stimulates a potent antitumor immune response in the cancer lesion microenvironment, increasing antitumor immune cells including CD8+ T cells, as well as elevating antitumor cytokines such as interferon-γ. Overall, combination immunotherapy via the Ge1MT/Mel hydrogel after surgery represents a promising strategy to minimize residual tumor burden and reduce recurrence risk following tumor resection."

Journal • Breast Cancer • Colorectal Cancer • Oncology • Solid Tumor • CD8 • IFNG

T Cell Clonal Expansion Predicts Clinical Outcome in Medulloblastoma Patients Treated With Indoximod (ASPHO 2026) - P1, P2 | "These findings provide crucial scientific support for our upcoming pivotal randomized multicenter phase 2 registration trial of the second-generation indoximod-prodrug (NLG802) plus temozolomide, versus standard-of-care chemotherapy for pediatric patients with non-WNT/non-SHH medulloblastoma in first recurrence. Lumos Pharma provided indoximod."

Clinical • Clinical data • IO biomarker • Brain Cancer • Medulloblastoma • Solid Tumor • CD8

IDO1 inhibition enables IFNγ-elicited responsiveness of pulmonary breast cancer metastases to hypoxia-directed tumoricidal agents (AACR 2024) - "In WT (wild type) mice with established 4T1 lung metastases, administration of the IDO1 inhibitors epacadostat, navoximod or indoximod each similarly resulted in rapid collapse of the metastatic tumor neovasculature and concomitantly increased intratumoral hypoxia and sensitivity to PERK inhibition...Combining chemotherapy with immune checkpoint blockade (ICB) is recognized as an effective strategy for treating lung cancer, with first-line therapy for some patients including the alkylating agent carboplatin in conjunction with pembrolizumab...Elevated intratumoral hypoxia has also previously been linked to increased expression levels of PDL1, a favorable indicator of ICB responsiveness, and we have confirmed the upregulation of PDL1 in 4T1 lung metastases following IDO1 inhibitor administration. Our data in the lung metastasis model support future studies to evaluate whether IDO1 inhibition can be effectively combined with evofosfamide and anti-PD1 treatment to improve..."

IO biomarker • Breast Cancer • Lung Cancer • Oncology • Solid Tumor • IFNG • IL6 • PD-L1

Significance of the tryptophan catabolism pathway in triple-negative breast cancer shows potential targets in certain subsets relating to the serine pathway (AACR 2024) - "To understand the effective function of the pathway with regards to proliferation, we targeted the upper-most step of the catabolism pathway by inhibiting IDO1 with epacadostat and indoximod in different types of TNBC cell-lines and observed for changes in their growth rates via proliferation assays. Targeting the IDO1 enzyme in the kynurenine pathway shows significant correlations between the de novo serine pathway and the tryptophan catabolism pathway in TNBCs that may lead to metabolic targets conferring potential therapeutic benefits."

IO biomarker • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • HER-2

Trogocytosis-derived regulatory cluster of differentiation 8-positive T cells facilitate induction of immune tolerance after lung transplantation. (PubMed, JTCVS Open) - "Conversely, blockade of IDO with anti-IFN-γ antibody or 1-MT significantly decreased the expression (P < .001). MHC-II+CD8+CD45RClowTregs secreted high levels of IL-10, and the adoptive transfer of MHC-II+ trogocytosis Tregs notably prolonged the survival of lung-transplanted rats (40.2 ± 8.1 days vs 9.05 ± 2.3 days). MHC-II+CD8+CD45RClowTregs mediate lung transplantation transient immune tolerance through the IFN-γ/IDO signaling pathway, providing theoretical support for the development of donor-specific immune tolerance clinical strategies."

IO biomarker • Journal • Transplantation • CD8 • HLA-DRB1 • IFNG • IL10

Mechanism of Trichinella spiralis-mediated CD4+ T cell functional imbalance via IDO-dependent tryptophan metabolism. (PubMed, Int Immunopharmacol) - "This effect was suppressed after 1-methyltryptophan (1-MT) treatment, indicating that it is IDO-dependent...Experimental evidence has revealed that mouse CD4+ T cells undergo apoptosis via IDO following T. spiralis infection, and that weakened proliferation leads to an imbalance in mouse immune function, facilitating the smooth survival of T. spiralis and evasion of host immune attack. These findings provide new directions and insights for studying the immune escape mechanism of T. spiralis and for the prevention and treatment of T. spiralis infection."

IO biomarker • Journal • Infectious Disease • Oncology • CD4 • EIF2S1 • FOXP3 • IFNG • IL10 • IL2RA • ISG20 • TNFA

Dietary advanced glycation products combined with chronic restraint stress induced anxiety-like and depression-like behaviors in male mice. (PubMed, NPJ Sci Food) - "Secondly, IDO1 inhibitor, 1-methyltryptophan (1-MT), restored the TRP-KYN pathway disturbance post CRA, and inhibited neuronal ferroptosis post CRA...In conclusion, combined exposure may first disturb gut microbiota homeostasis, followed by intestinal inflammatory responses, subsequently triggering tryptophan towards kynurenine metabolism via the gut-brain axis. These pathological processes led to the abnormal accumulation of neurotoxic metabolites, i.e., KYN and 3-HK, within neurons, which then induced neuronal ferroptosis."

Journal • Preclinical • CNS Disorders • Depression • Inflammation • Inflammatory Bowel Disease • Mental Retardation • Mood Disorders • Psychiatry

Estrogen regulates cognitive function in APP/PS1 female mice via modulation of IDO1-mediated Trp/Kyn metabolism through ERβ. (PubMed, Horm Behav) - "This study used APP/PS1 transgenic female mice with ovariectomy (OVX),E2, IDO1 inhibitor (1-MT), and agonists and antagonists of estrogen receptors to explore the potential roles of estrogen and IDO1 in AD...Furthermore, the ERβ antagonist could reverse the effects of E2 and the ERβ agonist had comparable effects to E2 on the Trp/Kyn pathway. These findings indicate that E2 has positive effects on the cognitive function of the APP/PS1 female mice undergoing OVX, and the mechanism may be related to the modulation of IDO1-mediated Trp/Kyn pathway via activation of ERβ."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Immunology • Inflammation • ER • IDO1

Biomimetic Iridium-Based Photothermal Nanozyme to Trigger Ferroptosis and Pyroptosis and Activate the cGAS-STING Pathway for Improved Tumor Immunotherapy. (PubMed, Adv Sci (Weinh)) - "Here, an iridium (Ir)-based nanozyme (IIN) was constructed through coordination-driven co-assembly using photosensitizer indocyanine green (ICG), Ir, and indoleamine 2,3-dioxygenase (IDO) inhibitor NLG8189...Furthermore, it could suppress distant tumor progression by triggering the immune response, especially under photothermal irradiation, which was accompanied by increased DC maturation, M1 macrophage polarization, and T cell infiltration in tumor tissue. This study proposed a promising strategy for effective Ir-based nanozyme in tumor immunotherapy."

Journal • Oncology • CGAS • STING

Enhanced Upconversion Luminescent Nanocarrier for Effective Tumor-Targeted Photodynamic Therapy Combined with Immunotherapy. (PubMed, Adv Healthc Mater) - "In this study, we produced near-infrared (NIR)-induced multi-shell upconversion nanoparticle (MUN)-based therapeutic nanocarriers co-loaded with chlorin e6 (Ce6) and indoximod (IND) (FMUN3-Ce6/IND) to combine tumor-targeted photodynamic therapy (PDT) with immunotherapy...Furthermore, the synergistic antitumor efficacy of FMUN3-Ce6/IND combining PDT and immunotherapy under in vivo conditions is demonstrated. These results suggest that multi-shell FMUN-based nanocarriers offer a promising platform for synergistic combination therapy, addressing the limitations of monotherapy with IDO inhibitors and overcoming the restricted tissue penetration and low ROS generation associated with conventional PDT."

Journal • Oncology • CD4 • CD8 • FOXP3

Iridium(III) and rhenium(I) complexes containing an IDO inhibitor induce apoptosis and pyroptosis. (PubMed, J Inorg Biochem) - "Four novel Ir(III)/Re(I)-1-methyl-D-tryptophan conjugates (Ir-MT-1-2 and Re-MT-1-2) were designed and synthesized for the first time, among which 1-methyl-D-tryptophan (1-MT) is an indoleamine 2,3-dioxygenase (IDO) inhibitor...Mechanistic investigations revealed that these complexes selectively localized to mitochondria, inducing mitochondrial membrane potential (MMP) depolarization, elevating intracellular reactive oxygen species (ROS) levels, activating mitochondrial apoptotic pathways, and simultaneously inducing the cleavage of pyroptosis marker (GSDME) to cause pyroptosis. These results demonstrate the potential of combing transition metals with IDO inhibitors for cancer treatment."

IO biomarker • Journal • Cervical Cancer • Oncology • Solid Tumor • GSDME

Chemo-immunotherapy Using Ibrutinib Plus Indoximod for Patients With Pediatric Brain Cancer (clinicaltrials.gov) - P1 | N=37 | Recruiting | Sponsor: Theodore S. Johnson | Trial completion date: Sep 2026 ➔ Sep 2028 | Trial primary completion date: Aug 2026 ➔ Mar 2028

Trial completion date • Trial primary completion date • Brain Cancer • Ependymoma • Glioblastoma • Medulloblastoma • Oncology • Pediatrics • Solid Tumor

Pediatric Trial of Indoximod With Chemotherapy and Radiation for Relapsed Brain Tumors or Newly Diagnosed DIPG (clinicaltrials.gov) - P2 | N=130 | Active, not recruiting | Sponsor: Theodore S. Johnson | Recruiting ➔ Active, not recruiting | Trial primary completion date: Oct 2025 ➔ Aug 2026

Enrollment closed • Trial primary completion date • Brain Cancer • Diffuse Intrinsic Pontine Glioma • Ependymoma • Glioblastoma • Glioma • Medulloblastoma • Oncology • Pediatrics • Solid Tumor