Improved anti-tumor immunity and efficacy upon combination of the IDO1 inhibitor GDC-0919 with anti-PD-l1 blockade versus anti-PD-l1 alone in preclinical tumor models

Spahn, Jessica; Peng, Jing; Lorenzana, Edward; Kan, David; Hunsaker, Thomas; Segal, Ehud; Mautino, Mario R.; Brincks, Erik L.; Pirzkall, Andrea; Kelley, Sean K.; Mahrus, Sami; Liu, Liling; Dale, Stephanie; Quiason, Cristine; Liu, Yichin; Latham, Sheerin; Salphati, Laurent; DeMent, Kevin; Merchant, Mark; Hatzivassiliou, Georgia

doi:10.1186/2051-1426-3-s2-p303

Cited by 25 publications

(14 citation statements)

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“…Its oral administration reduced plasma kynurenine levels by approximately 50% in mice and it relieved IDO1-induced T cell suppression in human cell cultures. In preclinical models, navoximod greatly enhanced vaccine responses against B16 melanoma, reducing tumor size ~95% within 4 days of vaccination, and improved the efficacy of anti-PD-1 against EMT6 mammary carcinoma (95), where increased CD8 + T/Treg ratioes, plasma interferon-γ levels and activated intratumoral macrophages and DC were noted.…”

Section: Discovery and Preclinical Development Of Ido1 Inhibitorsmentioning

confidence: 99%

Discovery of IDO1 Inhibitors: From Bench to Bedside

et al. 2017

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Small molecule inhibitors of indoleamine 2,3-dioxygenase-1 (IDO1) are emerging at the vanguard of experimental agents in oncology. Here pioneers of this new drug class provide a bench-to-bedside review on preclinical validation of IDO1 as a cancer therapeutic target and on the discovery and development of a set of mechanistically distinct compounds – indoximod, epacadostat and navoximod – that were first to be evaluated as IDO inhibitors in clinical trials. As ‘immunometabolic adjuvants’ to widen therapeutic windows, IDO inhibitors may leverage not only immuno-oncology modalities but also chemotherapy and radiotherapy as standards of care in the oncology clinic.

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Section: Discovery and Preclinical Development Of Ido1 Inhibitorsmentioning

confidence: 99%

Discovery of IDO1 Inhibitors: From Bench to Bedside

et al. 2017

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“…In the B16 melanoma mouse model, co-administration of with pmel-1 T cells and gp100 peptide vaccination reduced relative tumor size ~95% within 4 days of vaccination. Additionally, in the EMT6 syngeneic model, combining GDC-0919 with an anti-PD-L1 antibody improved relative antitumor efficacy (Spahn et al , 2015). The combination led to an increased CD8+ T/Treg ratio and higher plasma levels of interferon-γ.…”

Section: Lead Clinical Agents: Indoximod Epacadastat and Gdc-0919/namentioning

confidence: 99%

Indoleamine 2,3-Dioxygenase and Its Therapeutic Inhibition in Cancer

Prendergast

Malachowski

Mondal

et al. 2018

International Review of Cell and Molecular Biology

227

214

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The tryptophan catabolic enzyme indoleamine 2,3-dioxygenase-1 (IDO1) has attracted enormous attention in driving cancer immunosuppression, neovascularization and metastasis. IDO1 suppresses local CD8+ T effector cells and natural killer cells and induces CD4+ T regulatory cells (iTreg) and myeloid-derived suppressor cells (MDSC). The structurally distinct enzyme tryptophan dioxygenase (TDO) also has been implicated recently in immune escape and metastatic progression. Lastly, emerging evidence suggests that the IDO1-related enzyme IDO2 may support IDO1-mediated iTreg and contribute to B-cell inflammed states in certain cancers. IDO1 and TDO are upregulated widely in neoplastic cells but also variably in stromal, endothelial and innate immune cells of the tumor microenviroment and in tumor-draining lymph nodes. Pharmacological and genetic proofs in preclinical models of cancer have validated IDO1 as a cancer therapeutic target. IDO1 inhibitors have limited activity on their own but greatly enhance ‘immunogenic’ chemotherapy or immune checkpoint drugs. IDO/TDO function is rooted in inflammatory programming, thereby influencing tumor neovascularization, MDSC generation and metastasis beyond effects on adaptive immune tolerance. Discovery and development of small molecule enzyme inhibitors of IDO1 derived from the hydroxylamidine and phenylimidazole chemotypes have advanced furthest to date in Phase II/III human trials (epacadastat and GDC-0919/navoximod, respectively). Second generation combined IDO/TDO inhibitors may broaden impact in cancer treatment, for example, in addressing IDO1 bypass (inherent resistance) or acquired resistance to IDO1 inhibitors. This review surveys knowledge about IDO1 function and how IDO1 inhibitors reprogram inflammation to heighten therapeutic responses in cancer.

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“…Navoximod (GDC-0919; previously NLG919) is an investigational small-molecule inhibitor of IDO1 with a potency of 75-90 nmol/L for IDO1 in cell-based assays (12). In preclinical models, combination treatment of navoximod with anti-PD-L1 more effectively activates intratumoral CD8 þ T cells and inhibits tumor growth compared with either single agent alone (13). The openlabel phase Ia clinical study of navoximod in 22 patients with solid tumors demonstrated that navoximod was generally well-tolerated, and as expected had limited clinical activity, as a single agent (14).…”

Section: Introductionmentioning

confidence: 99%

Phase I Study of the Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitor Navoximod (GDC-0919) Administered with PD-L1 Inhibitor (Atezolizumab) in Advanced Solid Tumors

Jung

LoRusso

Burris

et al. 2019

Clinical Cancer Research

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193

155

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Purpose: IDO1 induces immune suppression in T cells through L-tryptophan (Trp) depletion and kynurenine (Kyn) accumulation in the local tumor microenvironment, suppressing effector T cells and hyperactivating regulatory T cells (Treg). Navoximod is an investigational small-molecule inhibitor of IDO1. This phase I study evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of navoximod in combination with atezolizumab, a PD-L1 inhibitor, in patients with advanced cancer.Patients and Methods: The study consisted of a 3 þ 3 doseescalation stage (n ¼ 66) and a tumor-specific expansion stage (n ¼ 92). Navoximod was given orally every 12 hours continuously for 21 consecutive days of each cycle with the exception of cycle 1, where navoximod administration started on day À1 to characterize pharmacokinetics. Atezolizumab was administered by intravenous infusion 1,200 mg every 3 weeks on day 1 of each cycle.Results: Patients (n ¼ 157) received navoximod at 6 dose levels (50-1,000 mg) in combination with atezolizu-mab. The maximum administered dose was 1,000 mg twice daily; the MTD was not reached. Navoximod demonstrated a linear pharmacokinetic profile, and plasma Kyn generally decreased with increasing doses of navoximod. The most common treatment-related AEs were fatigue (22%), rash (22%), and chromaturia (20%). Activity was observed at all dose levels in various tumor types (melanoma, pancreatic, prostate, ovarian, head and neck squamous cell carcinoma, cervical, neural sheath, nonsmall cell lung cancer, triple-negative breast cancer, renal cell carcinoma, urothelial bladder cancer): 6 (9%) doseescalation patients achieved partial response, and 10 (11%) expansion patients achieved partial response or complete response.Conclusions: The combination of navoximod and atezolizumab demonstrated acceptable safety, tolerability, and pharmacokinetics for patients with advanced cancer. Although activity was observed, there was no clear evidence of benefit from adding navoximod to atezolizumab.

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Improved anti-tumor immunity and efficacy upon combination of the IDO1 inhibitor GDC-0919 with anti-PD-l1 blockade versus anti-PD-l1 alone in preclinical tumor models

Cited by 25 publications

References 0 publications

Discovery of IDO1 Inhibitors: From Bench to Bedside

Discovery of IDO1 Inhibitors: From Bench to Bedside

Indoleamine 2,3-Dioxygenase and Its Therapeutic Inhibition in Cancer

Phase I Study of the Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitor Navoximod (GDC-0919) Administered with PD-L1 Inhibitor (Atezolizumab) in Advanced Solid Tumors

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