Indoximod (NLG-8189)

Indoximod is an Indoleamine 2,3-dioxygenase (IDO) pathway inhibitor. IDO is a tryptophan-catabolizing enzyme that tumors use to create a state of immunosuppression. [1]
The immunosuppressive activity of IDO leads to an increase in the number of T-regulatory cells, as measured by their Foxp3+/CD4+/CD25+ phenotype. Indoximod has also been shown to reduce the number of T-regulatory cells [2]. In MMTV-Neu mice, researchers looked at the activity of indoximod with and without paclitaxel [3]. The combination of docetaxel and indoximod is more toxic than docetaxel monotherapy.  A single 1200 mg dose of indoximod almost totally saturates the gut, and higher doses do not significantly increase peak serum levels. The single-agent phase I trial of indoximod demonstrated very good oral bioavailability and a mild toxicity profile with no significant myelosuppression, and no maximally tolerated dose was identified up to 2000 mg orally twice daily [1].
Blockade of IDO with indoximod enhanced the adoptive immunologic response to antigens and dendritic cell (DC) vaccines in LLC mouse models.
References:
[1]. Soliman HH, Jackson E, Neuger T et al. A first in man phase I trial of the oral immunomodulator, indoximod, combined with docetaxel in patients with metastatic solid tumors. Oncotarget. 2014 Sep 30;5 (18):8136-46.
[2]. Munn DH. Blocking IDO activity to enhance anti-tumor immunity. Front Biosci (Elite Ed). 2012 Jan 1;4:734-45.
[3]. Muller AJ, DuHadaway JB, Donover PS et al.Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy. Nat Med. 2005 Mar;11(3):312-9. Epub 2005 Feb 13.

Effects of indoleamine 2,3-dioxygenase inhibitor in non-Hodgkin lymphoma model mice.[Pubmed:26243621]

Int J Hematol. 2015 Sep;102(3):327-34.

Indoleamine 2,3-dioxygenase (IDO) catalyzes the rate-limiting step in the metabolism of tryptophan along the kynurenine pathway. In tumors, increased IDO activity inhibits proliferation and induces apoptosis of T cells and natural killer cells. We investigated the therapeutic potential of IDO inhibitor 1-methyl-D-tryptophan (D-1MT) with cyclophosphamide (CY) in a mouse model of lymphoma. To examine the effect of D-1MT, mice were killed on day 28. Serum concentrations of L-kynurenine and L-tryptophan were measured by high-performance liquid chromatography. Regulatory T cells (Tregs) were counted by flow cytometry, and mRNA expressions of IDO1, Foxp3, IFN-gamma, and COX-2 were examined by quantitative real-time reverse transcription-polymerase chain reaction. D-1MT+CY combination treatment significantly inhibited tumor growth as compared to either treatment alone. There were no significant differences in the serum L-kynurenine/L-tryptophan ratio or the IDO1 expression level in the tumors among the treatment groups. The expression levels of IFN-gamma and COX-2 mRNA in tumor-draining lymph nodes (TDLNs) were found to be significantly up-regulated in the CY and D-1MT+CY groups. The number of Tregs in TDLNs in the D-1MT+CY group was significantly lower than that in CY groups on day 17. These results suggest that D-1MT in combination with CY is an effective treatment for lymphoma in a mouse model.

Suppression of immunodominant antitumor and antiviral CD8+ T cell responses by indoleamine 2,3-dioxygenase.[Pubmed:24587363]

PLoS One. 2014 Feb 28;9(2):e90439.

Indoleamine 2,3-dioxygenase (IDO) is a tryptophan-degrading enzyme known to suppress antitumor CD8(+) T cells (TCD8). The role of IDO in regulation of antiviral TCD8 responses is far less clear. In addition, whether IDO controls both immunodominant and subdominant TCD8 is not fully understood. This is an important question because the dominance status of tumor- and virus-specific TCD8 may determine their significance in protective immunity and in vaccine design. We evaluated the magnitude and breadth of cross-primed TCD8 responses to simian virus 40 (SV40) large T antigen as well as primary and recall TCD8 responses to influenza A virus (IAV) in the absence or presence of IDO. IDO(-/-) mice and wild-type mice treated with 1-methyl-D-tryptophan, a pharmacological inhibitor of IDO, exhibited augmented responses to immunodominant epitopes encoded by T antigen and IAV. IDO-mediated suppression of these responses was independent of CD4(+)CD25(+)FoxP3(+) regulatory T cells, which remained numerically and functionally intact in IDO(-/-) mice. Treatment with L-kynurenine failed to inhibit TCD8 responses, indicating that tryptophan metabolites are not responsible for the suppressive effect of IDO in our models. Immunodominant T antigen-specific TCD8 from IDO(-/-) mice showed increased Ki-67 expression, suggesting that they may have acquired a more vigorous proliferative capacity in vivo. In conclusion, IDO suppresses immunodominant TCD8 responses to tumor and viral antigens. Our work also demonstrates that systemic primary and recall TCD8 responses to IAV are controlled by IDO. Inhibition of IDO thus represents an attractive adjuvant strategy in boosting anticancer and antiviral TCD8 targeting highly immunogenic antigens.