On April 17, 2018 NewLink Genetics Corporation (NASDAQ:NLNK) reported that it presented a poster entitled "Indoximod modulates AhR-driven transcription of genes that control immune function" in the Immunomodulatory Agents and Interventions session at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2018 Annual Meeting in Chicago (Press release, NewLink Genetics, APR 17, 2018, View Source [SID1234525425]).
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"The data demonstrate that indoximod has a unique mechanism of action, remarkably differentiated from IDO enzymatic inhibitors. This different mechanism may contribute to antitumor immune responses in the IDO pathway and through activity independent of IDO," said Charles J. Link, Jr., M.D., Chairman and Chief Executive Officer.
The data suggest that indoximod regulates the differentiation of helper T cells toward an immuno-stimulatory helper function and downregulates genes that control the differentiation of T cells into immuno-suppressive regulatory T cells (Tregs) in an AhR dependent manner. This leads to an increase in the ratio of helper T cells to Tregs. Additionally, it was shown that indoximod reduces the level of IDO protein in dendritic cells in vitro, leading to increased stimulation of CD8 T cell proliferation and reduced production of kynurenine. Moreover, indoximod stimulation of mTOR in T cells appears to increase the proliferation of effector T cells in an IDO and TDO-independent manner. Through this mechanism, indoximod may be able overcome the effects of Trp degradation mediated by both IDO and TDO. Thus, in addition to opposing immunosuppression mediated by the IDO pathway, indoximod may drive antitumor immune responses independent from IDO.
In summary, indoximod has immunostimulatory effects involving 4 main cell types: CD8+ T cells, T helper cells, T regulatory cells, and dendritic cells. Indoximod appears to function through three main mechanisms to inhibit the IDO pathway:
Reversing the effects of low tryptophan by increasing proliferation of effector T cells
Increasing the ratio of T helper to T regulatory cells by both favoring differentiation of activated CD4 T cells into helper T cells and directly reprogramming T regulatory cells into helper T cells
Downregulating IDO expression in dendritic cells
About Indoximod
Indoximod is an investigational, orally available small molecule targeting the IDO pathway. The IDO pathway is a key immuno-oncology target involved in regulating the tumor microenvironment and immune escape. Indoximod is being evaluated in combination with treatment regimens including anti-PD-1/PD-L1 agents, cancer vaccines, radiation and chemotherapy across solid and liquid tumors.