Epacadostat (INCB24360) in Combination With Sirolimus in Advanced Malignancy

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Indoleamine 2,3 dioxygenase-1 (IDO1) is a target of cancer immunotherapy. Epacadostat (INCB24360) is an oral IDO1 inhibitor. IDO1 activation blocks T-cell activation, enhances T-cell apoptosis and promotes the differentiation of naïve T cells to regulatory T cells (Tregs). Preclinical findings sugge...

Indoleamine 2,3 dioxygenase-1 (IDO1) is a target of cancer immunotherapy. Epacadostat (INCB24360) is an oral IDO1 inhibitor. IDO1 activation blocks T-cell activation, enhances T-cell apoptosis and promotes the differentiation of naïve T cells to regulatory T cells (Tregs). Preclinical findings suggest that IDO1 is critical for cancers to evade immune surveillance and can be exploited for cancer immunotherapy. Sirolimus is an oral Mammalian Target Of Rapamycin (mTOR) inhibitor. Protein Kinase B mTOR pathway has been considered one of major signaling cascade downstream of receptor kinases in human cells. Its activation in human cancer cells prompted scientists to develop its inhibitors. Preclinical findings found that sirolimus can enhance activity of anti-Programmed Death-1 (PD-1) antibody by suppressing Programmed Death Ligand-1 (PD-L1) expression in human lung cancer models. Sirolimus is also known to suppress function of Tregs which contribute to immune evasion in cancer. Other research groups also reported that autophagy is essential for Thymus cell/lymphocyte (T-cell) -mediated apoptosis which can be enhanced by AKT/mTOR/Phosphoinositide 3-kinase (PI3K) inhibitors. These studies indicate that autophagy is essential for T-cell mediated apoptosis signaling. Because autophagy is at least partially down-regulated by mTOR, mTOR inhibitors such as sirolimus can be used to pharmacologically induce autophagy. Overall, these findings suggest that activation of mTOR and resultant suppression of autophagy play a critical role in resistance of IDO1 inhibitor. There is a clear unmet need for patients with advanced NSCLC whose median survival is approximately one year. Those who progressed on both standard first-line chemotherapy and second line anti-PD-1 inhibitor do not have any standard therapeutic option. Novel therapeutic strategy needs to develop for this population. The IDO1 inhibitor epacadostat is currently being investigated in clinical trials in combination with various agents. However, these existing studies do not consider that mTOR and/or autophagy are key mechanisms of its resistance despite the abovementioned background information. The purpose of this phase I study is to test the combination of sirolimus with the IDO1 inhibitor in order to overcome potential resistance mechanisms associated with the use of IDO1.

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