Identification of a Transcriptional Signature of IDO1 inhibition at the Site of Tumor in Patients with Ovarian Cancer Patients in CITN-05 by nCounter® PanCancer Immune Profiling
Sarah Warren1, Steve Fling2, Patrick Danaher1, Nathan Elliott1, Nirasha Ramchurren2, Leonard D’Amico2, Andrew White1, Lucas Dennis1, Kevin Eng3, Amit Lugade3, Junko Matsuzaki3, Anthony Miliotto3, Steve Kussick4, Hiroomi Tada5, Melissa Geller2, Joseph Beechem1, Mac Cheever2, Kunle Odunsi2
1NanoString Technologies; 2Cancer Immunotherapy Trials Network; 3Roswell Park Cancer Institute; 4PhenoPath Laboratories; 5Incyte Corporation
IDO1 expressed by tumor cells and myeloid derived suppressor cells limits T cell expansion within the tumor by catabolizing tryptophan into kynurenine. Epacadostat (Incyte INCB024360) is an inhibitor of IDO1 that is being tested as adjuvant therapy prior to surgical resection in a Phase I trial of ovarian cancer patients (CITN-05). We profiled pre and post treatment tumor tissue using the NanoString® nCounter platform to identify biomarkers associated with IDO1 inhibition.
15 patients were treated with epacadostat b.i.d. for 14 days, followed by surgical resection. RNA from pretreatment and resected tumor tissue was profiled with the PanCancer Immune Profile panel. Additionally, T cells were enumerated by immunohistochemistry and tryptophan/kynurenine levels were quantified from serum at day 0 and day 14/15.
We identified a gene signature of IFNγ induced genes that was modestly but significantly upregulated in the post treatment tumor samples. A single patient displayed a dramatic upregulation of CXCL9, CXCL10, and CXCL11. Gene signatures specific to cytotoxic T cells revealed an increase in the frequency of CD8+ T cells in the tumor, and this was confirmed by immunohistochemistry.
This study demonstrates that systemic IDO1 inhibition elicits local anti-tumor immune effects and promotes recruitment of CD8+ T cells. It also demonstrates that the the NanoString platform can be used to identify subtle biomarker signatures of efficacy. Future work will explore additional gene signatures associated with IDO1 inhibition.
Credits: None available.
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