Abstract B020: Biomarkers of IDO1 inhibition in patients with locally advanced rectal cancer treated with radiation and chemotherapy
Authors: Ciorba Matthew A. , Pedersen Katrina , Henke Lauren , Chaudhuri Aadel , Mutch Matthew , Kim Hyun , Park Haeseong 
Published: December 2022

Abstract
Background: To date, immunotherapy has not advanced the initial care of locally advanced rectal cancer (LARC) where a combination of radiation and chemotherapy remains the standard of care. In evaluation of other targets, we identified that the immune-oncology target indoleamine 2,3 dioxygenase-1 (IDO1) is universally overexpressed in rectal cancers after radiation therapy (RT) regardless of MSI status. IDO1 initiates tryptophan metabolism along the kynurenine pathway (KP) and activation of the KP exerts immune-suppressive effects in the tumor microenvironment. Our preclinical data identified that epacadostat, a potent inhibitor of IDO1, reduced CRC growth in vitro and in vivo. Furthermore, we found that epacadostat augmented the anti-tumor effects of RT by directly increasing apoptosis in neoplastic cells as well as by relieving RT induced immune-suppression. Based on these findings, we initiated a Phase I study in patients with LARC where epacadostat was used in combination with short-course RT (5 Gy x 5) and chemotherapy. This study is ongoing with the primary endpoint of determining the recommended phase II dose (RP2D) of epacadostat in this population. The study is a dose escalating design including 300, 400, and 600 mg BID. Aim: To present preliminary results from the corollary studies on sequentially acquired biospecimens. Methods: We collected tumor tissue and blood pre-treatment, post-radiation/pre-chemo, sequentially throughout chemo, and at treatment completion or surgery. Analyses include global metabolomics, focused evaluation of tryptophan pathway metabolites, single cell RNAseq, flow cytometry, ctDNA and tissue analysis for IDO1 and other immune checkpoint targets. We also established tumor-derived organoids/tumoroids and have established a “tumor-on-a-chip” model to conduct ex vivo tumor modeling. Results: Preliminary studies confirm an elevation of kynurenine to tryptophan ratio after SCRT which is reversed by epacadostat. Changes in the global metabolomics profiles and immune profiles shift from baseline through the stages of SCRT and chemotherapy revealing consistent patterns. Changes in ctDNA were assessed using the CAPP-Seq based AVENIO platform providing a personalized oncogenomic analysis and demonstrated of rapid clearance from post-SCRT which persisted throughout chemotherapy. Studies with tumoroids and the analysis of scRNAseq data are ongoing and will be presented. Conclusions: Preliminary analysis of biospecimens from this actively accruing study of epacadostat plus RT and chemotherapy reveals distinct changes in metabolomic, immunologic, and genomic profiling across the stages of treatment. These results have the potential to inform a precision design for the Phase II study and will also inform the most promising disease and treatment related biomarkers.
Citation Format: Matthew A. Ciorba, Katrina Pedersen, Lauren Henke, Aadel Chaudhuri, Matthew Mutch, Hyun Kim, Haeseong Park. Biomarkers of IDO1 inhibition in patients with locally advanced rectal cancer treated with radiation and chemotherapy [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr B020.