Project Summary/Abstract: More than 40,000 new rectal cancers occur annually in the US and the majority are locally advanced when diagnosed (LARC). Current total neoadjuvant therapy (TNT) with chemoradiation followed by surgery provides modest outcomes with a 20-25% pathologic complete response (pCR) rate and 5-year disease survival of only 65%. Therefore, there is an unmet need for new treatment approaches that improve LARC clinical outcomes and reduce morbidity. Using LARC patient samples and pre-clinical modeling, we recently identified a rationale for combining short course radiation therapy (SCRT) with inhibitors of the immuno-oncology target IDO1. Indoleamine 2,3 dioxygenase 1 (IDO1) metabolizes tryptophan along the kynurenine pathway and is recognized as a potent suppressor of tumor reactive immunity. Our robust findings identify IDO1 overexpression as a pathologic response in LARC therapy leading to immune-independent treatment resistance and an immunosuppressive TME. We found that: 1) Radiation induces IDO1 overexpression universally across LARC patients and in colorectal cancer (CRC) models regardless of MSI status. 2) IDO1 activity directly promotes critical mediators of CRC growth and treatment resistance (β-catenin and PI3K/AKT; 3) In mice, the potent IDO1 inhibitor epacadostat (EPA) sensitizes CRC to simulated SCRT radiation by relieving immune suppression and augmenting radiation induced CRC apoptosis. We have conducted a Phase I dose escalation study of epacadostat in combination with SCRT/chemotherapy, and identified EPA 400mg BID to be safe and shows preliminary evidence of efficacy. These findings lead us to conclude with following central hypothesis: IDO1 inhibition is a rationally selected adjunctive immunotherapy in CRC that enhances anti-tumor immunity, synergizes with DNA damaging therapy, and protects the normal small intestine. Project goals include: Defining efficacy of EPA/SCRT/chemotherapy as TNT for LARC and a pharmacodynamic basis for EPA in a biospecimen accruing Phase II trial with a randomized biomarker cohort (Aim 1). Defining biomarkers and identifying precision medicine approaches to support the further clinical study of this combination (Aim 2). We will leverage institutional experience and expertise, our established clinical trial infrastructure (NCT03516708), and a standard-of-care cohort, to address this central hypothesis Impact: If successful, we will take this approach to a potentially practice-changing, randomized phase III clinical trial using precision medicine approaches to address the unmet need to improve LARC patient outcomes. As IDO1 is also upregulated in other solid tumors treated by RT (cervix, anal, etc), the approach of combining EPA with genotoxic therapies might be expanded to other solid tumor types.