Abstract IA23: Enhancing anti-tumor immunity through selective inhibition of IDO1

Abstract

Abstract Tryptophan catabolism serves as an important metabolic immunoregulatory checkpoint, functioning in anti-inflammatory, immunosuppressive and tolerance-inducing processes. Three distinct heme-containing enzymes—indoleamine 2,3-dioxygenase (IDO) 1, IDO2 and tryptophan 2,3-dioxygenase (TDO)—have the capacity to initiate the first and rate-limiting step in this metabolic process, catalyzing the conversion of tryptophan to kynurenine. A growing body of scientific evidence indicates that this pathway, and more specifically, the IDO1 enzyme, may be of fundamental importance to tumor immune evasion. Through the depletion of local tryptophan and the production of kynurenine and other downstream metabolites, IDO1 activity has been shown to have an anti-proliferative effect on T cells, to promote Treg differentiation and to bias dendritic cells and macrophages toward an immunosuppressive phenotype. Further, IDO1 expression is a negative prognostic factor across numerous cancer histologies. Therefore, the selective inhibition of IDO1 has emerged as an attractive therapeutic approach to enhance anti-tumor immunity. This presentation will review the immunologic basis for targeting tryptophan catabolism in cancer, describe the emerging preclinical and clinical data on epacadostat, a novel first-in-class selective IDO1 inhibitor, and discuss the therapeutic rationales for epacadostat-based combination immunotherapies. Citation Format: Reid Huber. Enhancing anti-tumor immunity through selective inhibition of IDO1. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr IA23.