Abstract 3847: Creating the tumor microenvironment for effective immunotherapy: Antitumor activity of intratumoral IMO-2125, a TLR9 agonist is further enhanced by inhibition of indoleamine-pyrrole 2,3-dioxygenase (IDO)

Abstract

Abstract In recent years, understanding of tumor immunology has led to significant advances in cancer immunotherapy. New approaches include selective blockade of checkpoints, harnessing tumor infiltrating lymphocytes (TILs) and use of intratumoral oncolytic viruses. Evolving data has continued to provide evidence that the tumor microenvironment (TME) is critical for effective immunotherapy. In preclinical studies, intratumoral delivery (i.t.) of the Toll-like receptor (TLR) 9 agonist IMO-2125 resulted in increased IFNα, IL-12, Th1 responses, TIL infiltration and dose-dependent antitumor activity against treated and distant tumors. However, gene expression analysis of the treated tumors showed that levels of IDO1 was increased, thereby hampering the optimal TME. We hypothesized that combination of i.t. IMO-2125 and an IDO1 inhibitor would lead to modulation of the TME and more potent antitumor activity versus either agent alone. In the present study, we evaluated the antitumor activity of i.t. IMO-2125 in combination with an IDO1 inhibitor in a murine syngeneic colon carcinoma CT26 model. Each BALB/c mouse was implanted with two tumors: subcutaneous solid tumor and lung metastatic tumor by s.c. (1×107) and i.v. (3×106) inoculation with CT26 cells. Treatment was initiated when tumor nodules reached 100-200 mm3 with 2.5 mg/kg intratumoral IMO-2125 and 75 mg/kg oral IDO1 inhibitor. All treatments were well tolerated. In the placebo-treated group, the tumor volume was 1039 ± 262 mm3 (mean ± SD). In groups treated with IMO-2125 and IDO1 inhibitor, the tumor volume was 369 ± 216 mm3 (64% tumor growth inhibition, TGI) and 745 ± 252 mm3 (27% TGI), respectively. In the group treated with the combination of IMO-2125 and IDO1 inhibitor, the tumor volume was 45 ± 75 mm3, showing 95% tumor growth inhibition. Similar treatment-related results were observed in the lung nodules, with the combination group showing a 76% reduction in the number of lung tumor nodules over PBS control. Tumors treated with IMO-2125 alone showed 90-fold increase in IDO1 expression which was inhibited 47% in tumors treated with a combination of IMO-2125 and IDO1 inhibitor. The inhibition of IDO1 in combination with i.t. IMO-2125 also resulted in increased TILs. Overall, these preclinical data showed that combination of i.t. IMO-2125 and an IDO1 inhibitor stimulated systemic immune responses and primed the TME to enable potent antitumor activity. In previous preclinical studies IMO-2125 has shown potent antitumor activity in multiple tumor models in combination with anti-CTLA4 and anti-PD1 agents. Citation Format: Daqing Wang, Wayne Jiang, Bhagat Lakshmi, Jillian DiMuzio, Fugang Zhu, Sudhir Agrawal. Creating the tumor microenvironment for effective immunotherapy: Antitumor activity of intratumoral IMO-2125, a TLR9 agonist is further enhanced by inhibition of indoleamine-pyrrole 2,3-dioxygenase (IDO). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3847.