Abstract B196: Intratumoral administration of IMO-2125, a novel TLR9 agonist, modulates tumor microenvironment and potentiates antitumor activity of anti-PD-1 mAb in a murine colon carcinoma model (2015)

Abstract Immunotherapeutic advances in the treatment of cancer by targeting immune checkpoint pathways has shown promising results, however, data for agents currently in development have only shown responses in subgroups of patients. Current research is focused on identifying predictors of response to immunotherapy, including characteristics of the tumor and its microenvironment. It is becoming evident that infiltration of immune cells in the tumor microenvironment is critical to the success of immune-directed strategies. We designed a novel, oligonucleotide-based Toll-like receptor (TLR) 9 agonist to activate immune responses and induce expression of interferon-α. In previously completed preclinical studies, intratumoral (i.t.) administration of IMO-2125 affected the tumor microenvironment by stimulating TIL infiltration, modulated levels of various checkpoints, and exerted anti-tumor activity in injected as well as distant tumors. In the present study, we have evaluated the antitumor activity of i.t. IMO-2125 in combination with anti-murine PD-1 mAb (clone J43, BioXCell) in a murine syngeneic colon carcinoma model. Female BALB/c mice (6 to 8 week-old, n = 8 per group) were subcutaneous (s.c.) implanted with CT26 cells on the right and left flanks. Animals with tumors were randomized in four groups to be treated with placebo, i.t. IMO-2125, intraperitoneal (i.p.) anti-PD-1 mAb, and a combination of i.t. IMO-2125 and i.p. anti-PD-1 mAb. Treated mice received 50 μg IMO-2125 only in their right tumor and 200 μg anti-PD-1 mAb. Treatment was initiated on day 7 when tumor nodules reached 200-300 mm3 and both agents were administered four times on days 7, 8, 11 and 12. All treatments were well tolerated. Treatment with IMO-2125 alone resulted in 59% and 45% growth inhibition in treated and distant tumors respectively compared to placebo. Treatment with anti-PD-1 mAb showed limited antitumor activity with less than 15% tumor growth inhibition in both the tumor lesions compared to placebo. Treatment with a combination of IMO-2125 and anti-PD-1 mAb resulted in increased antitumor activity, leading to 81% growth inhibition in the treated tumors and 65% growth inhibition in the distant tumors compared to placebo. At day 14, the mean tumor volume in the group treated with the combination of IMO-2125 and anti-PD-1 mAb was 180 mm3, whereas mean tumor volume in the IMO-2125 group was 380 mm3 (p&amp;lt;0.01) and in anti-PD-1 mAb group it was 809 mm3 (p&amp;lt;0.01). Post-treatment analyses of tumors, including TIL infiltration and changes in various checkpoints, will be presented. Combination treatment with IMO-2125 and an anti-PD-1 mAb showed significant improvements in survival and tumor volume compared to either drug alone. Planning is currently underway for a Phase 1/2 clinical trial with intratumoral IMO-2125 in combination with an anti-CTLA-4 checkpoint inhibitor. Collectively, these data demonstrate additional opportunities to combine intratumoral IMO-2125 with an anti-PD-1 mAb and potentially other checkpoint inhibitors in future clinical trials. Citation Format: Daqing Wang, Fugang Zhu, Jillian DiMuzio, Sudhir Agrawal. Intratumoral administration of IMO-2125, a novel TLR9 agonist, modulates tumor microenvironment and potentiates antitumor activity of anti-PD-1 mAb in a murine colon carcinoma model. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B196.