Abstract 5659: Local treatment with novel TLR9 agonist IMO-2125 demonstrates antitumor activity in preclinical models of pancreatic cancer

Abstract

Abstract Pancreatic cancer remains a serious unmet medical need. The majority of pancreatic tumors are composed of stromal cells that make tumors resistant to conventional therapies. We are developing an approach in which a TLR9 agonist, IMO-2125, is administered intratumorally, which induces local Th1 responses and modulates the tumor microenvironment. This approach has shown promising antitumor activity in preclinical models of multiple tumor types in combination with checkpoint inhibitors. We are employing a similar approach to the treatment of pancreatic cancer. We evaluated the local therapeutic effect of IMO-2125 in a murine syngeneic pancreatic ductal adenocarcinoma (Panc02) cancer models. In the first study, C57BL/6 mice were intraperitoneally (i.p.) implanted with Panc02 cells to generate peritoneal metastatic cancer. Tumor-bearing mice (n=10 per group) were then treated with 2.5 mg/kg IMO-2125 either by i.p. or subcutaneous (s.c.) injections for six times in two weeks. In the second study, to establish dual solid tumors in C57BL/6 mice, Panc02 cells were subcutaneously implanted in both the right and left flanks of the animals. When tumors reached to 50-150 mm3, we started the intratumoral (i.t.) administration of IMO-2125 in right tumors at doses of either 0.25 mg/kg, 1 mg/kg or 2.5 mg/kg, or PBS (n=10 per group), 3x/week for three weeks. In the peritoneal metastatic pancreatic tumor model, 80% of IMO-2125 intraperitoneally treated mice survived for more than 88 days, while 90% of the control group died within 29 days. Compared to i.p. treatment, the s.c. treated group survived for only 36 days. Tumor-free mice from the IMO-2125 i.p treatment group (n=7) rejected the same tumor rechallenge, suggesting establishment of durable tumor-specific immune response. In the dual solid pancreatic tumor model, intratumoral IMO-2125 treatment led to a dose dependent antitumor activity in both injected and distant tumors. Tumors treated with 0.25, 1 and 2.5 mg/kg doses of IMO-2125 showed reductions in tumor volume by 66% (p = 0.004), 74% (p = 0.002) and 95% (p = 0.003), respectively. Moreover, the distant tumors exhibited a reduction of 0% (p = 0.65), 64% (p = 0.006) and 69% (p = 0.001), respectively. Antitumor activity was associated with increased T-cell infiltration and upregulation of the gene expression of various checkpoints in both treated and distant tumors. In an independent study, treatment with a control IMO showed minimal antitumor activity. All treatments were well tolerated. In summary, local treatment with IMO-2125 exerts antitumor activity in preclinical pancreatic cancer models, associated with an increase in T-cell infiltration in the tumor microenvironment, providing a novel approach to the treatment of pancreatic cancer. The clinical trial of intratumoral IMO-2125 is in progress in patients with melanoma. Citation Format: Daqing Wang, Evren Kocabas Argon, Fugang Zhu, Sudhir Agarwal. Local treatment with novel TLR9 agonist IMO-2125 demonstrates antitumor activity in preclinical models of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5659. doi:10.1158/1538-7445.AM2017-5659