Abstract 3264: A novel TLR8 agonist induces immune responses and tumor regression

Toll like receptors (TLRs) have been a recent focus of drug discovery for cancer immunotherapy. TLRs play a crucial role in bridging innate and adaptive immunity. TLR8 is distinguished from other TLRs by its functions in reversing regulatory T (Treg) cell and myeloid derived suppressor cell (MDSC)’s immune suppression effects. Treg and MDSCs induce an immunosuppressive microenvironment that is a major cause of failed tumor immunotherapy. Therefore, activation of TLR8 can exert potent immune-mediated anticancer activity. We discovered a novel TLR8 selective agonist DN052 and demonstrated that DN052 clearly differentiated from motolimod, the only TLR8 agonist drug candidate in clinical development. DN052 was more potent than motolimod and exhibited better PK profiles and more strongly induced immune responses in the in vivo monkey and ex vivo human PBMC studies. However, it has been challenging to characterize TLR8 agonists in vivo partially due to the phylogenetic specificity of TLR8 and its diminished activity in rodents. We developed two new in vivo approaches using mouse syngeneic and mouse xenograft tumor models. Our in vivo studies showed that DN052 strongly suppressed tumor growth in a dose-dependent manner as a single agent and combination with the chemotherapeutic agent or PD-1 monoclonal antibody further enhanced the efficacy of the single agents in several tumor models. Remarkably, DN052 caused complete tumor regression as a single agent or in combination in some of the immune-competent tumor-bearing mice. GLP toxicity studies in rats and monkeys showed that DN052 had favorable safety profiles. Taken together, DN052 is a novel Best-in-Class TLR8 selective agonist for immunotherapy as a single agent or in combination with other immuno-oncology agents or chemotherapeutics for broad cancer indications. DN052 warrants further clinical development. Citation Format: Yuxun Wang, Heping Yang, Huanping Li, Shuda Zhao, Yin Zhang, Renjie Huang, Jinmiao Wu, Yikun Zeng, Panpan Zhang, Xingzhong Zhang, Longsheng Wang, Guangliang Fu, Zhiheng Wu, Panhu Zhu, Hui Xu, Yaqiao Gao, Pei Wang, Daxin Gao. A novel TLR8 agonist induces immune responses and tumor regression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3264.