Abstract 4696: Development of an inhaled TLR9 agonist for the immunotherapy of lung cancer

CpG-oligonucleotides (CpG-ODN) stimulate innate immune responses through Toll-like receptor-9 (TLR9). Intratumoral (IT) administration of CpG-ODN has been shown to be safe and clinically effective in humans and in multiple animal species. An important feature of local administration of a CpG-ODN is the ability to stimulate immune responses that control the growth of distant, uninjected tumors. Such treatment is especially effective when combined with a complementary mode of immunotherapy, such as anti-PD-1 or radiation. However, repeated IT injection is not practical for many tumor types, including most lung cancers. In mild asthmatic patients and healthy subjects, CpG-ODN have demonstrated safety and pharmacologic activity when delivered by inhalation directly to the lungs. Thus, inhaled CpG presents an alternative to IT injection for primary lung cancers and for other tumor types with prominent lung metastases. In the 4T1 mouse model of metastatic breast cancer, treatment of mice with a CpG-ODN administered intranasally led to a marked reduction in the number of lung metastases. This reduction was accompanied by infiltration of tumors with activated CD8+ and CD4+ T cells and the formation of highly organized tertiary lymphoid structures. These changes are similar to those observed after IT injection of solid tumors growing subcutaneously, and are consistent with changes observed in human tumors responsive to immunotherapy. In the 4T1 model, intranasal CpG-ODN strongly synergized with systemic anti-PD-1 treatment and induced complete clearance of lung tumors, as well as metastases in tissues not exposed to the CpG-ODN, including liver, pancreas and bone. This generation of systemic immunity resulted in long-term survival in the majority of mice. Immune cell subset depletion studies implicate both CD8 and CD4 T cells in the rejection of lung tumors treated with inhaled CpG-ODN plus anti-PD1. Dynavax has developed a CpG-ODN, DV281, that is optimized for aerosol delivery and plans to initiate clinical studies in NSCLC patients in 2017. Citation Format: Marilena Gallotta, Hikmat Assi, Robert L. Coffman, Cristiana Guiducci. Development of an inhaled TLR9 agonist for the immunotherapy of lung 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 4696. doi:10.1158/1538-7445.AM2017-4696