Development of an Inhaled TLR9 Agonist for the Immunotherapy of Lung Cancer
Marilena Gallotta, Hikmat Assi, Mary Janatpour, Robert L. Coffman and Cristiana Guiducci
Dynavax Technologies, USA
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 can control growth of distant, uninjected tumors. Such treatment is especially effective when combined with a complementary immunotherapy, such as anti-PD-1 or radiation. However, repeated IT injection is not practical for many tumor types, including lung cancers. In non-tumor settings, CpG-ODN has demonstrated safety and efficacy when delivered by inhalation directly to the lungs,in humans and in multiple animal species. Thus, inhaled CpG presents an alternative to IT injection for primary lung cancers and 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, remarkable infiltration of tumors with activated CD8+ and CD4+ T cells and formation of highly organized tertiary lymphoid structures. These changes are similar to those observed after IT injection of solid tumors growing subcutaneously, and consistent with changes observed in human tumors responsive to immunotherapy. In the 4T1 model, intranasal CpG-ODN strongly synergizes 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 and pancreas. 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 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.
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