Abstract 4639: Spherical nucleic acids induce an antitumor immune response against triple-negative breast cancer

Abstract

Abstract Triple-negative breast cancer (TNBC) represents a breast cancer subtype with some of the poorest outcomes and is defined as tumors that lack the functional expression of estrogen and progesterone receptors and human epidermal growth factor receptor 2. TNBC has a high rate of reccurrence and therefore new therapies are needed for this disease. Recent clinical data have identified a correlation between intratumoral T cells and overall survival, suggesting the use of immunotherapy as a viable option for treating TNBC tumors. Spherical nucleic acids (SNAs) are a new class of molecules that can modulate the immune system through molecular interactions with immune cells. Immune-stimulatory SNAs consist of a dense shell of nucleic acids having multiple cytosine (C) and guanine (G) nucleotide repeats (CpG) that are radially oriented and attached to a liposomal nanoparticle core. These CpG motifs are recognized by Toll-like receptor 9 (TLR9) and used to induce an innate immune response. TNBC-specific antigens were encapsulated within the liposomal core to direct the antitumor immune response against TNBC cells. The SNAs were tested in a 4T1 syngeneic tumor mouse model for their ability to activate the immune system and initiate an antitumor response against TNBC mammary tumors. The SNA architecture increased the co-delivery of the TLR9 activating nucleic acids and antigens into the same dendritic cell by 50% compared with delivering the nucleic acids and antigens as free entities. SNAs were retained in the tumor-draining lymph node 24 hours after a subcutaneous injection whereas the linear nucleic acids were cleared by 1 hour post-injection. Tumor-bearing mice were treated on day 6, 11, and 15 after tumor initiation with a 50 µM dose of SNAs and the primary tumor volume was measured until day 28. Treatment with SNAs enabled a 30% reduction in the final tumor volume compared with untreated tumor-bearing animals. Flow cytometric analysis of the primary tumors showed an increase in the intratumoral T-cell lymphocyte population and a decrease in the myeloid-derived suppressive cell (MDSC) population in the SNA treated group compared with the untreated group, suggesting treatment with immune-stimulatory SNAs can alter the immunosuppressive microenvironment of TNBC tumors. In addition, T cells from lymph nodes of the SNA treated group secreted more IFN-gamma after ex vivo stimulation with 4T1 lysates, indicating an antigen-specific response was generated with delivery of TNBC-specific antigens encapsulated within the SNA core. Lastly, treatment with SNAs greatly reduced the number of lung metastases in these animals. Future studies are aimed at probing how SNAs are reducing the metastatic burden and ways to increase potency against the primary tumor through potential combination therapies. Citation Format: Lisa E. Cole, Dai Horiuchi, Chad A. Mirkin. Spherical nucleic acids induce an antitumor immune response against triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4639.