(F-227) Development of a STING-activating polymer for cancer immunotherapy

Introduction:: The Stimulator of Interferon Genes (STING) pathway is a promising target for cancer immunotherapy. STING activation leads to pro-inflammatory cytokine secretion and exerts an antitumor effect. Despite recent advances, therapies targeting the STING pathway are often limited by routes of administration, insufficient STING activation or off-target toxicity. In many cases, STING agonists need to be delivered through intratumoral injections to achieve moderate STING activation without generating systemic toxicity. We developed a polymer-based STING agonist delivery platform that (a) provides targeted STING agonist delivery to immune cells, (b) is conjugated to a self-immolative linker for controlled release in the endosomes and, (c) allows for systemic administration with excellent safety profiles. We demonstrate that our STING agonist-based polymer induces DC activation, T cell infiltration into the tumors and improves therapeutic efficacy compared to the free STING agonist-3.


Materials and Methods:: STING agonist-3 was synthetically modified by dynamic covalent coupling into a methacrylate-based monomer which was subsequently co-polymerized with a solubilizing mannose-based monomer using reversible addition-fragmentation chain-transfer (RAFT) polymerization. STING activation was determined by evaluating cytokine levels in blood 4 hours post-administration and dendritic cell activation in the tumor-draining lymph nodes (TDLNs) and tumor-infiltrating lymphocytes were evaluated using flow cytometry 24 hours post-injection. Tumor reduction studies were evaluated in two murine cancer models: BALB/c mice with orthotopic 4T1 breast tumors and C57BL/6 mice with subcutaneous B16F10 melanoma tumors. PBS, free STING and polySTING were given intravenously for a total of 2 to 3 times.


Results, Conclusions, and Discussions:: PolySTING increased the plasma IFNβ level and ifnb1 and cxcl10 expression in tumors compared to free STING, demonstrating its higher STING activation both systemically and inside the tumors. In addition, polySTING increased the expression of the co-stimulatory molecules CD86, CD80 and CD40 on dendritic cells in the TDLNs (Figure 1), which could be due to a combination of STING agonist’s adjuvating effect and in situ vaccination with tumor antigens. PolySTING also slowed tumor growth compared to free STING in both the 4T1 breast cancer model and the B16F10 melanoma model (Figure 2).

Here, we report a polymer platform to deliver STING agonists for cancer immunotherapy. The polymer delivers STING agonists to antigen-presenting cells (APCs) after systemic administration and generates strong anti-tumor efficacy with minimal side effects..

Acknowledgements: : K.S. and D.C.N. contributed equally to this work. This work was supported by the U.S. National Institutes of Health, National Cancer Institute Grant R01CA257563. We thank Prof. Hao Yuan Kueh for providing anti-TCF-1 and anti-PD-1 antibodies.