Molecular Engineering of Tumor Targeted STING Agonists to Enhance Neuroblastoma Immunotherapy
Mentor: Dr. John Wilson
Neuroblastoma (NB) is the 3rd most common form of childhood cancer. Although several therapeutic advancements have been developed, patients with high-risk NB still only face a 50% chance of surviving beyond five years. Immune checkpoint blockade (ICB) is revolutionizing the treatment of some adult cancers; however, emerging clinical evidence indicates the vast majority of NB patients do not respond to ICB. This can be attributed to an immunogenically “cold” tumor microenvironment, which lacks sufficient T-cell infiltration required for proper therapeutic outcomes. Our lab has recently explored the stimulator of interferon genes (STING) pathway as a way to modulate the innate immune response through the delivery of cyclic dinucleotides (CDNs). CDNs are potent STING agonists but are highly water-soluble molecules and their therapeutic efficacy is limited by low bioavailability and poor drug-like properties. To address this challenge, we have shown that the delivery of STING agonists using nanoparticle (NP) technology can induce expression of interferon-stimulated genes, pro-inflammatory cytokines, and also cause NB cell death. Importantly, NP-mediated STING activation can increase T cell infiltration, inhibit tumor growth, and improve response rates to anti-PD-L1 checkpoint blockade.
Based on these studies, our group is now optimistic that nanoparticle-mediated delivery of STING agonists is a promising therapeutic strategy for NB. But we have also identified areas where our delivery technology could be further improved. Current barriers facing our delivery system are 1) premature release of CDNs from the nanoparticle and 2) a lack of tumor-specific targeting. Therefore, we plan to design a new platform using novel CDNs that are conjugated directly to pH-responsive polymer nanoparticles. We further plan to improve tumor specificity by covalently incorporating GD2 targeting antibodies into this new CDN delivery system. The project will focus primarily on the chemical synthesis and in vitro validation of this platform in NB tumor cell lines. Near the end of the summer, we hope to evaluate this new platform in a 9464D model of NB both alone and in combination with anti-PD-L1 immune checkpoint blockade therapeutics to achieve a synergistic, anti-tumor effect. These novel immunotherapeutic agents show great potential for increasing tumor immunogenicity and potentially hold the key to enhancing immunotherapy responses in NB and other pediatric cancers.
