Monitoring Melanoma Responses to STING Agonism and Focused Ultrasound Thermal Ablation Using Microneedles and Ultrasensitive Single Molecule Arrays

Abstract

Real‐time monitoring of immune state and response to therapy can provide a means to stratify patients and increase the number of responders who will benefit from approved and emerging immunotherapies. The accessibility of immune cells in the skin provides an opportunity for local immune modulation as well as for noninvasive sampling of disease biomarkers in the skin interstitial fluid (ISF). Here, a monitoring strategy for melanoma immunotherapy is investigated by longitudinal sampling of biomarkers in the skin ISF using Hyaluronic acid (HA)‐based microneedles (MNs). Focused ultrasound ablation and delivery of nanoparticulate stimulator of interferon genes agonist are used as model immunotherapies. It is shown that this combination therapy induces potent inflammatory responses in a melanoma mouse model, promoting tumor elimination and immune memory formation. Indeed, quantifying soluble, protein‐based biomarkers following therapy using conventional immunoassay reveals a pronounced proinflammatory program in the tumor. However, conventional assays fail to detect the low concentration of biomarkers in plasma and in MN‐sampled ISF. It is shown that ultrasensitive single molecule arrays (Simoa) effectively detected proinflammatory biomarkers that are upregulated in response to the therapy in MN‐sampled ISF, in plasma, and in tumors, supporting the feasibility of monitoring melanoma immunotherapy using MNs.

Components, Formulations, Deliveries, and Combinations of Tumor Vaccines

“…In addition, when designing tumor vaccines, different functional TLR agonists can also be combined together to induce a stronger anti-tumor immune response. , STING agonists. STING is a transmembrane protein that exists as a dimer on the endoplasmic reticulum, and it is widely distributed in macrophages, T cells, DCs, endothelial cells, epithelial cells, and fibroblasts. – STING proteins directly recognize bacterial cyclic dinucleotides (CDN) to induce the production of type I interferons and pro-inflammatory cytokines by innate immune cells . In addition, when circular GMP-AMP synthase (cGAS) detects dsDNA released from dead cells, tumor cells, or pathogens, as well as mtDNA that undergoes leakage into the cytoplasm, cGAS catalyzes the synthesis of the second messenger 2′,3′-cGAMP derived from ATP and GTP, thus activating the STING signaling pathway. , STING agonists can be used not only as adjuvants for tumor vaccines, but also in combination with Anti-CTLA-4, Anti-PD-1, or Anti-PD-L1, to directly produce better anti-tumor effects. – Researchers from the Johns Hopkins University School of Medicine have prepared a tumor vaccine called STINGVAX using CDN derivatives, tumor antigens, and GM-CSF .…”