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Background Immune checkpoint therapy (ICT) harnesses the host immune system to attack cancer cells, leading to durable remissions in some patients. Yet many cancers evade anti-tumor immunity by recruiting suppressive myeloid cells such as macrophages and neutrophils.Methods To overcome this, we developed a novel vector using alphavirus replicon particles (VRPs) that carry a self-amplifying RNA encoding interleukin-12 (IL-12), referred to IL12-VRP (VLPONC-01). This vector is designed to deliver IL-12 directly to the tumor microenvironment (TME), while avoiding systemic exposure.Results Our preclinical studies show that direct injection of murine VLPONC-01 into several different mouse tumor models results more substantial tumor regression compared to lipid nanoparticle formulated saRNA. Leveraging alphavirus’s tropism to myeloid cells, our single cell transcriptomic analysis of mouse tumor tissues demonstrated that intratumoral (i.t.) injection of IL-12 VRPs effectively delivered to macrophages and neutrophils in the TME ( figure 1) and reprogrammed tumor-promoting macrophages and neutrophils to an anti-tumor phenotype via interferon signaling triggered by innate immune responses, further enhanced by IL-12 expression. IL12-VRP treatment resulted in significant inhibition of tumor growth in multiple solid tumor mouse models (figure 2a). The treatment also prevented nodal and distant metastases (figure 2b), while establishing an antigen-specific CD8 T + cell memory.Conclusions By converting the TME into an immune active environment, our approach has the potential to extend the benefits of ICT to non-responsive cancers. This underscores the promise of targeting tumor-supporting immune cells to improve treatment outcomes in cancer patients. Based on our preclinical findings in head and neck squamous cell carcinoma (HNSCC), we aim conduct a phase I trial to test the safety of neoadjuvant (before surgery) of VLPONC-01 and its effect on the primary tumor microenvironment and draining-lymph nodes in HNSCC patients. We will correlate the changes in anti-tumor immunity and pathologic tumor response for either VLPONC-01 alone or in combination with pembrolizumab treatment.Trial Registration NCT06736379Abstract 711 Figure 1Alphavirus VRP transduces myeloid cells and neutrophils in 4T1 mouse TME. (a) Alphavirus VRP structure. (b) Single cell transcriptomic analysis with UMAP and cell type annotation of the merged datasets. (c) Cellular transduction by VRPs in vivoAbstract 711 Figure 2IL12-VRP inhibits mouse tumor growth (a) as well as nodal and distant metastasis (b) by impacting local immune environment using MOC2 mouse syngeneic tumor model to evaluate inhibition of primary tumor growth and metastasis