attenuated S. typhimurium carrying IL-15/IL-15Ra and engineered STING-encoding DNA plasmid ACTM-838

A genetically modified attenuated Salmonella typhimurium strain carrying a DNA plasmid that encodes payloads consisting of IL-15plex, a complex of the immunostimulating cytokine interleukin (IL-15) and its receptor alpha unit (IL-15Ra), and an engineered, constitutively active stimulator of interferon genes (STING; transmembrane protein 173; TMEM173), with potential immunostimulatory and antineoplastic activities. Upon administration, attenuated S. typhimurium carrying IL-15/IL-15Ra and eSTING-encoding DNA plasmid ACTM-838 accumulates and replicates in the adenosine-rich tumor microenvironment (TME), and is internalized by the phagocytic antigen presenting cells (APCs). This activates innate immunity. Also, ACTM-838 expresses IL-15/IL-15Ra and eSTING, thereby delivering these payload directly into the TME. eSTING activates the STING pathway, which leads to the production of pro-inflammatory cytokines, including interferons (IFNs), enhances the cross-presentation of tumor-associated antigens (TAAs) by dendritic cells (DCs), and induces a cytotoxic T-lymphocyte (CTL)-mediated immune response against cancer cells. IL-15 stimulates the proliferation of natural killer (NK) cells, CTLs and memory T cells, which further induces an anti-tumor immune response. IL-15Ra complexed with IL-15 increases IL-15 signaling and IL-15 half-life upon expression.