ACTM-838, a novel systemically delivered bacterial immunotherapy that enriches in solid tumors and delivers IL-15/IL-15Rα and STING payloads to engage innate and adaptive immunity in the TME and enable a durable anti-tumor immune response

// Kyle R. Cron 1 , Ping Fang 1 , Oanh Pham 1 , Julie Janes 1 , John Brandenburg 1 , William Lu 1 , Jonathan Zhu 1 , Bret Peterson 1 , Sara Tribble 1 , Haixing Kehoe 1 , Anastasia Makarova 1 , Alex Iannello 1 , Jean Chan 1 , Justin Skoble 1 , Hailey He 1 , Chris Rae 1 , Christopher D. Thanos 1 and Akshata R. Udyavar 1 1 Actym Therapeutics, Berkeley, CA 94710, USA Correspondence to: Akshata R. Udyavar, email: akshata.udyavar@pfizer.com Keywords: tumor microenvironment; bacterial vector; myeloid cells; STING; IL-15 Received: February 19, 2025 Accepted: September 25, 2025 Published: October 06, 2025 Copyright: © 2025 Cron et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT STACT is a modular, genetically engineered live attenuated S. Typhimurium bacterial platform that enables tissue-specific localization and cell-targeted delivery of large, multiplexed payloads via systemic administration. It has been engineered to minimize systemic toxicity and to enrich in the tumor microenvironment (TME) via metabolic dependency and showed a decreased systemic inflammatory cytokine profile compared to its parent strain VNP20009. ACTM-838 utilizes the STACT platform to deliver IL-15/IL15Rα and a constitutively active STING to tumor-resident phagocytic antigen-presenting cells. Upon intravenous (IV) dosing to tumor-bearing mice, ACTM-838 distributed and enriched in the TME, exhibited specific uptake in tumor-resident phagocytic cells and led to expression of human IL-15/IL15Rα and murine IFNα in the tumor. ACTM-838 induced comprehensive TME changes to an immune permissive anti-tumor phenotype with a decrease in exhausted T-cells and Tregs and an increase in cytolytic T-cells and MHCII-high proliferating myeloid cells. ACTM-838-treated tumors exhibited upregulated anti-tumor innate and adaptive immunity expression profiles, T-, NK- and B-cell infiltration and downregulated cell cycle, DNA damage and TGFβ responses. Single-cell RNAseq and flow cytometry data confirmed activation and infiltration of both innate and adaptive immune cells. ACTM-838 showed durable anti-tumor efficacy in multiple murine tumor models and synergized with anti-PD1 therapy in combination.