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1065 ACTM-838, a microbial-based immunotherapy that enriches in solid tumors after IV dosing, reverses the immunosuppressive TME to promote durable anti-tumor immunity, alone and in combination with anti-PD1 in mice
  1. Akshata Udyavar,
  2. Hailey He,
  3. John Brandenburg,
  4. Julie Janes,
  5. Oanh Pham,
  6. Sara Tribble,
  7. Ryan Daroy,
  8. Keith Cheung,
  9. Haixing Kehoe,
  10. Bret Peterson,
  11. Emily Miyashita-Lin,
  12. Omkar Joshi,
  13. Nick Eisele,
  14. Christopher Thanos and
  15. Chan Whiting
  1. Actym Therapeutics, Hayward, CA, USA


Background Effective treatment of metastatic cancers requires reversal of the immunosuppressive tumor microenvironment (TME) and priming a broad repertoire of tumor-specific CD8+ T cells. ACTM-838 is an attenuated, precision genome-engineered, S.Typhimurium-Attenuated Cancer Therapy (STACT) strain carrying a DNA plasmid that encodes payloads consisting of IL-15plex and engineered, constitutively active STING (eSTING). ACTM-838 is designed to colonize the TME and deliver payloads to phagocytic APCs, inducing a durable anti-tumor immune response, after IV dosing.

Methods STACT was developed through genome editing of the parental strain, VNP20009. Single payload (IL-15plex or eSTING) STACT strains and ACTM-838 were bactofected into immune cell lines and primary immune cells. Uptake, payload expression and activity were measured in vitro using ELISAs, MSD, and flow cytometry. ACTM-838 was evaluated in multiple murine tumor models for efficacy as a monotherapy or in combination with anti-PD1 antibodies. Modulation of immune responses in the TME and payload effects were assessed using IHC, RNAseq, flow cytometry and ELISA. ACTM-838 tolerability studies were performed in NHPs and mice.

Results Expression of encoded IL-15plex and eSTING payloads led to IFN-b expression and IL-15 secretion in cell lines and primary M2 macrophages. Furthermore, primary human M2 macrophages polarized toward a novel, co-stimulatory and phagocytic M1/M2 hybrid phenotype. ACTM-838 preferentially colonizes tumors in mice upon IV administration and is well tolerated in NHPs, with enhanced safety compared to VNP20009 in mice. ACTM-838 is selectively taken up by phagocytic APCs in vitro and by tumor-resident APCs in vivo. ACTM-838 treatment showed dose- and payload-dependent anti-tumor efficacy in an anti-PD1 refractory, myeloid rich and T cell excluded, orthotopic EMT6 mouse model as a single agent, and induced a durable anti-tumor CD8+ T cell-dependent memory response upon tumor re-challenge. ACTM-838 induced profound immune reprogramming and remodeling of the TME through increased myeloid cell activation and CD8+ T cell infiltration. Synergistic combination anti-tumor activity was observed when dosed with anti-PD1.

Conclusions ACTM-838 delivers IL-15plex + eSTING payloads to phagocytic APCs in the TME after systemic administration, leading to potent immune reprogramming. Indeed, myeloid cell repolarization, T-cell activation and recruitment promotes durable anti-tumor efficacy as a monotherapy and in combination with anti-PD1. IV-delivered ACTM-838 possesses a compelling safety profile in mice and primates, and is currently in IND-enabling, preclinical development.

Ethics Approval All animals were used according to protocols approved by an Institutional Animal Care and Use Committee and maintained in specific pathogen-free conditions in a AAALAC accredited barrier facility.

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