Abstract 576: ACTM-838, a novel immunotherapy that enriches in solid tumors after IV dosing and comprehensively reverses the immunosuppressive TME to promote durable anti-tumor immunity

Abstract

Abstract ACTM-838 is an avirulent bacterial immunotherapy that encodes an engineered IL-15 (IL-15plex) and a constitutively active STING variant (eSTING). The ACTM-838 strain is a highly modified, attenuated S. Typhimurium that lacks several major inflammatory and immunogenic components on the surface of the microbe and is designed to naturally and specifically enrich in the tumor microenvironment (TME) via auxotrophic dependency on metabolites of the adenosine pathway and purines, to achieve tumor-specific payload delivery. ACTM-838 was selectively internalized by phagocytic, primary human antigen presenting cells (APCs) but not endothelial cells. ACTM-838 was stable in human whole blood and is not inactivated by complement. Human macrophage uptake of labeled ACTM-838 led to acidic lysosomes and nuclear delivery with a concomitant increase in expression of encoded IL-15plex and eSTING payloads such as IL-15, IRF3 reporter activity and IFN ⍺/β secretion, respectively. Primary human and murine macrophages polarized towards a dual co-stimulatory and phagocytic M1/M2 dual phenotype in response to ACTM-838. ACTM-838 delivered eSTING payload in STING knockout macrophages and induced significantly higher Type I IFN production over a negative control strain. IV delivered ACTM-838 showed dose and payload dependent tumor enrichment and potent single-agent efficacy in two independent syngeneic tumor models, EMT6 (orthotopic) and MC38. Sustained memory anti-tumor immunity upon tumor rechallenge in cured animals was demonstrated. ACTM-838 treated tumors exhibited a significant increase in human IL-15plex protein payload. ACTM-838 as a single agent induced profound immune reprogramming and remodeling of the TME over time through increased infiltration and activation of myeloid, NK, B and cytolytic CD8 T cells, MHC class I and II, antigen presentation as well as decreased Treg, PD1+Lag3+ exhausted T cells, and a remodeled stromal signature, as assessed by bulk RNAseq, and confirmed by flow cytometry. Synergistic anti-tumor activity was observed in multiple tumor models when ACTM-838 was dosed in combination with anti-PD1, safely inducing complete responses. No significant body weight loss or death was observed in any treatment regimens of ACTM-838 alone (single or multiple doses) or in combination with anti-PD1. Analyses of public RNAseq datasets from patients with primary or metastatic disease revealed cancer types with high levels of myeloid infiltration and adenosine enrichment, suggesting that ACTM-838 efficacy could provide benefit in these indications. ACTM-838 is a novel immunotherapy delivering IL-15plex + eSTING payloads to phagocytic APCs, inducing a durable anti-tumor immune response, after IV dosing. It possesses a compelling safety profile, and is currently in IND-enabling, preclinical development. Citation Format: Ping Fang, Kyle R. Cron, Oanh Pham, Julie R. Janes, John Brandenburg, Fauna Yarza, Bret Peterson, Christopher Thanos, Chan Whiting, Akshata R. Udyavar. ACTM-838, a novel immunotherapy that enriches in solid tumors after IV dosing and comprehensively reverses the immunosuppressive TME to promote durable anti-tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 576.