Abstract 4165: A systemically administered killed bacteria-based multiple immune receptor agonist for pulsed anti-tumor immunotherapy

Abstract

Abstract Systemic activation of multiple immune receptors, such as Toll-like (TLR), NOD-like (NLR) and Stimulator of Interferon Genes (STING) is essential for efficient innate and adaptive immune responses. Attempts to use single receptor agonists for advanced cancers have not produced approved products. Limitations include insufficient immune activation and dose-limiting toxicities associated with continuous exposure. Gram-negative bacteria (G-NB) contain multiple TLR, NOD and STING agonists. Potential utility of G-NB for cancer immunotherapy is supported by observation of tumor regression in the setting of infection and Coley’s Toxins. Coley reported that i.v. administration was likely most effective but produced toxicity. The discovery of TLRs, particularly the broad/potent activities of the TLR4 agonist lipopolysaccharide (LPS) suggest that it may be both a critical active ingredient and a dose-limiting feature of i.v. G-NB. Non-pathogenic E. coli were treated with polymyxin to achieve ~90% reduction of LPS activity without lysis and were then killed and stabilized with glutaraldehyde. The resulting product, Decoy10, was shown to contain multiple TLR, NOD and STING agonists and exhibited reduced i.v. toxicity (mice, rabbits) relative to unprocessed cells. Surprisingly, despite reduction in LPS activity and toxicity, Decoy10 induced secretion of similar or higher levels of most cytokines/chemokines by peripheral blood mononuclear cells, compared to unprocessed bacteria. Higher cytokine/chemokine induction was also observed compared to monospecific TLR agonists. Administration of 4 to 8 weekly or twice a week i.v. doses of Decoy10 to mice with established s.c., orthotopic or metastatic syngeneic breast, colorectal, hepatocellular, pancreatic carcinomas or syngeneic or human non-Hodgkin’s lymphoma was well-tolerated and produced single agent anti-tumor activity and/or combination-mediated durable tumor regressions, with induction of immunological memory. Regressions were observed, without significantly increased toxicity, when Decoy10 was combined with chemotherapy, a non-steroidal anti-inflammatory drug, anti-PD-1 therapy or rituximab. Tumor regressions were associated with activation of innate and adaptive immune pathways in tumors after one dose of Decoy10 and were mediated by NK, CD4+ and CD8+ T cells. Published studies have demonstrated that systemic bacteria are engulfed by and activate immune cells in the liver and spleen, with rapid clearance in mice, rabbits, and humans. Systemic bacteria have also been shown to accumulate in or around tumors. We have taken advantage of these phenomena to produce a detoxified but potent multiple immune agonist that induces systemic innate and adaptive anti-tumor immune activation without requirement for continuous systemic exposure. A Decoy product has been cleared by the US FDA for a Phase 1 oncology trial. Citation Format: Michael J. Newman. A systemically administered killed bacteria-based multiple immune receptor agonist for pulsed anti-tumor immunotherapy. [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 4165.