Abstract 5016: STACT-TREX1: A systemically-administered STING pathway agonist targets tumor-resident myeloid cells and induces adaptive anti-tumor immunity in multiple preclinical models

Abstract

Systemic delivery of STING agonists to tumor-resident myeloid cells will be required to elicit optimal type I interferon-mediated anti-tumor immunity in a metastatic disease setting. To this end, we have generated a microbial-based immunotherapy (STACT- Salmonella Typhimurium (Attenuated) Checkpoint Therapy) that utilizes a highly attenuated, clinically developed strain that is specifically enriched in tumors after intravenous administration. The strain has been modified to reduce pro-inflammatory TLR signaling in order to limit its immunosuppressive microbial profile and significantly improve its therapeutic index. An inhibitory microRNA to TREX1 was designed and introduced into the STACT strain. TREX1 is a 3′ exonuclease immune checkpoint that degrades cytosolic DNA, thereby preventing it from binding cGAS and activating the STING pathway. Mutations in human TREX1 cause a type I interferonopathy known as Aicardi-Goutières syndrome and autoimmune chilblain lupus. Systemic delivery of small-molecule inhibitors targeting TREX1 are intractable due to its ubiquitous expression in healthy tissue. We have engineered our systemically administered therapy to specifically deliver RNAi against TREX1 to the myeloid compartment of the tumor microenvironment, rather than to the inflammatory TNFα- and IL-6-producing stromal compartment. This enables targeted cGAS/STING induction of type I interferon, thereby promoting optimal T cell priming against tumor neoantigens. STACT-TREX1 was evaluated for therapeutic efficacy in several tumor models, including CT26 and MC38 colon carcinoma models, and B16.F10 melanoma. A high degree of tumor-specific colonization of STACT-TREX1 therapy was observed after a single intravenous tail vein administration, with 100,000-fold enrichment detected in tumor tissue relative to spleen and liver. The therapy was well tolerated, with very low TNFα and IL-6 serum cytokines detected. In multiple flank tumor models, potent tumor growth inhibition and complete tumor regressions were observed as a monotherapy. Efficacy was CD8-dependent, and cured mice were protected from tumor re-challenge. Importantly, immune correlates post-treatment demonstrated a significant shift away from the recruitment of microbe-induced innate myeloid populations, and towards type I interferon-induced adaptive immunity. This novel therapeutic approach will allow for systemic delivery of a STING pathway agonist that induces type I interferon specifically in tumor-resident myeloid cells, inducing potent adaptive anti-tumor immunity in solid tumors that are refractory to existing immunotherapies. Citation Format: Anastasia M. Makarova, Alexandre Iannello, Chris S. Rae, Beverly King, Marina Besprozvannaya, John Faulhaber, Justin Skoble, Christopher D. Thanos, Laura Hix Glickman. STACT-TREX1: A systemically-administered STING pathway agonist targets tumor-resident myeloid cells and induces adaptive anti-tumor immunity in multiple preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5016.

Cytosolic bacterial pathogens activate TLR pathways in tumors that synergistically enhance STING agonist cancer therapies

“…Another novel bacterial-based immunotherapy is an attenuated Salmonella Typhimurium strain (STACT) that carries an inhibitor of TREX-1, the exonuclease that prevents activation of STING by degrading cytosolic DNA. Pre-clinical work found that intravenously delivery caused tumor colonization, tumor regression, and immunity to rechallenge 45,65 . Such microbial-based cancer therapies are advantageous as they can be administrated systemically and thus can target tumors throughout the body.…”

Beyond DNA sensing: expanding the role of cGAS/STING in immunity and diseases

“…The TREX-1 exonuclease prevents the activation of the STING pathway by degrading cytosolic DNA. Preclinical studies illustrated that intravenous injections of STACT-TREX-1 into CT26 and MC38 murine models produced very low systemic levels of inflammatory cytokines and demonstrated tumor-specific colonization, tumor regression, and durable immunity upon rechallenge (Makarova et al 2019 ).…”

GAS-STING: a classical DNA recognition pathways to tumor therapy

“…When further combined with an anti-PD-L1 antibody, an exceptional anti-tumor effect was observed ( 127 ). The utilization of bacteria to deliver STING agonists to tumor interiors is also under active investigation ( 136 , 137 ).…”