On April 16, 2018 Synlogic, Inc. (Nasdaq: SYBX), a clinical-stage drug discovery and development company applying synthetic biology to probiotics to develop novel living medicines, reported that preclinical data from its immuno-oncology (IO) program were featured in two presentations at the annual meeting of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) (Press release, Synlogic, APR 16, 2018, View Source [SID1234525360]). The data demonstrate that, in mouse models, Synlogic’s Synthetic Biotic medicines were shown to stimulate an antitumor response and robustly reprogram the tumor microenvironment potentially enabling the treatment of a variety of cancers.
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"Our IO program highlights the potential of our Synthetic Biotic platform for the design and engineering of novel living medicines with multiple mechanisms of action to treat a broad range of diseases, including cancer," said J.C. Gutiérrez-Ramos, Ph.D., Synlogic’s president and chief executive officer. "Our approach enables us, in a single treatment, to locally deliver multiple, regulatable activities that stimulate an immune response and modulate the tumor environment in order to mobilize the immune system against the tumor and its metastases. We intend to advance our first IO program into IND enabling studies this year."
Synlogic is focused initially on developing Synthetic Biotic medicines to treat so-called "cold tumors," which lack infiltrating anti-tumor T-cells by first stimulating an innate anti-tumor response to make the tumor "hot" and then modifying the tumor microenvironment (TME) to enable T cell expansion and the development of memory, using a single agent to both prime T-cells to mount an immune response and sustain the response. Recent studies have demonstrated that activation of the stimulator of interferon genes (STING) pathway can play a critical role in the initiation of an anti-tumor immune response via activation of antigen presenting cells (APCs) and presentation of tumor antigens. The TME has long been understood to have a role in preventing or interrupting this process. Certain metabolites produced within the tumor such as kynurenine or adenosine can lead to T cell dysfunction and exhaustion, significantly blunting anti-tumor immune responses. Data presented at AACR (Free AACR Whitepaper) demonstrate the potential of Synlogic’s Synthetic Biotic medicines to manipulate both pathways to enable efficient anti-tumor activity in mouse models.
In a presentation in the late-breaking research immunology session, Activation of Innate and Adaptive Immunity via Combinatorial Immunotherapy using Synthetic Biotic Medicines,Synlogic described two new genetic circuits engineered into E. coli Nissle, an immune "initiator" STING activating circuit (SYN-STING) and an immune "sustainer" kynurenine consuming circuit (SYN-Kyn). SYN-STING can be delivered directly into the tumor enabling its localized site of action. The approach of using intra-tumoral injection elicits innate responses in the tumor but not in the circulation, potentially decreasing the risk of adverse events that may arise from the production of systemic type I interferon. In contrast to other therapeutic approaches in development, SYN-Kyn lowers levels of the kynurenine metabolite by degrading it, a mechanism that is independent of the enzyme(s) used by both immune and tumor cells to produce kynurenine (IDO1/2 and/or TDO).
In preclinical studies, Synlogic has demonstrated that:
In vitro, SYN-STING produces biologically-relevant levels of ci-di-AMP, activating APCs, while SYN-Kyn consumes kynurenine at concentrations comparable to those found in patients’ tumors;
SYN-STING treatment of either B16.F10 or A20 tumors results in robust tumor rejection or control, which correlates with an early rise in innate-immune cytokines and later results in T cell activation in tumors and tumor-draining lymph nodes;
Combining SYN-Kyn with a checkpoint inhibitor led to profound anti-tumor activity in the CT26 immunocompetent tumor model; and
A strain engineered to combine both genetic circuits (SYN-STING:Kyn) demonstrates equivalent production of ci-di-AMP and consumption of kynurenine in vitro compared to the individual strains SYN-STING and SYN-Kyn, respectively.
A second presentation entitled Metabolic Modulation of the Tumor Microenvironment using Synthetic Biotic Medicines demonstrated that engineered bacterial strains designed to consume either kynurenine (SYN-Kyn) or adenosine (SYN-Ade) effectively relieved TME immunosuppression and promoted anti-tumor activity.
In summary:
Invitro SYN-Kyn and SYN-Ade can deplete kynurenine and adenosine, respectively, at concentrations that are clinically relevant;
SYN-Kyn demonstrated rapid and near-complete reductions in tumor kynurenine levels in vivo;
A combination of either SYN-Kyn or SYN-Ade with checkpoint inhibition led to superior anti-tumor activity in the MC38 immunocompetent tumor model compared with checkpoint inhibitors alone.
About Synthetic Biotic Medicines
Synlogic’s innovative new class of Synthetic Biotic medicines leverages the tools and principles of synthetic biology to genetically engineer probiotic microbes to perform or deliver critical functions missing or damaged due to disease. The company’s two lead programs, SYNB1020 and SYNB1618, target hyperammonemia as a result of liver damage or genetic disease, and phenylketonuria, respectively. Patients with these diseases are unable to break down commonly occurring by-products of digestion that then accumulate to toxic levels and cause serious health consequences. When delivered orally, these medicines can act from the gut to compensate for the dysfunctional metabolic pathway and have a systemic effect, with the potential to significantly improve symptoms of disease for affected patient. Synlogic has earlier-stage programs that apply the broad potential of its Synthetic Biotic platform in other disease areas, from inflammatory and immune disorders to cancer.