On June 25, 2018 Synlogic, Inc. (Nasdaq: SYBX), a clinical-stage drug discovery and development company applying synthetic biology to probiotics to develop novel living medicines, reported the presentation of new preclinical data from its Synthetic Biotic medicine oncology program at the annual meeting of the Federation of Clinical Immunology Societies (FOCIS 2018) held June 20-23, in San Francisco, CA (Press release, Synlogic, JUN 25, 2018, View Source [SID1234527454]). The data demonstrate the breadth of the company’s platform to generate Synthetic Biotic medicines that secrete or consume immunologically relevant compounds for the potential treatment of cancer and inflammation.

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"These data highlight the plasticity of our Synthetic Biotic platform and its potential as a robust engine for the production and delivery of a variety of immunological payloads, which can have a profound effect on the tumor microenvironment and potential therapeutic use in immune-related conditions," said Jose Lora, Ph.D., Synlogic’s vice president of research. "Our ability to control the expression of these payloads using the tools of synthetic biology, and to combine multiple effectors into a single Synthetic Biotic medicine has the potential to provide potent stimulation of the immune response locally while limiting systemic toxicity. We continue to explore the capability of this platform in immunomodulation and look forward to advancing our first immuno-oncology program into IND-enabling studies in the second half of 2018."

These preclinical data demonstrate that intra-tumorally injected E. coli Nissle has the ability to colonize and persist in the tumor. Synlogic uses a strain of probiotic bacteria, E. coli Nissle, as the parent strain or "chassis" for its Synthetic Biotic medicines as it is well-characterized, readily engineerable and non-pathogenic. In addition, multiple functions can be engineered into a single bacterial strain. These properties support the development of a Synthetic Biotic immuno-oncology approach for the potential treatment of solid tumors, particularly "cold" tumors that may be resistant to current immunotherapies due to their lack of infiltrating immune cells or a highly immunosuppressive tumor microenvironment.

In a presentation at FOCIS: A Synthetic Biology Approach for the Treatment of Cancer and Inflammation, Synlogic described the engineering of Synthetic Biotic strains to execute a range of functions that are potentially useful for the treatment of cancer, including:

Consumption of immune-suppressive metabolites that accumulate in tumors, such as adenosine and kynurenine. Synthetic Biotic strains capable of consuming these metabolites have the potential to relieve immunosuppression in the tumor microenvironment, enabling immune cells to initiate an anti-tumor response;
Secretion of proteins, including immunomodulatory cytokines such as IL-15, TNF-alpha and IFN-gamma, and production of small molecules, such as STING agonists, that are able to trigger robust anti-tumor immune responses as single agents; and
In situ conversion of pro-drugs, such as 5FC, to enable local release of an active chemotherapy agent, 5FU, potentially reducing the systemic toxicity of such drugs.
The data also demonstrate the use of "switches" to control the engineered genetic circuits; Synthetic Biotic medicines can be engineered to perform functions in response to environmental cues or exogenously administered small molecules, such as tetracycline, salicylate and cumate.

In a second presentation, Using Synthetic Biotic Medicines to Activate Innate and Adaptive Immunity and Drive Antitumor Immune Responses, data were presented from mouse tumor model studies of two genetic circuits engineered into E. coli Nissle to generate two bacterial strains, an immune "initiator" STING activating circuit (SYN-STING) and an immune "sustainer" kynurenine consuming circuit (SYN-Kyn). In contrast to other therapeutic approaches in development, SYN-Kyn lowered levels of the kynurenine metabolite by degrading it, a mechanism that is independent of the enzymes used by both immune and tumor cells to produce kynurenine (IDO1/2 and/or TDO). The preclinical data demonstrate:

SYN-STING treatment of either B16.F10 or A20 tumors resulted 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 checkpoint inhibitors led to significant anti-tumor activity in multiple immunocompetent tumor models; 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.