In 1891, Dr. William B. Coley successfully treated cancer by injecting streptococcus into a patient’s tumor1. Since then, we have learned a lot about the role of the immune system but the search for methods to stimulate the innate immune response to cancer continues. Several groups have explored the use of attenuated pathogenic bacteria as cancer treatments. These approaches have been limited as the strains used have either failed to demonstrate robust efficacy or exhibited unacceptable side effects2. We asked whether synthetic biology would allow us to take non-pathogenic bacteria and engineer specific attributes including efficacy and safety features that would extend William Coley’s work as a new way to build living medicines.
A non-pathogenic bacteria E coli Nissle 1917 (EcN) is highly engineerable, easily scalable for manufacturing, and has a long history of safe use in humans as a probiotic3. We have pioneered the development, manufacturing, and clinical translation of E coli Nissle based medicines4 for metabolic diseases5,6, inflammation, and cancer. Using synthetic biology techniques, we designed genetic circuits that enable the bacteria to sense and modulate a disease. Our approach is differentiated from many previous efforts to engineer bacteria, which while highly creative, have failed to include design elements important to translate from bench-to-bedside.
In our most recent study in Nature Communications we develop an immunotherapeutic EcN strain, SYNB1891, designed for the treatment of difficult to treat cancers and describe the implementation of design elements critical for its use as a human therapeutic.
Our team assessed the capabilities of EcN as a potential cancer therapeutic including its ability to survive in tumors and evaluated an array of relevant immunomodulatory molecules and reusable parts that could be expressed in EcN (see Figure 1).
We focused on a few potential therapeutic approaches. The first is the Stimulator of Interferon Genes (STING) pathway which is promising for activating antitumor immune responses. The use of small molecule STING agonists has yielded mixed results. While the intended target is antigen-presenting cells (APCs), at high doses these agonists often lose efficacy7 as they may also be taken up by T cells triggering apoptosis and blunting the antitumor response8 .
Since bacteria can remain metabolically active and localize within tumors for days-weeks and are naturally engulfed by phagocytic APCs, we created SYNB1891 which produces a STING agonist, as a targeted therapy. Furthermore, the use of a bacterial delivery vehicle provided additional immune stimulation of its own. Keeping in mind the potential clinical application of our strain, we evaluated and incorporated critical engineering features like a control element and auxothrophies to create SYNB1891 to be efficacious, scalable, and suitable for use in humans (see Figure 2).
In our study we demonstrated encouraging results using SYNB1891 to treat preclinical mouse models of cancer and to activate human APCs in vitro. With strong preclinical data in hand, the next step is translation of these findings to the treatment of human cancer.
SYNB1891 is being evaluated in an ongoing Phase I clinical trial in patients with advanced solid tumors or lymphoma (NCT04167137). Positive signs of SYNB1891 efficacy and tolerability will provide further support for the potential development of additional engineered EcN strains using one or multiple sets of immunomodulatory effectors tailored to the needs of a specific cancer or patient subtypes.
Daniel Leventhal, Anna Sokolovska, Synlogic, Inc.
We thank a great team of people who had a vision, worked together to design and move this new living medicine to a clinical trial in just 2 years; and are still working today to bring SYNB1891 to patients.
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