Creating “living medicines” is one goal of the synthetic biology field. These therapeutics could take many forms, one of which is bacteria that are created to address the underlying drivers of disease. Now, the company Synlogic has published data on the preclinical development of SYNB1891, which is being developed as a living biotherapeutic as a clinical immuno-oncology program for the treatment of cancer. The therapeutic is being evaluated in a Phase I clinical trial in patients with advanced solid tumors or lymphoma.
The work is published in Nature Communications in a paper titled, “Immunotherapy with engineered bacteria by targeting the STING pathway for anti-tumor immunity.” Data described in the publication demonstrate that SYNB1891 treatment cleared tumors and stimulated antitumor immunity in preclinical models of cancer.
“The targeted delivery and dual immune stimulatory activity of SYNB1891 offer distinct advantages over other approaches,” said Aoife Brennan, MB, ChB, Synlogic’s president and chief executive officer. “The preclinical data published today highlight the transformative potential of SYNB1891. Together with the early experience in the clinic demonstrating feasibility and tolerability in the initial cohorts of the clinical trial, these data provide support for the continued development of SYNB1891 as a potential therapeutic option to expand the benefits of immunotherapy to more patients with cancer.”
The paper details the engineering and characterization of SYNB1891, describes preclinical studies that demonstrate antitumor activity and generation of immunological memory by SYNB1891 in mouse models of cancer, as well as its robust activation of human antigen-presenting cells (APCs) that are key to the generation of an antitumoral immune response.
The team of scientists used nonpathogenic E. coli as a platform for the development of the strain SYNB1891. The engineered bacterial strain produces cyclic di-AMP (CDA), a stimulator of the STING (STimulator of INterferon Genes) pathway. This mechanism can play a critical role in the initiation of an antitumor immune response via activation of APCs and presentation of tumor antigens. The bacterial chassis of SYNB1891 also stimulates the innate immune system by several other mechanisms, including via Toll-like receptors (TLRs), potentially adding to the magnitude of the overall immune response.
An advantage of SYNB1891 is that the STING agonist is not released by the bacteria until they have been engulfed by the target cells (APCs) and so there is less risk of deleterious effects on other immune cells such as T cells. Also, while SYNB1891 has been engineered with safety features that are designed to prevent its replication unless supplemented with specific nutrients, the bacteria remain active for several days within the injected tumor to stimulate a local immune response.
Intra-tumorally administered SYNB1891 is being evaluated as a monotherapy in an ongoing Phase I open-label, multicenter, dose escalation clinical trial (NCT04167137) in patients with advanced solid tumors or lymphoma. Synlogic expects to release data from the monotherapy arm of this study in late 2020. After establishing a maximum tolerated dose for SYNB1891 as monotherapy, Synlogic expects to initiate a second arm of the trial in which subjects will receive escalating dose levels of SYNB1891 in combination with a fixed dose of the checkpoint inhibitor, atezolizumab (Tecentriq®), to establish a recommended dose for the combination regimen.
This work, the authors wrote, “provides a roadmap for the development of future therapeutics and demonstrates the transformative potential of synthetic biology for the treatment of human disease when drug development criteria are incorporated into the design process for a living medicine.”