Phase I Study of SYNB1891, an Engineered E. coli Nissle Strain Expressing STING Agonist, with and without Atezolizumab in Advanced Malignancies

Abstract

Purpose: SYNB1891 is a live, modified strain of the probiotic E. coli Nissle 1917 (EcN) engineered to produce cyclic dinucleotides under hypoxia leading to stimulator of interferon genes (STING)-activation in phagocytic antigen-presenting cells in tumors and activating complementary innate immune pathways. Patients and Methods: This first-in-human study (NCT04167137) enrolled participants with refractory advanced cancers to receive repeat intratumoral (IT) injections of SYNB1891 either alone or in combination atezolizumab, with the primary objective of evaluating the safety and tolerability of both regimens. Results: Twenty-four participants received monotherapy across 6 cohorts, and 8 participants received combination therapy in 2 cohorts. Five cytokine release syndrome events occurred with monotherapy, including one that met the criteria for dose-limiting toxicity at the highest dose; no other SYNB1891-related serious adverse events occurred, and no SYNB1891-related infections were observed. SYNB1891 was not detected in the blood at 6 or 24h after the first IT dose or in tumor tissue 7 days following the first dose. Treatment with SYNB1891 resulted in activation of the STING pathway and target engagement as assessed by upregulation of interferon-stimulated genes, chemokines/cytokines, and T-cell response genes in core biopsies obtained pre-dose and 7 days following the third weekly dose. In addition, a dose‑related increase in serum cytokines was observed, as well as stable disease in 4 participants refractory to prior PD-1/L1 antibodies. Conclusions: Repeat IT injection of SYNB1891 as monotherapy and in combination atezolizumab was safe and well tolerated and evidence of STING pathway target engagement was observed.

The interplay between autophagy and cGAS-STING signaling and its implications for cancer

“…One of the major constraints is the delivery of these drugs, which significantly limits their clinical application. This led to the development of new delivery systems such as extracellular vesicles loaded with cyclic dinucleotides (referred to as exoSTING) or SYNB1891, an engineered E. coli strain capable of producing cyclic dinucleotides when injected intratumorally ( 287 – 289 ).…”

Probiotic-guided CAR-T cells for solid tumor targeting

“…Although not assessed here, humans are more sensitive to endotoxins than mice, and an important concern for clinical translation will be the potential toxicity from systemic administration of a Gram-negative bacterial therapy ( 55 ). Thus, a critical approach for translation will be to introduce genetic attenuations that have previously enabled both local and intravenous administration of bacterial therapies in clinical trials ( 33 , 56 ). Structural modifications to LPSs have been shown to substantially reduce TLR4 stimulation without disrupting bacteria viability and tumor colonization ( 57 , 58 ).…”

Harnessing innate immune pathways for therapeutic advancement in cancer

“…It produces cyclic dinucleotides when oxygen levels are low. 538 NCT04167137 ONM-500 nanovaccine STING Novel pH-sensitive polymer Subcutaneous Proven efficacy in TC-1 cervical cancer murine model A new polymer acts as a carrier for delivering antigens to DCs while also functioning as an adjuvant by activating the STING pathway. This pH-sensitive polymer forms antigen-encapsulating nanoparticles.…”

“…Additionally, there was a dose-related increase in serum cytokines, and stable disease was observed in four participants who were previously resistant to PD-1/L1 antibodies (NCT04167137). 538 …”