Abstract
Background: Live biotherapeutic products (LBPs) are emerging novel anti-cancer therapies. MRx0518 is a gut microbiome-derived oral LBP, consisting of a single strain of Enterococcus gallinarum, which has demonstrated potent anti-tumorigenic efficacy pre-clinically. We have previously shown MRx0518 monotherapy is associated with significant genomic, immune, microbiome, and metabolomic changes, consistent with anti-cancer efficacy in treatment-naïve patients. Here, we report long-term subject follow-up, and further signals of immune modulatory changes from flow cytometry analysis. Methods: NCT03934827 is a Phase 1B single-centre study in treatment-naive patients with confirmed cancer, planned for surgical resection. 17 patients (8 breast, 4 prostate, 3 uterine, 1 bladder & 1 melanoma) received MRx0518 (1x10 10 -1x10 11 CFU) BID monotherapy for 7-28 days from inclusion until surgery. Safety data was collected from dosing until 1-year following cessation. Exploratory analysis included evaluation of pre- and post-treatment peripheral blood mononuclear cells (PBMCs) by multiparametric flow cytometry for leucocyte activation, indicative of anti-cancer efficacy. Results: A total of 29 adverse events (AEs), all CTCAE grade 1 (96%) and grade 2 (4%), were reported. Only 8 (28%) were deemed related to MRx0518. No grade 3/4 toxicities or serious AEs were recorded. At 30-days, and 1-year follow-up no further serious AEs occurred. At a median follow-up of 41 months, 13 (76%) patients remain cancer-free, with 2 (11%) reoccurrences and 2 (11%) lost to follow-up. Analysis of pre- and post-treatment PBMCs identified statistically significant increases in CD3 + CD56 + (p<0.0005), natural killer cells (p<0.005), natural killer T-cells (p<0.01), CD8 + CD62L + (p<0.001), and CD4 + CD62L + (p<0.0001) subsets following MRx0518 therapy. A positive trend was also seen in CD3 + CD8 + cells. Furthermore, we observed a significant increase in both subsets of T-regulatory lymphocytes (nTreg (p<0.05) and eTreg (p<0.05)) and a decrease in both CD4 + (p<0.05) and CD8 + (p<0.005) central memory cells. Sub-analysis of the breast cancer patient group showed a significantly higher increase in CD3 + CD56 + cells (p<0.0001) and intermediate monocytes (p<0.01). Conclusions: This study demonstrates the long-term safety profile of MRx0518 therapy in treatment-naïve cancer patients. Analysis of PBMCs reveals clear evidence of immune modulation, consistent with significant anti-cancer efficacy. This is concordant with prior findings from this study. Notably, significant changes in CD3 + CD56 + have also been demonstrated in other studies of microbiome modulation (e.g., NCT03341143), and may be important determinant of anti-cancer efficacy. Despite the limitations of a small sample size, this effect is particularly prominent in the breast cancer subgroup, warranting further evaluation. Clinical trial information: NCT03934827 .