Immune modulation and the oral live biotherapeutic product, MRx0518, in treatment-naïve patients with cancer: Updated safety data.

person Mark Lythgoe Imperial College, London, London, United Kingdom info_outline Mark Lythgoe, Paola Dama, Adam Enver Frampton, Emily Pickford, Laura Tookman, Paula Cunnea, Christina Fotopoulou, Daniel Liu, James Clark, Jingky Lozano-kuehne, Philip David Badman, Aaron Clarke, Sasha Chetal, Gayle Fyvie, Alex Stevenson, Jonathan Krell

Authors person Mark Lythgoe Imperial College, London, London, United Kingdom info_outline Mark Lythgoe, Paola Dama, Adam Enver Frampton, Emily Pickford, Laura Tookman, Paula Cunnea, Christina Fotopoulou, Daniel Liu, James Clark, Jingky Lozano-kuehne, Philip David Badman, Aaron Clarke, Sasha Chetal, Gayle Fyvie, Alex Stevenson, Jonathan Krell Organizations Imperial College, London, London, United Kingdom, University of Sussex, Falmer, Brighton, IL, United Kingdom, University of Surrey, Guildford, United Kingdom, Imperial College NHS Trust, London, United Kingdom, Imperial College Healthcare NHS Trust, London, London, United Kingdom, Department of Surgery and Cancer, Imperial College London, London, United Kingdom, Imperial College London, London, United Kingdom, 4D Pharma Research Ltd, Aberdeen, United Kingdom, 4D Pharma plc, Leeds, United Kingdom, 4D Pharma Plc, Leeds, United Kingdom Abstract Disclosures Research Funding Institutional Funding Imperial College London 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.

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