Abstract 1024P
Background
MRx0518 is a novel, gut microbiome derived, single strain oral Live Biotherapeutic Product (LBP) with potent anti-tumour efficacy in multiple cancer models. MRx0518 has been shown to induce activation of CD8+ T-cells and suppress differentiation of Treg cells in vitro, and to increase the CD8/Treg cell ratio in murine models of cancer. In an ongoing phase I/II study (NCT03637803), preliminary antitumor activity has been observed in patient’s refractory to ICIs when MRx0518 is administered in combination with pembrolizumab. This clinical data has been previously reported, and here we present data from biomarker analysis indicating characteristics of patients that have responded.
Methods
Patients received MRx0518 1 capsule PO BID (1x1010 to 1x1011 CFU) and pembrolizumab (200mg Q3W) for up to 2 years or until progression. Eligible patients have experienced clinical benefit from a prior ICI before eventually progressing. Tumour response was assessed every 9 weeks by RECIST v1.1. Responders were classed as patients who experienced CR, PR or SD ≥6 months. To date, baseline FFPE tumour biopsies from 12 patients, 4 responders and 8 non responders, were immunoprofilling using a mIF panel against; CD3, CD8, PD-1, FOXP3, Ki-67, PD-L1, CD68, and cytokeratin antibodies in tumor and stroma compatments form the tissue using image analysis.
Results
Response to therapy was associated with higher baseline densities of tumour infiltrating Treg (CD3+Foxp3+) (P=0.0381) and proliferating total T-cells (CD3+Ki67+) (P=0.0048) at baseline, whereas higher densities of macrophages (CD68+ cells, P=0.0303) were detected in the stroma and tumour tissue compartment of non-responders.
Conclusions
Understanding mechanisms of resistance to ICIs is key in identifying patients who may respond to subsequent therapies. This limited analysis, together with the observations of increased CD8+ T-cell activation and reduced induction of Treg cells in the presence of tolerogenic cytokines in vitro and in preclinical models, provides insight for further investigation into the potential for MRx0518 + pembrolizumab to overcome Treg-mediated acquired resistance to ICIs.
Clinical trial identification
NCT03637803.
Editorial acknowledgement
Legal entity responsible for the study
4D Pharma PLC.
Funding
4D Pharma PLC.
Disclosure
M. Adriani: Other, Institutional, Full or part-time Employment: 4D Pharma PLC. R. Parikh: Other, Institutional, Full or part-time Employment: 4D Pharma PLC. A. Stevenson: Other, Institutional, Full or part-time Employment: 4D Pharma PLC. C. Badham: Other, Institutional, Full or part-time Employment: 4D Pharma PLC. G. Fyvie: Other, Institutional, Full or part-time Employment: 4D Pharma PLC. M. Chisamore: Other, Institutional, Full or part-time Employment: 7Merck & Co., Inc. All other authors have declared no conflicts of interest.