Abstract 772P
Background
The gut microbiome of cancer patients impacts response to Immune Checkpoint Inhibitor (ICI) therapy. However, neither which bacteria, nor their mechanism of influence on immunotherapy are yet well characterised. Microbiotica’s precision microbiome profiling of melanoma patients recruited to the MelResist (Cambridge, UK) study has identified a consortium of 9 diverse bacteria, including 4 novel species, which correlate with immune checkpoint inhibitor response across multiple published melanoma cohorts. This consortium, MB097 is being developed as an anti-PD1 co-therapy for melanoma patients. We are working to understand how the bacteria interact with the immune system to influence ICI response.
Methods
Human monocyte-derived dendritic cells were incubated with live bacteria (individually or as a consortium) firstly anaerobically, then aerobically. The stimulated dendritic cells were also used to activate primary allogenic Cytotoxic T lymphocytes (CTL) and NK cells. CTL and NK activation was assessed by intracellular FACS and tumour cell (SKOV3).
Results
MB097 bacteria, individually or as a consortium, strongly activated dendritic cells, upregulating maturation markers CD83 and CD86. Importantly, the strains were more potent inducers of IL-12 than IL-10 (up to 30-fold higher) resulting in a higher IL-12:IL10 ratio than other stimuli, LPS, PolyI:C and other bacteria. These bacteria-stimulated dendritic cells triggered Cytotoxic T Lymphocytes to upregulate Granzyme B, Perforin and IFNg, and kill tumour cells. The MB097 strains stimulated dendritic cells triggered NK cells to release IFNg release and kill tumour cells.
Conclusions
MB097 is a consortium of bacteria strongly linked to ICI response across multiple published series. In vitro, the bacteria activated dendritic cells, which in turn activated CTLs and NK cells. Interesting, the bacteria that most potently induced CTL activation triggered the highest IL-12 to IL-10 ratio from dendritic cells. This included 3 novel species. This IL-12 axis was less tightly linked to NK cell activation, suggesting other as yet undefined mechanisms may influence these cells.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Microbiotica.
Funding
Microbiotica.
Disclosure
M.J. Robinson: Financial Interests, Personal, Full or part-time Employment: Microbiotica; Financial Interests, Personal, Stocks/Shares: Microbiotica, AstraZeneca. K. Vervier: Financial Interests, Personal, Full or part-time Employment: Microbiotica. S. Harris: Financial Interests, Personal, Stocks/Shares: Microbiotica. A. Popple: Financial Interests, Personal, Full or part-time Employment: Microbiotica. R. Hudson: Financial Interests, Personal, Full or part-time Employment: Microbiotica. G. Bakdash: Financial Interests, Personal, Full or part-time Employment: Microbiotica. C. Villemin: Financial Interests, Personal, Full or part-time Employment: Microbiotica. D. Adams: Financial Interests, Personal, Advisory Board: Microbiotica; Financial Interests, Personal, Royalties: BMS; Financial Interests, Institutional, Invited Speaker: AstraZeneca. P.G. Corrie: Financial Interests, Personal, Advisory Board: Merck Sharpe and Dohme; Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb, Pierre Fabre; Financial Interests, Personal, Other, Consultancy: Microbiotica; Financial Interests, Institutional, Invited Speaker: Bristol Myers Squibb, Novartis, Achilles, AstraZeneca, Array Pharmaceuticals, Merck Sharpe and Dohme; Financial Interests, Institutional, Research Grant: Pierre Fabre. T. Lawley: Financial Interests, Personal, Stocks/Shares: Microbiotica; Financial Interests, Personal, Full or part-time Employment: Microbiotica; Financial Interests, Personal, Member of the Board of Directors: Microbiotica. All other authors have declared no conflicts of interest.