1005P - Microbial ecosystem therapeutics 4 (MET4) treatment mediates a humoral response in patients treated with immune checkpoint inhibition (ICI)

Background

Gut microbiome is a mediator of ICI response. MET-4 (NuBiyota) is an oral mixture of functionally diverse taxa, associated with ICI response. MET4-IO is a single-center, FIH study to evaluate MET4 safety/engraftment in patients (pts) with advanced solid tumours receiving ICI. We describe the anti-MET4 antibody dynamics during treatment and their association with patient peripheral immune cell composition.

Methods

Thirty pts with advanced solid tumours (melanoma n=14, head and neck n=14, RCC n=1 and urothelial n=1), naïve to ICI, were recruited in Arm B of MET4-IO and randomized (3:1) to MET4 with anti-PD1-based ICI (run-in period of 1 cycle of ICI) (n=22), or ICI alone (ctrl arm, n=8). Bacterial flow cytometry was used to detect patient plasma IgG antibodies against MET4 microbial antigens. Pts were categorized into high (>3) or low (<3) IgG response index (RI). Dynamic changes in PMBCs were analysed by CyTOF. Samples were collected prior to ICI initiation (T_-1), prior to MET4 initiation (T₀) and 3-4 weeks after MET4 initiation (T₂).

Results

Changes in circulating IgG levels and PBMC frequencies were calculated between T₀/T_-1 (n=21 pts) and T₂/T₀ (n=19 pts) to determine associations with ICI or MET4. MET4 recipients had an increased anti-MET4 IgG response vs ctrl (mean RI: MET4= 3.176; Ctrl= 0.9483; p=0.0524), with 5/15 (33%) MET4 recipients demonstrating high IgG RI (>3). High IgG RI was associated with changes in peripheral immune profile between T₂ and T₀ vs low RI. Frequency of B cells increased to a greater extent in pts with high IgG RI [average log₂(T₂/T₀) =0.91 vs. Low IgG RI (average log₂(T₂/T₀) = -0.01, adj p = 0.08]. Meanwhile, Foxp3⁺ CD4 T cells were decreased in IgG low pts (average log₂(T₂/T₀) = -0.61) vs IgG high (average log₂(T₂/T₀) = 0.52, p = 0.02). Finally, both CD14⁺ (IgG high average log₂(T₂/T₀) = -0.9, IgG low average log₂(T₂/T₀) = 0.49) and CD16⁺ (IgG high average log₂(T₂/T₀) = -1.89, IgG low average log₂(T₂/T₀) = 0.27) monocytes were reduced in IgG high pts vs. Low (adj p = 0.05 and 0.08, respectively). These differences were not observed with ICI alone (T₀/T_-1) nor in ctrl pts at any time.

Conclusions

Anti-MET4 IgG response is associated with dynamic changes in PBMCs following combination of ICI and MET4.

Clinical trial identification

NCT03686202.

Editorial acknowledgement

Legal entity responsible for the study

Princess Margaret University Network.

Funding

NuBiyota.

Disclosure

P. Spiliopoulou: Financial Interests, Personal, Funding: Novartis; Financial Interests, Personal, Invited Speaker: Eisai, Pfizer; Non-Financial Interests, Institutional, Local PI: Moderna, AstraZeneca. S. Saibil: Financial Interests, Personal, Invited Speaker: Medison, Novartis. L.L. Siu: Financial Interests, Personal, Advisory Board: Merck, AstraZeneca, Roche, Voronoi, Arvinas, Navire, Relay Therapeutics, Amgen, Marengo, Medicenna, Tubulis, LTZ Therapeutics, Pangea, GSK, Daiichi Sankyo; Financial Interests, Personal, Other, Spouse is co-founder: Treadwell Therapeutics; Financial Interests, Personal, Stocks/Shares, Spouse has stock ownership: Agios; Financial Interests, Institutional, Local PI: Novartis, Bristol Myers Squibb, Pfizer, Boerhinger Ingelheim, GSK, Roche/Genentech, AstraZeneca, Merck, Bayer, Amgen, EMD Serono, Biontech, Gilead, Daiichi Sankyo; Financial Interests, Institutional, Coordinating PI: EMD Serono; Non-Financial Interests, Advisory Role: ICR, Dana Farber Harvard Cancer Center, Cancer Grand Challenge, Break Through Cancer. A. Spreafico: Financial Interests, Personal, Advisory Board: Janssen, Merck, BMS, Oncorus, Alentis; Financial Interests, Coordinating PI, Funding paid to the Institutions for trial conduct: Merck, BMS, Roche, Novartis, Oncorus, Janssen, AstraZeneca, Bayer, Treadwell, Nubiyota; Financial Interests, Coordinating PI, Funding paid to the Institution for trial conduct: Symphogen; Financial Interests, Coordinating PI, Funding paid to the Institution for clinical trial conduct: Janssen Oncology/Johnson & Johnson, Regeneron, Alkermes, ArrayBiopharma/Pfizer, GSK, Amgen, ALX Oncology; Financial Interests, Institutional, Local PI, Funding paid to the Institution for trial conduct: Alentis, Servier, Seagen; Financial Interests, Institutional, Local PI, Funding paid to the Institution for trail conduct: Incyte. All other authors have declared no conflicts of interest.