1663MO - DAV132 prevents antibiotic-induced intestinal microbiota dysbiosis and maintains anti-PD-1 efficacy: A proof-of-concept in tumor-bearing mice transplanted with human feces

Background

Antibiotics (ABX) prior to immune checkpoint inhibitors (ICI) induce intestinal dysbiosis and decrease ICI efficacy. DAV132 is a colon-targeted ABX adsorbent designed to prevent ABX-related dysbiosis. We investigated whether DAV132 could protect microbiota diversity and composition post ABX, and determined anti-PD-1 efficacy through fecal microbiota transplantation (FMT) in germ-free (GF) mice.

Methods

Twenty-four human healthy volunteers (HV) were randomized to receive either ceftazidime-avibactam (CZA, 2g/0.5g q8h IV for 5 days) or CZA + DAV132 (12g PO tid for 7 days). CZA plasmatic and fecal levels were measured, and microbiome was profiled with 16S metagenomics. FMT in GF mice was performed using samples from 3 HV in each group before CZA +/- DAV132 or at D6, thereafter mice were inoculated with MCA-205 tumor and treated with anti-PD-1, 4 times every 3 days.

Results

DAV132 did not impact plasmatic CZA concentrations, but significantly reduced ceftazidime concentration in feces compared to HV treated with CZA alone. Moreover, DAV132 significantly prevented the reduction in microbiota alpha- and beta-diversities. Mice transplanted with feces collected prior to CZA +/- DAV132 exhibited a significant reduction in tumor size when treated with anti-PD-1 antibodies. This anti-tumor response was inhibited in mice transplanted with D6 feces from any of the 3 CZA-treated HV. Conversely, the anti-tumor response was maintained in mice transplanted with D6 feces from any of the 3 HV treated with CZA + DAV132.

Conclusions

DAV132 strongly reduced CZA-induced dysbiosis in HV without effect on CZA plasmatic concentrations. In a murine model, FMT from HV treated with CZA + DAV132 was able to preserve anti-PD-1 efficacy. These results provide rationale to launch clinical trials combining DAV132 with ABX on patients amenable to ICI.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Da Volterra SA, Paris, France & University of Montreal Hospital Research Centre (CRCHUM), Montreal, Quebec, QC, Canada.

Funding

Da Volterra.

Disclosure

N. Saint-Lu: Financial Interests, Personal, Full or part-time Employment: Da Volterra. F. Sablier-Gallis: Financial Interests, Personal, Full or part-time Employment: Da Volterra; Financial Interests, Personal, Stocks/Shares: Da Volterra. S. Ferreira: Financial Interests, Personal, Full or part-time Employment: Da Volterra. C. Le Bescop: Financial Interests, Personal, Full or part-time Employment: Da Volterra; Financial Interests, Personal, Stocks/Shares: Da Volterra. C. Féger: Financial Interests, Personal, Advisory Role: Da Volterra. A. Andremont: Financial Interests, Personal, Advisory Role: Da Volterra; Financial Interests, Personal, Stocks/Shares: Da Volterra. J. de Gunzburg: Financial Interests, Personal, Stocks/Shares: Da Volterra; Financial Interests, Personal, Member of the Board of Directors: Da Volterra; Financial Interests, Personal, Advisory Role: Da Volterra. B. Routy: Financial Interests, Personal, Research Grant: Da Volterra. All other authors have declared no conflicts of interest.