DAV132 colon-targeted adsorbent prevents antibiotic-related dysbiosis in human volunteers and mitigates anti-PD-1 resistance in murine models
The deleterious impact of antibiotics (ATB) on the microbiome negatively impacts immune checkpoint inhibitor (ICI) response. We assessed the efficacy of DAV132, a colon-targeted adsorbent in 70 healthy volunteers (HV) randomized to receive ceftazidime-avibactam or piperacillin-tazobactam alone or in combination with oral administration of DAV132. DAV132 significantly decreased fecal but not plasma ATB concentration. When coadministered with either ATB, DAV132 prevented loss of microbiome diversity and induced rapid recovery of the baseline microbiota composition. Moreover, bacterial probe set qPCR-based assay confirmed metagenomics results that DAV132 preserved several commensals such as Alistipes shahii, Blautia obeum and Faecalibacterium praunsnitzii. Fecal microbiota transplantation in murine tumor models from HV treated with ATB alone reduced antitumor responses to anti-PD-1, while transplanted samples from HV treated with ATB+DAV132 circumvented resistance to anti-PD-1. This anti-tumor response in mice was associated with tumor microenvironment increased the ratio of total CD8+ T cells/ regulatory T cells, and three distinct activated CD8+ T cell population whiting the tumor within the tumor, as well as gene expression of interferon gamma (INF?) in the mesenteric lymph nodes. In addition, a unique gene signature with downregulation of IL-6 and reactive oxygen pathways was found in the mice treated with FMT from ATB+DAV132 sample and treated with anti-PD-1. DAV132 represents a new strategy for overcoming ATB-related dysbiosis and further studies are warranted to evaluate its efficacy in cancer patients on ICI. Overall design: 2 weeks after FMT with HV stools treated with CZA or CZA+DAV132 for 6 days, C57Bl6 mice were implanted subcutaneously with 0.8 × 10^6 MCA-205 cells. When tumors reached 25 to 35 mm2 in size, mice were treated four times intraperitoneally every three days with aPD-1 mAb (250 µg/mouse; clone RMP1-14, Bio X Cell) or isotype control (clone 2A3, Bio X Cell). The mice were sacrificed 2 days after the last treatment and the tumor were harvested and snap frozen for a tumor bulk RNAseq analysis for gene expression analysis. A duplicate of this experiemnst was performed with the same setting and using the same FMT samples, the tumor were also harvested at the sacrifice and the CD8+ T cells were cell sorted and immediately snap frozen for a specific analysis of the gene expression of this cell population.