{
  "abstract": "Background Increasing evidence suggests that gut microbiome composition modulates tumor response to therapies, including immune checkpoint inhibitors (ICI). Clinical proofs of concept were obtained in pilot studies using healthy or ICI-responder donor-derived fecal matter transfers to modulate the gut microbiome of non-responding cancer patients and improve their response to ICI. 1–3 We have developed Microbiome Ecosystem TherapiesTM (MET) replicating at large industrial scale the effects of ICI-responders gut microbiome. MaaT034, the first-in-class co-cultured microbiome product, has been selected through artificial intelligence and in vitro screening assays for optimizing intestinal homeostasis and to activate immune functions alone and in combination with an ICI treatment.Methods We used germ-free mice to evaluate MaaT034 engraftment and safety, as well as its impact on metabolite production, immunity, gut morphology as well as tumor growth inhibition in combination with anti-PD1 treatment.Results Metagenomic analysis demonstrates that MaaT034 replicates the richness, diversity and functions of native-based microbiome ecosystems. Metagenomic analysis demonstrates that MaaT034 engrafts in the gut of germ-free mice, as evidenced by the presence of the four major phyla of the human product in mice. KEGG (Kyoto Encyclopedia of Genes and Genomes) analysis revealed the presence of genes involved in the synthesis of key metabolites such as short chain fatty acids, indoles, as well as secondary biliary acids. In line, metabolite quantification in the feces of mice further confirmed the capability of MaaT034 microbes to produce these metabolites. MaaT034-treated mice displayed a reduction of the size of cecum, which translates in decreased cecal content, suggesting that MaaT034 improves food digestion. MaaT034-treated mice displayed an increase in the depth of intestinal crypts, highlighting an improvement of gut physiology compared to control germ-free mice. All mice remained healthy throughout the experiment and no adverse event was observed. MaaT034 was able to potentiate anti-PD1 mediated antitumoral activity in germ-free mice bearing MC38 tumors. RNAseq analysis of the tumors revealed key pathways modulated in response to MaaT034 as well as changes in the proportions of tumor-infiltrating immune cells.Conclusions Altogether, these findings underscore MaaT034’s potential to safely colonize the gastro-intestinal tract of mice and to produce key metabolites allowing to restore a healthy gut physiology and to stimulate immunity. MaaT034 was able to potentiate anti-PD1 mediated antitumoral activity in tumor-bearing germ-free mice. MaaT034 could offer a promising therapeutic benefit for the treatment of solid tumors in combination with ICI therapy.References Davar D, Dzutsev AK, McCulloch JA, Rodrigues RR, Chauvin JM, Morrison RM, et al. Fecal microbiota transplant overcomes resistance to anti-PD-1 therapy in melanoma patients. Science. 2021 Feb 5 2021;371(6529):595–602.Baruch EN, Youngster I, Ben-Betzalel G, Ortenberg R, Lahat A, Katz L, et al. Fecal microbiota transplant promotes response in immunotherapy-refractory melanoma patients. Science. 2021 Feb 5;371(6529):602–9.Routy B, Lenehan JG, Miller WH, Jamal R, Messaoudene M, Daisley BA, et al. Fecal microbiota transplantation plus anti-PD-1 immunotherapy in advanced melanoma: a phase I trial. Nature medicine. 2023 Aug;29(8):2121–2132.",
  "authors": [
    {
      "affiliations": [
        "MaaT Pharma, Lyon, France"
      ],
      "name": "Julie Reygner"
    },
    {
      "affiliations": [
        "MaaT Pharma, Lyon, France"
      ],
      "name": "Charlotte Petitjean"
    },
    {
      "affiliations": [
        "MaaT Pharma, Lyon, France"
      ],
      "name": "Emmanuel Prestat"
    },
    {
      "affiliations": [
        "MaaT Pharma, Lyon, France"
      ],
      "name": "Cyrielle Gasc"
    },
    {
      "affiliations": [
        "MaaT Pharma, Lyon, France"
      ],
      "name": "Aurore Duquenoy"
    },
    {
      "affiliations": [
        "MaaT Pharma, Lyon, France"
      ],
      "name": "Sophie Declomesnil"
    },
    {
      "affiliations": [
        "MaaT Pharma, Lyon, France"
      ],
      "name": "Carole Schwintner"
    },
    {
      "affiliations": [
        "MaaT Pharma, Lyon, France"
      ],
      "name": "Nathalie Corvaia"
    },
    {
      "affiliations": [
        "Snyder Institute of Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada"
      ],
      "name": "Kathy D McCoy"
    },
    {
      "affiliations": [
        "MaaT Pharma, Lyon, France"
      ],
      "name": "Bastien Laperrousaz"
    }
  ],
  "title": "1150 MaaT034, a new co-cultured microbiome ecosystem therapy candidate, potentiates anti-PD1 mediated antitumoral activity in germ-free mice",
  "uid": "14e3741e-3bce-54be-a43b-3c773b713721"
}