{
  "abstract": "Background Immune checkpoint inhibitors (ICI) have transformed cancer therapy but are frequently complicated by immune-related adverse events (irAEs), particularly immune-related diarrhea or colitis (irColitis), which can necessitate immunosuppression and ICI discontinuation. Fecal microbiota transplantation (FMT) has shown promise in treating irColitis, but concerns around donor variability, infection risk, and scalability limit the utility and scalability of FMT. KAN-004 is a defined live biotherapeutic product (LBP) composed of >100 commensal strains, rationally selected from FMT-qualified healthy human donors to restore gut microbial composition, metabolic function, and microbiome-immune balance in patients with irColitis.Methods Preclinical studies evaluated the impact of KAN-004 in two murine models of antibiotics-induced dysbiosis, and an acute dextran sodium sulfate (DSS)-induced colitis model. Further, the impact of KAN-004 as a co-treatment concurrent with anti-PD-1 therapy was investigated in two tumor models (MCA-205 in germ-free mice and E0771 in SPF mice). Endpoints included microbial engraftment, metabolite recovery, histopathologic scoring, clinical colitis indices, tumor response and flow cytometry.Results In murine models oral supplementation of KAN-004 achieved rapid, durable engraftment with strain detection by day 2 and sustained levels through day 60. While targeted Short Chain Fatty Acids (SCFAs) were undetectable at baseline following antibiotic pre-treatment, KAN-004 restored a naïve-like SCFA profile by day 9, unlike the delayed and imbalanced recovery seen with vehicle. In an DSS colitis model, KAN-004 significantly improved survival (80% vs. 10%, p = 0.0027), reduced clinical severity (p = 0.002), and preserved epithelial barrier integrity. When combined with anti-PD-1 therapy in an MCA-205 tumor model, KAN-004 enhanced anti-PD-1 efficacy compared to FMT from ICI responder donors (p = 0.008). In an E0771 ICI resistant tumor model, combination anti-PD-1 and KAN-004 treatment showed a trend for decrease in tumor size compared to isotype control (p = 0.055), with increased tumor infiltration of CD8+ effector T cells compared to FMT from ICI responder donors (p = 0.02).Conclusions KAN-004 demonstrates preclinical efficacy in resolving irColitis and enhancing antitumor immunity in various models. Novel method developments by Kanvas Biosciences provide precise strain-level composition for assessing microbial kinetics and GMP manufacturing. In collaboration with the Centre Hospitalier de l’Université de Montréal (CHUM), a phase I clinical trial of KAN-004 in patients with irColitis is planned to begin in Q4 2025.",
  "authors": [
    {
      "affiliations": [
        "Kanvas Biosciences, South San Francisco, CA, USA"
      ],
      "name": "James Berleman"
    },
    {
      "affiliations": [
        "Kanvas Biosciences, South San Francisco, CA, USA"
      ],
      "name": "Lee R Swem"
    },
    {
      "affiliations": [
        "Kanvas Biosciences, South San Francisco, CA, USA"
      ],
      "name": "Kyle Jacoby"
    },
    {
      "affiliations": [
        "Kanvas Biosciences, Monmouth Junction, NJ, USA"
      ],
      "name": "Peter Diebold"
    },
    {
      "affiliations": [
        "Kanvas Biosciences, South San Francisco, CA, USA"
      ],
      "name": "Keiramarie Robertson"
    },
    {
      "affiliations": [
        "Kanvas Biosciences, South San Francisco, CA, USA"
      ],
      "name": "Aditya Bhalla"
    },
    {
      "affiliations": [
        "Kanvas Biosciences, South San Francisco, CA, USA"
      ],
      "name": "Jackson Mintz"
    },
    {
      "affiliations": [
        "Kanvas Biosciences, South San Francisco, CA, USA"
      ],
      "name": "Pallavi Murugkar"
    },
    {
      "affiliations": [
        "Kanvas Biosciences, Monmouth Junction, NJ, USA"
      ],
      "name": "Hannah Bronson"
    },
    {
      "affiliations": [
        "CRCHUM, Montreal, QC, Canada"
      ],
      "name": "Meriem Messaoudene"
    },
    {
      "affiliations": [
        "CRCHUM, Montreal, QC, Canada"
      ],
      "name": "Anna Perez"
    },
    {
      "affiliations": [
        "CRCHUM, Montreal, QC, Canada"
      ],
      "name": "Wiam Belkaid"
    },
    {
      "affiliations": [
        "Kanvas Biosciences, South San Francisco, CA, USA"
      ],
      "name": "Marguerite Prior"
    },
    {
      "affiliations": [
        "Kanvas Biosciences, South San Francisco, CA, USA"
      ],
      "name": "Philip Burnham"
    },
    {
      "affiliations": [
        "Kanvas Biosciences, Monmouth Junction, NJ, USA"
      ],
      "name": "Hao Shi"
    },
    {
      "affiliations": [
        "Weinberg Consulting, Chicago, IL, USA"
      ],
      "name": "Mark Weinberg"
    },
    {
      "affiliations": [
        "University of Montreal (CHUM), Montréal, QC, Canada"
      ],
      "name": "Bertrand Routy"
    },
    {
      "affiliations": [
        "CRCHUM, Montreal, QC, Canada"
      ],
      "name": "Arielle Elkrief"
    },
    {
      "affiliations": [
        "Kanvas Biosciences, Monmouth Junction, NJ, USA"
      ],
      "name": "Matthew P Cheng"
    }
  ],
  "title": "1036 KAN-004, a metabolically complete live biotherapeutic product for the treatment of immune-related colitis",
  "uid": "cca9cd57-7957-5487-974b-df3a56b81ead"
}