{
  "abstract": "Background Cancer interception is a preventive strategy aimed at lowering cancer incidence by targeting premalignant lesions. Lynch syndrome (LS), one of the most prevalent hereditary cancer syndromes, is caused by germline mutations in DNA mismatch repair (MMR) genes. Deficiency in MMR results in microsatellite instability (MSI) and accumulation of frameshift peptide (FSP) neoantigens, commonly shared across MSI tumors and precancerous lesions. Nous-209 is an off-the-shelf immunotherapy using Great Ape Adenoviral (GAd) and Modified Vaccinia Ankara (MVA) encoding 209 FSP shared in MSI tumors. Here, we present the final Phase Ib/II trial results in LS carriers (N=45) including evaluation of a primary vaccination and revaccination at 1 year, reporting safety, immunogenicity, and initial signals of clinical activity.Methods The study enrolled two cohorts: Cohort 1 (initial vaccination) received a prime-boost GAd and MVA-209-FSPs (weeks 0 and 8). Cohort 2 included a subset of eligible participants from Cohort 1 randomized to receive either GAd20-209-FSPs at wk 52 followed by MVA-209-FSPs at wk 60 (Arm A), or MVA-209-FSPs at wk 52 (Arm B), to establish the optimal revaccination regimen. Immunogenicity was evaluated by ex-vivo IFN-γ ELISpot. Pts underwent screening lower endoscopy at baseline and wk 52/68.Results 45 LS carriers received GAd20-209-FSPs and MVA-209-FSPs. The majority harbored pathogenic germline variants in MSH2 (47%). 42% (19/45) were cancer survivors. Both the first cycle of vaccination and revaccination were well tolerated, with no serious adverse events attributed to the vaccine and no unexpected high grade reactogenicity. The most common treatment-related AEs included systemic reactogenicity symptoms and local injection site reaction. Neoantigen-specific immune responses were detected in 100% of participants (Cohort 1) following vaccination (N=37), with a mean peak magnitude of ~1,100 IFN-γ spot-forming cells per million PBMCs and polytopic responses. Tumor-specific T cells were detected up to 1 year in over 80% of participants, with effector memory phenotype and demonstration of cytolytic function ex-vivo. Revaccination at 1 year effectively boosted the immune response, with the greatest increase in T cell response observed in the Arm B. At the yearly colonoscopy following vaccination, the frequency of participants with ≥1 adenoma detected was ~28%, similar to baseline. Advanced adenomas were detected in 4.65% of patients at baseline, but none post Nous-209.Conclusions This trial demonstrates that annual revaccination with Nous-209 is safe, and effectively boosts neoantigen-specific T cell responses, supporting the importance of annual revaccination in the future clinical development of NOUS-209 for cancer interception in LS.Acknowledgements The authors acknowledge DMACC for its coordinating and support functions (U24CA242637). Support: NCI/NIH UG1CA242609, NouscomTrial Registration Clinical trial information: NCT05078866.",
  "authors": [
    {
      "affiliations": [
        "Nouscom SRL, Rome, Italy"
      ],
      "name": "Anna Morena D’Alise"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Jason Willis"
    },
    {
      "affiliations": [
        "Fox Chase Cancer Center, Philadelphia, PA, USA"
      ],
      "name": "Michael Hall"
    },
    {
      "affiliations": [
        "University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico"
      ],
      "name": "Marcia Cruz-Correa"
    },
    {
      "affiliations": [
        "City of Hope Comprehensive Cancer Center, Duarte, CA, USA"
      ],
      "name": "Gregory E Idos"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Selvi Thirumurthi"
    },
    {
      "affiliations": [
        "University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico"
      ],
      "name": "Veroushka Ballester"
    },
    {
      "affiliations": [
        "Nouscom SRL, Rome, Italy"
      ],
      "name": "Guido Leoni"
    },
    {
      "affiliations": [
        "Nouscom SRL, Rome, Italy"
      ],
      "name": "Irene Garzia"
    },
    {
      "affiliations": [
        "Nouscom SRL, Rome, Italy"
      ],
      "name": "Laura Antonucci"
    },
    {
      "affiliations": [
        "Nouscom SRL, Rome, Italy"
      ],
      "name": "Lorenzo De Marco"
    },
    {
      "affiliations": [
        "Nouscom SRL, Rome, Italy"
      ],
      "name": "Elisa Micarelli"
    },
    {
      "affiliations": [
        "Nouscom AG, Basel, Switzerland"
      ],
      "name": "Sven Gogov"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Wenli Dong"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "J Jack Lee"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Lana A Vornik"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Araceli Garcia-Gonzalez"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Laura Reyes Uribe"
    },
    {
      "affiliations": [
        "Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA"
      ],
      "name": "Ellen Richmond"
    },
    {
      "affiliations": [
        "Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA"
      ],
      "name": "Asad Umar"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Powel Brown"
    },
    {
      "affiliations": [
        "Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA"
      ],
      "name": "Luz Maria Rodriguez"
    },
    {
      "affiliations": [
        "Nouscom SRL, Rome, Italy"
      ],
      "name": "Elisa Scarselli"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Eduardo Vilar"
    }
  ],
  "title": "1336 Final Ph1b/2 results for nous-209 monotherapy in lynch syndrome carriers: annual revaccination boosts T cell immunity informing future cancer interception strategies",
  "uid": "e6f4fe33-9f67-55d3-b1bd-bbd085670368"
}