{
  "abstract": "Background Lynch syndrome (LS) is among the most common hereditary cancer predisposition syndromes and is caused by a heterozygous germline pathogenic variant in one of the DNA mismatch repair (MMR) genes. Loss of function of an MMR protein leads to the accumulation of mutations, insertions and deletions within microsatellite (MS) sequences, a phenomenon known as microsatellite instability (MSI). LS is characterized by the development of MSI-high tumors that express shared neoantigens, thereby offering promising targets for precision immunotherapy. NOUS-209 is a genetic vaccine encoding 209 neoantigens shared across sporadic and hereditary MSI tumors developed for interception and treatment of MSI tumors. 1 Methods In this study, we investigated the presence and dynamics of NOUS-209 target frameshift mutations (FSMs) in both primary and metachronous LS-associated cancers. Whole-exome sequencing was performed on 73 tumors, including 58 colorectal cancers (CRC) and 15 urothelial cancers (UC), from 58 LS individuals.Results A median of 57 in CRCs and 24 FSMs in UCs was found, with similar FSM burden in both primary and metachronous tumors. Analysis of nine matched primary-metachronous tumor pairs revealed evidence of immune editing, with FSMs predicted to generate highly immunogenic neoepitopes preferentially lost in metachronous tumors, whereas those with lower predicted immunogenicity were retained. Notably, all subsequent primary tumors acquired novel FSMs encoding neoantigens with strong predicted HLA binding affinity, reinforcing the rationale for NOUS-209-mediated immune interception. Analysis of B2M revealed loss in a subset of tumors, more frequently observed in advanced tumors than in early ones, suggesting that B2M loss is a late event and that vaccination at early stage before such escape mechanism are established might ensure optimal effectiveness.Conclusions Our results demonstrate the presence of NOUS-209 FSMs in both CRCs and UCs in LS, highlighting the broader therapeutic applicability beyond colorectal cancer. Furthermore, the emergence of new targetable FSMs in metachronous tumors supports the potential of NOUS-209 immunotherapy as a preventive strategy for both primary and recurrent LS-associated malignancies.Reference Leoni G, D’Alise AM, Cotugno G, Langone F, Garzia I, De Lucia M, Fichera I, Vitale R, Bignone V, Tucci FG, Mori F, Leuzzi A, Di Matteo E, Troise F, Abbate A, Merone R, Ruzza V, Diodoro MG, Yadav M, Gordon-Alonso M, Vanhaver C, Panigada M, Soprana E, Siccardi A, Folgori A, Colloca S, van der Bruggen P, Nicosia A, Lahm A, Catanese MT, Scarselli E. A genetic vaccine encoding shared cancer neoantigens to treat tumors with microsatellite instability. Cancer Res. 2020 Sep 15;80(18):3972–3982. doi: 10.1158/0008-5472.CAN-20-1072. Epub 2020 Jul 20. PMID: 32690723.",
  "authors": [
    {
      "affiliations": [
        "Nouscom srl, Rome, Italy"
      ],
      "name": "Anna Morena D’Alise"
    },
    {
      "affiliations": [
        "Nouscom srl, Rome, Italy"
      ],
      "name": "Lorenzo De Marco"
    },
    {
      "affiliations": [
        "Nouscom srl, Rome, Italy"
      ],
      "name": "Elisa Micarelli"
    },
    {
      "affiliations": [
        "Tampere University, Tampere, Finland",
        "Vaasa Central Hospital, Vaasa, Finland",
        "Tampere University Hospital, Tampere, Finland"
      ],
      "name": "Joni Panula"
    },
    {
      "affiliations": [
        "Tampere University, Tampere, Finland",
        "Tampere University Hospital, Tampere, Finland"
      ],
      "name": "Jussi Nikkola"
    },
    {
      "affiliations": [
        "Hospital Nova of Central Finland, Jyväskylä, Finland"
      ],
      "name": "Lauri Moilanen"
    },
    {
      "affiliations": [
        "Tampere University, Tampere, Finland"
      ],
      "name": "Matti Annala"
    },
    {
      "affiliations": [
        "Hospital Nova of Central Finland, Jyväskylä, Finland"
      ],
      "name": "Jouni Härkönen"
    },
    {
      "affiliations": [
        "Tampere University, Tampere, Finland"
      ],
      "name": "Kalle E Hokkanen"
    },
    {
      "affiliations": [
        "University of Helsinki, Helsinki, Finland"
      ],
      "name": "Kirsi Pylvänäinen"
    },
    {
      "affiliations": [
        "University of Helsinki, Helsinki, Finland",
        "Central Finland Hospital Nova, Wellbeing Services County of Central Finland, Jyväskylä, Finland"
      ],
      "name": "Päivi Peltomäki"
    },
    {
      "affiliations": [
        "Helsinki University Hospital, Helsinki, Finland"
      ],
      "name": "Maarit Ahtiainen"
    },
    {
      "affiliations": [
        "Hospital Nova of Central Finland, Jyväskylä, Finland"
      ],
      "name": "Jan Böhm"
    },
    {
      "affiliations": [
        "Central Finland Biobank, Jyväskylä, Finland",
        "Well Being Services County of Central-Finland, Jyväskylä, Finland"
      ],
      "name": "Jukka-Pekka Mecklin"
    },
    {
      "affiliations": [
        "Nouscom srl, Rome, Italy"
      ],
      "name": "Elisa Scarselli"
    },
    {
      "affiliations": [
        "Tampere University, Tampere, Finland",
        "Tampere University Hospital, Tampere, Finland",
        "University of Jyväskylä, Jyväskylä, Finland",
        "Tampere University Hospital, Wellbeing Services County of Pirkanmaa, Tampere, Finland"
      ],
      "name": "Toni T Seppälä"
    }
  ],
  "title": "118 NOUS-209 off-the-shelf immunotherapy enables broad targeting of primary and metachronous tumors in Lynch Syndrome",
  "uid": "c1621f17-8605-535a-a61e-6c0c7b2f1f88"
}