A genetic vaccine encoding shared cancer neoantigens to treat tumors with microsatellite instability

Guido Leoni, Anna Morena D'Alise, Gabriella Cotugno, Francesca Langone, Irene Garzia, Maria de Lucia, Imma Fichera, Rosa Vitale, Veronica Bignone, Fabio Giovanni Tucci, Federica Mori, Adriano Leuzzi, Elena Di Matteo, Fulvia Troise, Adele Abbate, Rossella Merone, Valentino Ruzza, Maria Grazia Diodoro, Mahesh Yadav, Monica Gordon-AlonsoCristophe Vanhaver, Maddalena Panigada, Elisa Soprana, Antonio Siccardi, Antonella Folgori, Stefano Colloca, Pierre van der Bruggen, Alfredo Nicosia, Armin Lahm, Maria Teresa Catanese, Elisa Scarselli

Research output: Contribution to journalArticlepeer-review

Abstract

Tumors with microsatellite instability (MSI) are caused by a defective DNA mismatch repair system that leads to the accumulation of mutations within microsatellite regions. Indels in microsatellites of coding genes can result in the synthesis of frameshift peptides (FSP). FSPs are tumor-specific neoantigens shared across patients with MSI. In this study, we developed a neoantigen-based vaccine for the treatment of MSI tumors. Genetic sequences from 320 MSI tumor biopsies and matched healthy tissues in The Cancer Genome Atlas database were analyzed to select shared FSPs. Two hundred nine FSPs were selected and cloned into nonhuman Great Ape Adenoviral and Modified Vaccinia Ankara vectors to generate a viral-vectored vaccine, referred to as Nous-209. Sequencing tumor biopsies of 20 independent patients with MSI colorectal cancer revealed that a median number of 31 FSPs out of the 209 encoded by the vaccine was detected both in DNA and mRNA extracted from each tumor biopsy. A relevant number of peptides encoded by the vaccine were predicted to bind patient HLA haplotypes. Vaccine immunogenicity was demonstrated in mice with potent and broad induction of FSP-specific CD8 and CD4 T-cell responses. Moreover, a vaccine-encoded FSP was processed in vitro by human antigen-presenting cells and was subsequently able to activate human CD8 T cells. Nous-209 is an “off-the-shelf” cancer vaccine encoding many neoantigens shared across sporadic and hereditary MSI tumors. These results indicate that Nous-209 can induce the optimal breadth of immune responses that might achieve clinical benefit to treat and prevent MSI tumors.

Original languageEnglish
Pages (from-to)3972-3982
Number of pages11
JournalCancer Research
Volume80
Issue number18
DOIs
Publication statusPublished - Sep 15 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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