TY - JOUR
T1 - A genetic vaccine encoding shared cancer neoantigens to treat tumors with microsatellite instability
AU - Leoni, Guido
AU - D'Alise, Anna Morena
AU - Cotugno, Gabriella
AU - Langone, Francesca
AU - Garzia, Irene
AU - de Lucia, Maria
AU - Fichera, Imma
AU - Vitale, Rosa
AU - Bignone, Veronica
AU - Tucci, Fabio Giovanni
AU - Mori, Federica
AU - Leuzzi, Adriano
AU - Di Matteo, Elena
AU - Troise, Fulvia
AU - Abbate, Adele
AU - Merone, Rossella
AU - Ruzza, Valentino
AU - Diodoro, Maria Grazia
AU - Yadav, Mahesh
AU - Gordon-Alonso, Monica
AU - Vanhaver, Cristophe
AU - Panigada, Maddalena
AU - Soprana, Elisa
AU - Siccardi, Antonio
AU - Folgori, Antonella
AU - Colloca, Stefano
AU - van der Bruggen, Pierre
AU - Nicosia, Alfredo
AU - Lahm, Armin
AU - Catanese, Maria Teresa
AU - Scarselli, Elisa
N1 - Funding Information:
We are grateful to Professor Riccardo Cortese, Nouscom founder and former CEO. Most of this work would not have been possible without his ideas and guidance. We thank Marina Udier, CEO of Nouscom, for critical reading of the article and helpful discussion. We acknowledge the animal facility of Plaisant in Castel Romano (Rome) for the maintenance and care of the mice used in this study.
Publisher Copyright:
© 2020 American Association for Cancer Research.
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2020/9/15
Y1 - 2020/9/15
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-20-1072
DO - 10.1158/0008-5472.CAN-20-1072
M3 - Article
C2 - 32690723
AN - SCOPUS:85096833356
VL - 80
SP - 3972
EP - 3982
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0008-5472
IS - 18
ER -