Proteogenomic discovery of neoantigens facilitates personalized multi-antigen targeted T cell immunotherapy for brain tumors

Samuel Rivero-Hinojosa, Melanie Grant, Aswini Panigrahi, Huizhen Zhang, Veronika Caisova, Catherine M. Bollard and Brian R. Rood ()
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Samuel Rivero-Hinojosa: Children’s National Research Institute
Melanie Grant: Children’s National Research Institute
Aswini Panigrahi: Children’s National Research Institute
Huizhen Zhang: Children’s National Research Institute
Veronika Caisova: Children’s National Research Institute
Catherine M. Bollard: Children’s National Research Institute
Brian R. Rood: Children’s National Research Institute

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract Neoantigen discovery in pediatric brain tumors is hampered by their low mutational burden and scant tissue availability. Here we develop a proteogenomic approach combining tumor DNA/RNA sequencing and mass spectrometry proteomics to identify tumor-restricted (neoantigen) peptides arising from multiple genomic aberrations to generate a highly target-specific, autologous, personalized T cell immunotherapy. Our data indicate that aberrant splice junctions are the primary source of neoantigens in medulloblastoma, a common pediatric brain tumor. Proteogenomically identified tumor-specific peptides are immunogenic and generate MHC II-based T cell responses. Moreover, polyclonal and polyfunctional T cells specific for tumor-specific peptides effectively eliminate tumor cells in vitro. Targeting tumor-specific antigens obviates the issue of central immune tolerance while potentially providing a safety margin favoring combination with other immune-activating therapies. These findings demonstrate the proteogenomic discovery of immunogenic tumor-specific peptides and lay the groundwork for personalized targeted T cell therapies for children with brain tumors.

Date: 2021
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DOI: 10.1038/s41467-021-26936-y

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