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Targeting the tumor mutanome for personalized vaccination in a TMB low non-small cell lung cancer

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  • Katy McCann
  • Adrian von Witzleben
  • Jaya Thomas
  • Chuan Wang
  • Oliver Wood
  • Divya Singh
  • Konstantinos Boukas
  • Kaidre Bendjama
  • Nathalie Silvestre
  • Finn Cilius Nielsen
  • Gareth Thomas
  • Tilman Sanchez-Elsner
  • Jason Greenbaum
  • Stephen Schoenberger
  • Bjoern Peters
  • Pandurangan Vijayanand
  • Natalia Savelyeva
  • Christian Ottensmeier
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BACKGROUND: Cancer is characterized by an accumulation of somatic mutations, of which a significant subset can generate cancer-specific neoepitopes that are recognized by autologous T cells. Such neoepitopes are emerging as important targets for cancer immunotherapy, including personalized cancer vaccination strategies.

METHODS: We used whole-exome and RNA sequencing analysis to identify potential neoantigens for a patient with non-small cell lung cancer. Thereafter, we assessed the autologous T-cell reactivity to the candidate neoantigens using a long peptide approach in a cultured interferon gamma ELISpot and tracked the neoantigen-specific T-cells in the tumor by T-cell receptor (TCR) sequencing. In parallel, identified gene variants were incorporated into a Modified Vaccinia Ankara-based vaccine, which was evaluated in the human leucocyte antigen A*0201 transgenic mouse model (HHD).

RESULTS: Sequencing revealed a tumor with a low mutational burden: 2219 sequence variants were identified from the primary tumor, of which 23 were expressed in the transcriptome, involving 18 gene products. We could demonstrate spontaneous T-cell responses to 5/18 (28%) mutated gene variants, and further analysis of the TCR repertoire of neoantigen-specific CD4+ and CD8+ T cells revealed TCR clonotypes that were expanded in both blood and tumor tissue. Following vaccination of HHD mice, de novo T-cell responses were generated to 4/18 (22%) mutated gene variants; T cells reactive against two variants were also evident in the autologous setting. Subsequently, we determined the major histocompatibility complex restriction of the T-cell responses and used in silico prediction tools to determine the likely neoepitopes.

CONCLUSIONS: Our study demonstrates the feasibility of efficiently identifying tumor-specific neoantigens that can be targeted by vaccination in tumors with a low mutational burden, promising successful clinical exploitation, with trials currently underway.

OriginalsprogEngelsk
Artikelnummere003821
TidsskriftJournal for ImmunoTherapy of Cancer
Vol/bind10
Udgave nummer3
ISSN2051-1426
DOI
StatusUdgivet - mar. 2022

Bibliografisk note

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.

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