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

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

Abstract

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.

Original languageEnglish
Article numbere003821
JournalJournal for ImmunoTherapy of Cancer
Volume10
Issue number3
ISSN2051-1426
DOIs
Publication statusPublished - Mar 2022

Keywords

  • Animals
  • Antigens, Neoplasm/genetics
  • CD8-Positive T-Lymphocytes
  • Carcinoma, Non-Small-Cell Lung/genetics
  • Humans
  • Lung Neoplasms/genetics
  • Mice
  • Vaccination

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