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



McCann, Katy, von Witzleben, Adrian, Thomas, Jaya, Wang, Chuan, Wood, Oliver, Singh, Divya, Boukas, Konstantinos, Bendjama, Kaidre, Silvestre, Nathalie, Nielsen, Finn Cilius
et al (show 8 more authors) (2022) Targeting the tumor mutanome for personalized vaccination in a TMB low non-small cell lung cancer. Journal for immunotherapy of cancer, 10 (3).

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Abstract

<h4>Background</h4>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.<h4>Methods</h4>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).<h4>Results</h4>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<sup>+</sup> and CD8<sup>+</sup> 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.<h4>Conclusions</h4>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.

Item Type: Article
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User: Symplectic Admin
Date Deposited: 19 Apr 2022 10:06
Last Modified: 15 Sep 2022 07:14
DOI: 10.1136/jitc-2021-003821
URI: https://livrepository.liverpool.ac.uk/id/eprint/3153209