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

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 va...

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Detalles Bibliográficos
Autores principales: McCann, Katy, von Witzleben, Adrian, Thomas, Jaya, Wang, Chuan, Wood, Oliver, Singh, Divya, Boukas, Konstantinos, Bendjama, Kaidre, Silvestre, Nathalie, Nielsen, Finn Cilius, Thomas, Gareth, Sanchez-Elsner, Tilman, Greenbaum, Jason, Schoenberger, Stephen, Peters, Bjoern, Vijayanand, Pandurangan, Savelyeva, Natalia, Ottensmeier, Christian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8971766/
https://www.ncbi.nlm.nih.gov/pubmed/35361728
http://dx.doi.org/10.1136/jitc-2021-003821
Descripción
Sumario: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.