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Targeting the tumor mutanome for personalized vaccination in a TMB low non-small cell lung cancer
- Source :
- McCann , K , Von Witzleben , A , Thomas , J , Wang , C , Wood , O , Singh , D , Boukas , K , Bendjama , K , Silvestre , N , Nielsen , F C , Thomas , G , Sanchez-Elsner , T , Greenbaum , J , Schoenberger , S , Peters , B , Vijayanand , P , Savelyeva , N & Ottensmeier , C 2022 , ' Targeting the tumor mutanome for personalized vaccination in a TMB low non-small cell lung cancer ' , Journal for ImmunoTherapy of Cancer , vol. 10 , no. 3 , e003821 .
- Publication Year :
- 2022
-
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.
Details
- Database :
- OAIster
- Journal :
- McCann , K , Von Witzleben , A , Thomas , J , Wang , C , Wood , O , Singh , D , Boukas , K , Bendjama , K , Silvestre , N , Nielsen , F C , Thomas , G , Sanchez-Elsner , T , Greenbaum , J , Schoenberger , S , Peters , B , Vijayanand , P , Savelyeva , N & Ottensmeier , C 2022 , ' Targeting the tumor mutanome for personalized vaccination in a TMB low non-small cell lung cancer ' , Journal for ImmunoTherapy of Cancer , vol. 10 , no. 3 , e003821 .
- Notes :
- application/pdf, English
- Publication Type :
- Electronic Resource
- Accession number :
- edsoai.on1372660980
- Document Type :
- Electronic Resource