Targeting the tumor mutanome for personalized vaccination in a TMB low non-small cell lung cancer. Issue 3 (31st March 2022)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: Journal for immunotherapy of cancer. Volume 10:Issue 3(2022)
• Publication Date: 2022-03-31
• Subjects: Immunogenicity, Vaccine -- Lung Neoplasms -- Lymphocytes, Tumor-Infiltrating -- T-Lymphocytes; Cancer -- Immunotherapy -- Periodicals; Cancer -- Immunological aspects -- Periodicals; Tumors -- Immunological aspects -- Periodicals; Immunotherapy -- Periodicals; 616.99406105
• DOI: 10.1136/jitc-2021-003821
• Languages: English
• ISSNs: 2051-1426

Abstract

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.