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

• DOI: 10.1136/jitc-2021-003821
• Publication Date: 2022-03-31T16:22:29Z
• Authors: 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-El...; Jason Greenbaum; Stephen Schoenberger; Bjoern Peters; Pandurangan Vijay...; Natalia Savelyeva; Christian Ottensm...
• Keywords: T-Lymphozyt; Lung Neoplasms; T-Lymphocytes; 610; Immungenetik; Lungenkrebs; CD8-Positive T-Lymphocytes; Mice; 03 medical and health sciences; Immunogenicity, Vaccine; Lung neoplasms; Antigens, Neoplasm; Carcinoma, Non-Small-Cell Lung; Animals; Humans; Lymphocytes; Tumor-Infiltrating; RC254-282; info:eu-repo/classification/ddc/610; Clinical/Translational Cancer Immunotherapy; Impfstoff; 0303 health sciences; Lymphocytes, Tumor-infiltrating; Vaccination; Neoplasms. Tumors. Oncology. Including cancer and carcinogens; Immunogenicity; 3. Good health; Vaccine

BackgroundCancer 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.MethodsWe 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).ResultsSequencing 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.ConclusionsOur 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.