title: Exome Sequencing to Predict Neoantigens in Melanoma.
abstract: The ability to use circulating peripheral blood cells and matched tumor sequencing data as a basis for neoantigen prediction has exciting possibilities for application in the personalized treatment of cancer patients. We have used a high-throughput screening approach, combining whole-exome sequence data, mRNA microarrays, and publicly available epitope prediction algorithm output to identify mutated proteins processed and displayed by patient tumors and recognized by circulating immune cells. Matched autologous melanoma cell lines and peripheral blood mononuclear cells were used to create mixed lymphocyte tumor cell cultures, resulting in an expansion of tumor-reactive T cells to use for mutated peptide screening. Five patients were investigated, three of whom had a durable complete response (CR; 15+ years) in an autologous melanoma-pulsed dendritic cell clinical trial. We identified seven mutated antigens in total that stimulated T-effector memory cells in two of the five patients. While the procedure did not result in clinically applicable neoantigens for all patients, those identified were likely important in tumor clearance, leading to durable CR. The nature of the screening process allows results to be obtained rapidly and is easily applicable to a wide variety of different tumor types.
authors.affiliation: Oncogenomics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. Antonia.Pritchard@qimrberghofer.edu.au.
authors.forename: Antonia L
authors.initials: AL
authors.lastname: Pritchard
authors.affiliation: Molecular Vaccinology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors.forename: Julie G
authors.initials: JG
authors.lastname: Burel
authors.affiliation: Cancer Immunotherapy, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Neller
authors.affiliation: Oncogenomics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors.forename: Nicholas K
authors.initials: NK
authors.lastname: Hayward
authors.affiliation: Cancer Immunotherapy, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. School of Natural Sciences, Griffith University, Brisbane, Queensland, Australia.
authors.forename: J Alejandro
authors.initials: JA
authors.lastname: Lopez
authors.affiliation: Third Medical Clinic (Hematology/Oncology/Pneumology), University Medical Center, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Fatho
authors.affiliation: Third Medical Clinic (Hematology/Oncology/Pneumology), University Medical Center, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Lennerz
authors.affiliation: Third Medical Clinic (Hematology/Oncology/Pneumology), University Medical Center, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wölfel
authors.affiliation: Cancer Immunotherapy, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Schmidt
mesh_terms: D000951:Antigens, Neoplasm / Q000235:genetics* / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D059472:Exome / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008545:Melanoma / Q000235:genetics* / Q000276:immunology*; D009154:Mutation
chemical_list: D000951:Antigens, Neoplasm; D018984:Epitopes, T-Lymphocyte; D007371:Interferon-gamma