title: Low Mutation Burden in Ovarian Cancer May Limit the Utility of Neoantigen-Targeted Vaccines.
abstract: Due to advances in sequencing technology, somatically mutated cancer antigens, or neoantigens, are now readily identifiable and have become compelling targets for immunotherapy. In particular, neoantigen-targeted vaccines have shown promise in several pre-clinical and clinical studies. However, to date, neoantigen-targeted vaccine studies have involved tumors with exceptionally high mutation burdens. It remains unclear whether neoantigen-targeted vaccines will be broadly applicable to cancers with intermediate to low mutation burdens, such as ovarian cancer. To address this, we assessed whether a derivative of the murine ovarian tumor model ID8 could be targeted with neoantigen vaccines. We performed whole exome and transcriptome sequencing on ID8-G7 cells. We identified 92 somatic mutations, 39 of which were transcribed, missense mutations. For the 17 top predicted MHC class I binding mutations, we immunized mice subcutaneously with synthetic long peptide vaccines encoding the relevant mutation. Seven of 17 vaccines induced robust mutation-specific CD4 and/or CD8 T cell responses. However, none of the vaccines prolonged survival of tumor-bearing mice in either the prophylactic or therapeutic setting. Moreover, none of the neoantigen-specific T cell lines recognized ID8-G7 tumor cells in vitro, indicating that the corresponding mutations did not give rise to bonafide MHC-presented epitopes. Additionally, bioinformatic analysis of The Cancer Genome Atlas data revealed that only 12% (26/220) of HGSC cases had a ≥90% likelihood of harboring at least one authentic, naturally processed and presented neoantigen versus 51% (80/158) of lung cancers. Our findings highlight the limitations of applying neoantigen-targeted vaccines to tumor types with intermediate/low mutation burdens.
authors.affiliation: Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency, Victoria, Canada.|Interdisciplinary Oncology Program, University of British Columbia, Vancouver, Canada.|Michael Smith's Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, Canada.
authors.forename: Spencer D
authors.identifier: 0000-0001-5914-0305
authors.initials: SD
authors.lastname: Martin
authors.affiliation: Michael Smith's Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, Canada.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Brown
authors.affiliation: Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency, Victoria, Canada.
authors.forename: Darin A
authors.initials: DA
authors.lastname: Wick
authors.affiliation: Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency, Victoria, Canada.
authors.forename: Julie S
authors.initials: JS
authors.lastname: Nielsen
authors.affiliation: Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency, Victoria, Canada.
authors.forename: David R
authors.initials: DR
authors.lastname: Kroeger
authors.affiliation: Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency, Victoria, Canada.
authors.forename: Kwame
authors.initials: K
authors.lastname: Twumasi-Boateng
authors.affiliation: Michael Smith's Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, Canada.|Molecular Biology and Biochemistry, Simon Fraser University, Vancouver, Canada.|Department of Medical Genetics, University of British Columbia, Vancouver, Canada.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Holt
authors.affiliation: Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency, Victoria, Canada.|Department of Medical Genetics, University of British Columbia, Vancouver, Canada.|Department of Microbiology and Biochemistry, University of Victoria, Victoria, Canada.
authors.forename: Brad H
authors.initials: BH
authors.lastname: Nelson
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D000939:Epitopes / Q000235:genetics / Q000276:immunology; D005260:Female; D007167:Immunotherapy; D008285:Major Histocompatibility Complex; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D000067552:Mutation Accumulation; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000276:immunology / Q000628:therapy
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D000939:Epitopes