Low Mutation Burden in Ovarian Cancer May Limit the Utility of Neoantigen-Targeted Vaccines

• Published in: PloS one Vol. 11; no. 5; p. e0155189
• Main Authors: Martin, Spencer D, Brown, Scott D, Wick, Darin A, Nielsen, Julie S, Kroeger, David R, Twumasi-Boateng, Kwame, Holt, Robert A, Nelson, Brad H
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 18.05.2016; Public Library of Science (PLoS)
• Subjects: Analysis; Animals; Antigens; Antigens, Neoplasm - immunology; Biochemistry; Biology and Life Sciences; Cancer; Cancer Vaccines - immunology; Cancer Vaccines - therapeutic use; Care and treatment; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; Cell Line, Tumor; Cell survival; Cytotoxicity; Epitopes; Epitopes - genetics; Epitopes - immunology; Female; Gene expression; Gene mutation; Genomes; Health aspects; Immunization; Immunotherapy; Lungs; Lymphocytes; Lymphocytes T; Major Histocompatibility Complex; Medicine and Health Sciences; Melanoma; Mice; Mice, Inbred C57BL; Missense mutation; Mutation; Mutation Accumulation; Neoantigens; Ovarian cancer; Ovarian carcinoma; Ovarian Neoplasms - genetics; Ovarian Neoplasms - immunology; Ovarian Neoplasms - therapy; Patients; Peptides; Proteins; Research and Analysis Methods; Risk factors; Studies; Tumor antigens; Tumor cell lines; Tumor cells; Tumors; Vaccines; British Columbia Canada; Canada
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0155189

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.