Blood Journal
Leading the way in experimental and clinical research in hematology

Systematic identification of personal tumor-specific neoantigens in chronic lymphocytic leukemia

  1. Mohini Rajasagi1,2,
  2. Sachet A. Shukla1,3,
  3. Edward F. Fritsch1,3,
  4. Derin B. Keskin1,2,
  5. David DeLuca1,3,
  6. Ellese Carmona4,
  7. Wandi Zhang1,2,
  8. Carrie Sougnez3,
  9. Kristian Cibulskis3,
  10. John Sidney5,
  11. Kristen Stevenson6,
  12. Jerome Ritz1,2,7,
  13. Donna Neuberg6,
  14. Vladimir Brusic1,
  15. Stacey Gabriel3,
  16. Eric S. Lander3,
  17. Gad Getz3,8,
  18. Nir Hacohen3,9, and
  19. Catherine J. Wu1,2,7
  1. 1Cancer Vaccine Center and
  2. 2Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
  3. 3Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA;
  4. 4Division of Medical Sciences: Biological and Biomedical Sciences, Harvard Medical School, Boston, MA;
  5. 5La Jolla Institute for Allergy and Immunology, La Jolla, CA;
  6. 6Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA;
  7. 7Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA;
  8. 8Massachusetts General Hospital Cancer Center and Department of Pathology, Massachusetts General Hospital, Boston, MA; and
  9. 9The Division of Allergy, Immunology, and Rheumatology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA

Key Points

  • Tumor neoantigens are a promising class of immunogens based on exquisite tumor specificity and the lack of central tolerance against them.

  • Massively parallel DNA sequencing with class I prediction enables systematic identification of tumor neoepitopes (including from CLL).

Abstract

Genome sequencing has revealed a large number of shared and personal somatic mutations across human cancers. In principle, any genetic alteration affecting a protein-coding region has the potential to generate mutated peptides that are presented by surface HLA class I proteins that might be recognized by cytotoxic T cells. To test this possibility, we implemented a streamlined approach for the prediction and validation of such neoantigens derived from individual tumors and presented by patient-specific HLA alleles. We applied our computational pipeline to 91 chronic lymphocytic leukemias (CLLs) that underwent whole-exome sequencing (WES). We predicted ∼22 mutated HLA-binding peptides per leukemia (derived from ∼16 missense mutations) and experimentally confirmed HLA binding for ∼55% of such peptides. Two CLL patients that achieved long-term remission following allogeneic hematopoietic stem cell transplantation were monitored for CD8+ T-cell responses against predicted or confirmed HLA-binding peptides. Long-lived cytotoxic T-cell responses were detected against peptides generated from personal tumor mutations in ALMS1, C6ORF89, and FNDC3B presented on tumor cells. Finally, we applied our computational pipeline to WES data (N = 2488 samples) across 13 different cancer types and estimated dozens to thousands of predicted neoantigens per individual tumor, suggesting that neoantigens are frequent in most tumors.

  • Submitted April 8, 2014.
  • Accepted May 22, 2014.
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