Mutated BCR-ABL generates immunogenic T-cell epitopes in CML patients

Ann Cai, Derin B. Keskin, David S. DeLuca, Anselmo Alonso, Wandi Zhang, Guang Lan Zhang, Naa Norkor Hammond, Valentina Nardi, Richard M. Stone, Donna Neuberg, John Sidney, Vladimir Brusic, Catherine J. Wu

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Abstract

Purpose: Characterization of an approach to identify leukemia neoantigens arising in the context of drug resistance. Experimental Design: We assessed whether leukemia neoantigens could be generated from drugresistant mutations in BCR-ABL after imatinib relapse in patients with chronic myelogenous leukemia (CML). Results: We computationally predicted that approximately 70 peptides derived from 26 BCR-ABL mutations would bind eight common alleles of MHC class I (IC50 < 1,000 nmol/L). Seven of nine imatinib-resistant CML patients were predicted to generate at least 1 peptide that binds autologous HLA alleles. We predicted and confirmed that an E255K mutation-derived peptide would bind HLA-A3 with high affinity (IC50 = 28 nmol/L), and showed that this peptide is endogenously processed and presented. Polyfunctional E255K-specific CD8+ T cells were detected in two imatinib-resistant HLA-A3+ CML patients concurrent with an effective anti-CML response to further therapy. Conclusions: Our in vitro studies support the hypothesis that leukemia-driven genetic alterations are targeted by the immune system in association with a clinical response, and suggest the possibility of immunizing relapsed patients with CML against newly acquired tumor neoantigens.

Original languageEnglish
Pages (from-to)5761-5772
Number of pages12
JournalClinical Cancer Research
Volume18
Issue number20
DOIs
Publication statusPublished - Oct 15 2012

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Cai, A., Keskin, D. B., DeLuca, D. S., Alonso, A., Zhang, W., Zhang, G. L., Hammond, N. N., Nardi, V., Stone, R. M., Neuberg, D., Sidney, J., Brusic, V., & Wu, C. J. (2012). Mutated BCR-ABL generates immunogenic T-cell epitopes in CML patients. Clinical Cancer Research, 18(20), 5761-5772. https://doi.org/10.1158/1078-0432.CCR-12-1182