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Clin Cancer Res. 2012 Oct 15;18(20):5761-72. doi: 10.1158/1078-0432.CCR-12-1182. Epub 2012 Aug 21.

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

Author information

1
Harvard-MIT Division of Health Sciences and Technology, Harvard Medical School, Boston, Massachusetts, USA.

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 drug-resistant 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 (IC(50) < 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 (IC(50) = 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.

PMID:
22912393
PMCID:
PMC3759991
DOI:
10.1158/1078-0432.CCR-12-1182
[Indexed for MEDLINE]
Free PMC Article

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