期刊
CLINICAL CANCER RESEARCH
卷 18, 期 20, 页码 5761-5772出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-12-1182
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资金
- Howard Hughes Medical Institute
- Department of Defense [W81XWH-07-1-0080]
- Claudia Adams Barr Program Award
- NCI [5R21CA115043-2]
- Damon-Runyon Cancer Research Foundation [CI-38-07]
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 (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. Clin Cancer Res; 18(20); 5761-72. (C) 2012 AACR.
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