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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 (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 ¼ 28 nmol/L), and showed that this peptide is endogenously processed and presented. Polyfunctional E255K-specific CD8þ T cells were detected in two imatinib-resistant HLA-A3þ 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.