Mutated BCR-ABL generates immunogenic T-cell epitopes in CML patients.
OBJECTIVE
Characterization of an approach to identify leukemia neoantigens arising in the context of drug resistance.


METHODS
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.
Harvard-MIT Division of Health Sciences and Technology, Harvard Medical School, Boston, Massachusetts, USA.
Ann
A
Cai
Derin B
DB
Keskin
David S
DS
DeLuca
Anselmo
A
Alonso
Wandi
W
Zhang
Guang Lan
GL
Zhang
Naa Norkor
NN
Hammond
Valentina
V
Nardi
Richard M
RM
Stone
Donna
D
Neuberg
John
J
Sidney
Vladimir
V
Brusic
Catherine J
CJ
Wu
D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology; D001549:Benzamides / Q000008:administration & dosage; D018414:CD8-Positive T-Lymphocytes; D019008:Drug Resistance, Neoplasm / Q000235:genetics / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000276:immunology; D006680:HLA Antigens / Q000235:genetics / Q000276:immunology; D006801:Humans; D000068877:Imatinib Mesylate; D007167:Immunotherapy; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics / Q000276:immunology; D008297:Male; D008875:Middle Aged; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D010879:Piperazines / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage
D000951:Antigens, Neoplasm; D001549:Benzamides; D018984:Epitopes, T-Lymphocyte; D006680:HLA Antigens; D010455:Peptides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl