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

Research output: Contribution to journalArticle

26 Citations (Scopus)

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
Externally publishedYes

Fingerprint

T-Lymphocyte Epitopes
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
HLA-A3 Antigen
Leukemia
Peptides
Mutation
Inhibitory Concentration 50
Alleles
Drug Resistance
Immune System
Research Design
T-Lymphocytes
Recurrence
Imatinib Mesylate
Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Cai, A., Keskin, D. B., DeLuca, D. S., Alonso, A., Zhang, W., Zhang, G. L., ... 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

Mutated BCR-ABL generates immunogenic T-cell epitopes in CML patients. / Cai, Ann; Keskin, Derin B.; DeLuca, David S.; Alonso, Anselmo; Zhang, Wandi; Zhang, Guang Lan; Hammond, Naa Norkor; Nardi, Valentina; Stone, Richard M.; Neuberg, Donna; Sidney, John; Brusic, Vladimir; Wu, Catherine J.

In: Clinical Cancer Research, Vol. 18, No. 20, 15.10.2012, p. 5761-5772.

Research output: Contribution to journalArticle

Cai, A, Keskin, DB, DeLuca, DS, Alonso, A, Zhang, W, Zhang, GL, Hammond, NN, Nardi, V, Stone, RM, Neuberg, D, Sidney, J, Brusic, V & Wu, CJ 2012, 'Mutated BCR-ABL generates immunogenic T-cell epitopes in CML patients', Clinical Cancer Research, vol. 18, no. 20, pp. 5761-5772. https://doi.org/10.1158/1078-0432.CCR-12-1182
Cai A, Keskin DB, DeLuca DS, Alonso A, Zhang W, Zhang GL et al. Mutated BCR-ABL generates immunogenic T-cell epitopes in CML patients. Clinical Cancer Research. 2012 Oct 15;18(20):5761-5772. https://doi.org/10.1158/1078-0432.CCR-12-1182
Cai, Ann ; Keskin, Derin B. ; DeLuca, David S. ; Alonso, Anselmo ; Zhang, Wandi ; Zhang, Guang Lan ; Hammond, Naa Norkor ; Nardi, Valentina ; Stone, Richard M. ; Neuberg, Donna ; Sidney, John ; Brusic, Vladimir ; Wu, Catherine J. / Mutated BCR-ABL generates immunogenic T-cell epitopes in CML patients. In: Clinical Cancer Research. 2012 ; Vol. 18, No. 20. pp. 5761-5772.
@article{11d604cc9ec341609a7763180d9fbdbd,
title = "Mutated BCR-ABL generates immunogenic T-cell epitopes in CML patients",
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.",
author = "Ann Cai and Keskin, {Derin B.} and DeLuca, {David S.} and Anselmo Alonso and Wandi Zhang and Zhang, {Guang Lan} and Hammond, {Naa Norkor} and Valentina Nardi and Stone, {Richard M.} and Donna Neuberg and John Sidney and Vladimir Brusic and Wu, {Catherine J.}",
year = "2012",
month = "10",
day = "15",
doi = "10.1158/1078-0432.CCR-12-1182",
language = "English",
volume = "18",
pages = "5761--5772",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "20",

}

TY - JOUR

T1 - Mutated BCR-ABL generates immunogenic T-cell epitopes in CML patients

AU - Cai, Ann

AU - Keskin, Derin B.

AU - DeLuca, David S.

AU - Alonso, Anselmo

AU - Zhang, Wandi

AU - Zhang, Guang Lan

AU - Hammond, Naa Norkor

AU - Nardi, Valentina

AU - Stone, Richard M.

AU - Neuberg, Donna

AU - Sidney, John

AU - Brusic, Vladimir

AU - Wu, Catherine J.

PY - 2012/10/15

Y1 - 2012/10/15

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84867530182&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84867530182&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-12-1182

DO - 10.1158/1078-0432.CCR-12-1182

M3 - Article

VL - 18

SP - 5761

EP - 5772

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 20

ER -