A degenerate HLA-DR epitope pool of HER-2/neu reveals a novel in vivo immunodominant epitope, HER-2/neu88-102

Lavakumar Karyampudi, Courtney Formicola, Courtney L. Erskine, Matthew J. Maurer, James N. Ingle, Christopher J. Krco, Peter J. Wettstein, Kimberly R. Kalli, John D. Fikes, Melanie Beebe, Lynn C. Hartmann, Mary L. Disis, Soldano Ferrone, Glenn Ishioka, Keith L Knutson

Research output: Contribution to journalArticle

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Abstract

Purpose: Over the past two decades, there has been significant interest in targeting HER-2/neu in immune-based approaches for the treatment of HER-2/neu+ cancers. For example, peptide vaccination using a CD8 T cell-activating HER-2/neu epitope (amino acids 369-377) is an approach that is being considered in advanced phase clinical trials. Studies have suggested that the persistence of HER-2/neu-specific CD8 T cells could be improved by incorporating human leukocyte antigen (HLA) class II epitopes in the vaccine. Our goal in this study was to identify broad coverage HLA-DR epitopes of HER-2/neu, an antigen that is highly expressed in a variety of carcinomas. Experimental Design: A combination of algorithms and HLA-DR-binding assays was used to identify HLA-DR epitopes of HER-2/neu antigen. Evidence of preexistent immunity in cancer patients against the identified epitopes was determined using IFN-γ enzyme-linked immunosorbent spot (ELIspot) assay. Results: Eighty-four HLA-DR epitopes of HER-2/neu were predicted, 15 of which had high binding affinity for ≥11 common HLA-DR molecules. A degenerate pool of four HLA-DR-restricted 15-amino acid epitopes (p59, p88, p422, and p885) was identified, against which >58% of breast and ovarian cancer patients had preexistent T-cell immunity. All four epitopes are naturally processed by antigen-presenting cells. Hardy-Weinberg analysis showed that the pool is useful in -84% of population. Lastly, in this degenerate pool, we identified a novel in vivo immunodominant HLA-DR epitope, HER-2/neu88-102 (p88). Conclusion: The broad coverage and natural immunity to this epitope pool suggests potential usefulness in HER-2/neu-targeting, immune-based therapies such as vaccines.

Original languageEnglish (US)
Pages (from-to)825-834
Number of pages10
JournalClinical Cancer Research
Volume16
Issue number3
DOIs
StatePublished - Feb 1 2010

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Immunodominant Epitopes
HLA Antigens
Epitopes
T-Lymphocytes
Immunity
Vaccines
Antigens
Amino Acids
Antigen-Presenting Cells
Innate Immunity
Ovarian Neoplasms
Neoplasms
Vaccination
Research Design
Enzyme-Linked Immunosorbent Assay
Clinical Trials
Breast Neoplasms
Carcinoma

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

A degenerate HLA-DR epitope pool of HER-2/neu reveals a novel in vivo immunodominant epitope, HER-2/neu88-102. / Karyampudi, Lavakumar; Formicola, Courtney; Erskine, Courtney L.; Maurer, Matthew J.; Ingle, James N.; Krco, Christopher J.; Wettstein, Peter J.; Kalli, Kimberly R.; Fikes, John D.; Beebe, Melanie; Hartmann, Lynn C.; Disis, Mary L.; Ferrone, Soldano; Ishioka, Glenn; Knutson, Keith L.

In: Clinical Cancer Research, Vol. 16, No. 3, 01.02.2010, p. 825-834.

Research output: Contribution to journalArticle

Karyampudi, L, Formicola, C, Erskine, CL, Maurer, MJ, Ingle, JN, Krco, CJ, Wettstein, PJ, Kalli, KR, Fikes, JD, Beebe, M, Hartmann, LC, Disis, ML, Ferrone, S, Ishioka, G & Knutson, KL 2010, 'A degenerate HLA-DR epitope pool of HER-2/neu reveals a novel in vivo immunodominant epitope, HER-2/neu88-102', Clinical Cancer Research, vol. 16, no. 3, pp. 825-834. https://doi.org/10.1158/1078-0432.CCR-09-2781
Karyampudi, Lavakumar ; Formicola, Courtney ; Erskine, Courtney L. ; Maurer, Matthew J. ; Ingle, James N. ; Krco, Christopher J. ; Wettstein, Peter J. ; Kalli, Kimberly R. ; Fikes, John D. ; Beebe, Melanie ; Hartmann, Lynn C. ; Disis, Mary L. ; Ferrone, Soldano ; Ishioka, Glenn ; Knutson, Keith L. / A degenerate HLA-DR epitope pool of HER-2/neu reveals a novel in vivo immunodominant epitope, HER-2/neu88-102. In: Clinical Cancer Research. 2010 ; Vol. 16, No. 3. pp. 825-834.
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abstract = "Purpose: Over the past two decades, there has been significant interest in targeting HER-2/neu in immune-based approaches for the treatment of HER-2/neu+ cancers. For example, peptide vaccination using a CD8 T cell-activating HER-2/neu epitope (amino acids 369-377) is an approach that is being considered in advanced phase clinical trials. Studies have suggested that the persistence of HER-2/neu-specific CD8 T cells could be improved by incorporating human leukocyte antigen (HLA) class II epitopes in the vaccine. Our goal in this study was to identify broad coverage HLA-DR epitopes of HER-2/neu, an antigen that is highly expressed in a variety of carcinomas. Experimental Design: A combination of algorithms and HLA-DR-binding assays was used to identify HLA-DR epitopes of HER-2/neu antigen. Evidence of preexistent immunity in cancer patients against the identified epitopes was determined using IFN-γ enzyme-linked immunosorbent spot (ELIspot) assay. Results: Eighty-four HLA-DR epitopes of HER-2/neu were predicted, 15 of which had high binding affinity for ≥11 common HLA-DR molecules. A degenerate pool of four HLA-DR-restricted 15-amino acid epitopes (p59, p88, p422, and p885) was identified, against which >58{\%} of breast and ovarian cancer patients had preexistent T-cell immunity. All four epitopes are naturally processed by antigen-presenting cells. Hardy-Weinberg analysis showed that the pool is useful in -84{\%} of population. Lastly, in this degenerate pool, we identified a novel in vivo immunodominant HLA-DR epitope, HER-2/neu88-102 (p88). Conclusion: The broad coverage and natural immunity to this epitope pool suggests potential usefulness in HER-2/neu-targeting, immune-based therapies such as vaccines.",
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T1 - A degenerate HLA-DR epitope pool of HER-2/neu reveals a novel in vivo immunodominant epitope, HER-2/neu88-102

AU - Karyampudi, Lavakumar

AU - Formicola, Courtney

AU - Erskine, Courtney L.

AU - Maurer, Matthew J.

AU - Ingle, James N.

AU - Krco, Christopher J.

AU - Wettstein, Peter J.

AU - Kalli, Kimberly R.

AU - Fikes, John D.

AU - Beebe, Melanie

AU - Hartmann, Lynn C.

AU - Disis, Mary L.

AU - Ferrone, Soldano

AU - Ishioka, Glenn

AU - Knutson, Keith L

PY - 2010/2/1

Y1 - 2010/2/1

N2 - Purpose: Over the past two decades, there has been significant interest in targeting HER-2/neu in immune-based approaches for the treatment of HER-2/neu+ cancers. For example, peptide vaccination using a CD8 T cell-activating HER-2/neu epitope (amino acids 369-377) is an approach that is being considered in advanced phase clinical trials. Studies have suggested that the persistence of HER-2/neu-specific CD8 T cells could be improved by incorporating human leukocyte antigen (HLA) class II epitopes in the vaccine. Our goal in this study was to identify broad coverage HLA-DR epitopes of HER-2/neu, an antigen that is highly expressed in a variety of carcinomas. Experimental Design: A combination of algorithms and HLA-DR-binding assays was used to identify HLA-DR epitopes of HER-2/neu antigen. Evidence of preexistent immunity in cancer patients against the identified epitopes was determined using IFN-γ enzyme-linked immunosorbent spot (ELIspot) assay. Results: Eighty-four HLA-DR epitopes of HER-2/neu were predicted, 15 of which had high binding affinity for ≥11 common HLA-DR molecules. A degenerate pool of four HLA-DR-restricted 15-amino acid epitopes (p59, p88, p422, and p885) was identified, against which >58% of breast and ovarian cancer patients had preexistent T-cell immunity. All four epitopes are naturally processed by antigen-presenting cells. Hardy-Weinberg analysis showed that the pool is useful in -84% of population. Lastly, in this degenerate pool, we identified a novel in vivo immunodominant HLA-DR epitope, HER-2/neu88-102 (p88). Conclusion: The broad coverage and natural immunity to this epitope pool suggests potential usefulness in HER-2/neu-targeting, immune-based therapies such as vaccines.

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