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Cancer Immunology Research
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Research Articles

Identification of T-cell Receptors Targeting KRAS-Mutated Human Tumors

Qiong J. Wang, Zhiya Yu, Kayla Griffith, Ken-ichi Hanada, Nicholas P. Restifo and James C. Yang
Qiong J. Wang
Surgery Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
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  • For correspondence: qiongwang@mail.nih.gov James_Yang@nih.gov
Zhiya Yu
Surgery Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
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Kayla Griffith
Surgery Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
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Ken-ichi Hanada
Surgery Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
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Nicholas P. Restifo
Surgery Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
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James C. Yang
Surgery Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
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  • For correspondence: qiongwang@mail.nih.gov James_Yang@nih.gov
DOI: 10.1158/2326-6066.CIR-15-0188 Published March 2016
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Abstract

KRAS is one of the most frequently mutated proto-oncogenes in human cancers. The dominant oncogenic mutations of KRAS are single amino acid substitutions at codon 12, in particular G12D and G12V present in 60% to 70% of pancreatic cancers and 20% to 30% of colorectal cancers. The consistency, frequency, and tumor specificity of these “neoantigens” make them attractive therapeutic targets. Recent data associate T cells that target mutated antigens with clinical immunotherapy responses in patients with metastatic melanoma, lung cancer, or cholangiocarcinoma. Using HLA-peptide prediction algorithms, we noted that HLA-A*11:01 could potentially present mutated KRAS variants. By immunizing HLA-A*11:01 transgenic mice, we generated murine T cells and subsequently isolated T-cell receptors (TCR) highly reactive to the mutated KRAS variants G12V and G12D. Peripheral blood lymphocytes (PBL) transduced with these TCRs could recognize multiple HLA-A*11:01+ tumor lines bearing the appropriate KRAS mutations. In a xenograft model of large established tumor, adoptive transfer of these transduced PBLs reactive with an HLA-A*11:01, G12D-mutated pancreatic cell line could significantly reduce its growth in NSG mice (P = 0.002). The success of adoptive transfer of TCR-engineered T cells against melanoma and other cancers supports clinical trials with these T cells that recognize mutated KRAS in patients with a variety of common cancer types. Cancer Immunol Res; 4(3); 204–14. ©2015 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Immunology Research Online (http://cancerimmunolres.aacrjournals.org/).

  • Received July 30, 2015.
  • Revision received October 14, 2015.
  • Accepted November 11, 2015.
  • ©2015 American Association for Cancer Research.
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Cancer Immunology Research: 4 (3)
March 2016
Volume 4, Issue 3
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Identification of T-cell Receptors Targeting KRAS-Mutated Human Tumors
Qiong J. Wang, Zhiya Yu, Kayla Griffith, Ken-ichi Hanada, Nicholas P. Restifo and James C. Yang
Cancer Immunol Res March 1 2016 (4) (3) 204-214; DOI: 10.1158/2326-6066.CIR-15-0188

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Identification of T-cell Receptors Targeting KRAS-Mutated Human Tumors
Qiong J. Wang, Zhiya Yu, Kayla Griffith, Ken-ichi Hanada, Nicholas P. Restifo and James C. Yang
Cancer Immunol Res March 1 2016 (4) (3) 204-214; DOI: 10.1158/2326-6066.CIR-15-0188
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