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Identification of T-cell Receptors Targeting KRAS-Mutated Human Tumors
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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.
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“Building on these results, TCRs targeting KRASG12D and KRASG12V were produced in HLAA11:01 transgenic mice, and peripheral blood lymphocytes were generated retrovirally [107].”
From RAS Mutations in Advanced Colorectal Cancer: Mechanisms, Clinical Implications, and Novel Therapeutic Approaches (2025) · cites this paper as [107]
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“Tumors with mutant KRAS can express neoantigen fragments containing the oncogenic driver mutation on the major histocompatibility complex [88,89].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [89]
In the citing paper
“The transduced PBLs could recognize multiple HLA-A*11:01(+) tumor lines bearing the appropriate KRAS mutations.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [606]
In the citing paper
“Adoptive transfer of these transduced PBLs resulted in a significant reduction in tumor growth in a xenograft model by detecting human KRAS-mutant pancreatic cells.606”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [606]
In the citing paper
“In 2016, Wang and co-workers isolated highly reactive T-cell receptors (TCR) to mutated KRAS variants G12V and G12D from murine T cells in immunized HLA-A*11:01 (258) transgenic mice, which were then transduced into peripheral blood lymphocytes (PBLs).”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [606]
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Metadata
- Authors
- Wang, Q. J., Yu, Z., Griffith, K., Hanada, K.-I., Restifo, N. P., & Yang, J. C.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Wang, Qiong J.
- Yang, James C.
- Venue
- Cancer Immunology Research
- Published
- 2016-02-29
- Volume
- 4
- Issue
- 3
- Pages
- 204-214
- ISSN
- 2326-6066 (ISSN-L)
- 2326-6074
- PMC
- PMC4775432
- OpenAlex
- W2239878160
- Cited by
- 240
- References
- 37
- Citations by year
- 2026: 17 · 2025: 27 · 2024: 27 · 2023: 30 · 2022: 36 · 2021: 29 · 2020: 24 · 2019: 19 · 2018: 11 · 2017: 13 · 2016: 7
- FWCI
- 10.11
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Immunology Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (Z99 CA999999)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Health Sciences › Medicine › Oncology › CAR-T cell therapy research
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- KRAS mutation, T cell receptor engineering, neoantigens, HLA-A*11:01, pancreatic cancer, adoptive T cell therapy, xenograft tumor growth, cancer immunotherapy
- MeSH terms
- Amino Acid Sequence, Animals, Humans, Lymph Nodes, Mice, Transgenic, Neoplasm Transplantation, Pancreatic Neoplasms, Receptors, Antigen, T-Cell, Spleen, Proto-Oncogene Proteins p21(ras), Mice, SCID, Mice, Inbred NOD, Adoptive Transfer, Mutation, Missense, Cell Line, Tumor, HLA-A11 Antigen
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