Identification of T-cell Receptors Targeting KRAS-Mutated Human Tumors.
Cancer Immunol Res
; 4(3): 204-14, 2016 Mar.
Article
en En
| MEDLINE
| ID: mdl-26701267
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*1101 could potentially present mutated KRAS variants. By immunizing HLA-A*1101 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*1101(+) 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*1101, 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.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Neoplasias Pancreáticas
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Receptores de Antígenos de Linfocitos T
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Proteínas Proto-Oncogénicas p21(ras)
Tipo de estudio:
Diagnostic_studies
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Prognostic_studies
Límite:
Animals
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Humans
Idioma:
En
Revista:
Cancer Immunol Res
Año:
2016
Tipo del documento:
Article