title: Identification of T-cell Receptors Targeting KRAS-Mutated Human Tumors.
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.
authors.affiliation: Surgery Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland. qiongwang@mail.nih.gov James_Yang@nih.gov.
authors.forename: Qiong J
authors.initials: QJ
authors.lastname: Wang
authors.affiliation: Surgery Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
authors.forename: Zhiya
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Surgery Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
authors.forename: Kayla
authors.initials: K
authors.lastname: Griffith
authors.affiliation: Surgery Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Hanada
authors.affiliation: Surgery Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Restifo
authors.affiliation: Surgery Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland. qiongwang@mail.nih.gov James_Yang@nih.gov.
authors.forename: James C
authors.initials: JC
authors.lastname: Yang
mesh_terms: D019264:Adoptive Transfer; D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D059870:HLA-A11 Antigen / Q000235:genetics; D006801:Humans; D008198:Lymph Nodes / Q000473:pathology; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D020125:Mutation, Missense; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000628:therapy*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics* / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D013154:Spleen / Q000473:pathology
chemical_list: C515740:HLA-A*11:01 antigen; D059870:HLA-A11 Antigen; C117307:KRAS protein, human; D011948:Receptors, Antigen, T-Cell; D016283:Proto-Oncogene Proteins p21(ras)