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Cited by 91Immunotherapy and Immune Responsesvaccines and immunoinformatics approachesT-cell and B-cell Immunology

Generation of Stable CD4+and CD8+T Cell Lines from Patients Immunized withrasOncogene-Derived Peptides Reflecting Codon 12 Mutations

Abrams, Scott I., Khleif, Samir N., Bergmann-Leitner, Elke S., Kantor, Judith A., Chung, Yoomie, Hamilton, J.Michael, Schlom, Jeffrey·1997·Cellular Immunology
DOI 10.1006/cimm.1997.1224
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Abstract

Previous studies have identified and characterized both murine in vivo and human in vitro T cell responses reflecting specific mutations in the ras proto-oncogenes at codon 12, 13, or 61. In an attempt to determine whether peptide epitopes reflecting point mutations in the ras oncogenes are immunogenic in humans for the production of CD4+ and/or CD8+ T cell responses, a phase I clinical trial was initiated in metastatic carcinoma patients whose primary tumors harbor mutations in the K-ras proto-oncogenes at codon 12. The peptides used here as immunogens, which were administered in Detox adjuvant, spanned the ras sequence 5-17 and reflected the amino acid substitution of glycine (Gly) at position 12 to aspartic acid (Asp), cysteine (Cys), or valine (Val). Three of eight evaluable patients have demonstrated peptide-specific cell-mediated immunity, as determined by the production of T cell lines resulting from the vaccination. First, an antigen (Ag)-specific, major histocompatibility complex (MHC) class II (DP)-restricted CD4+ T cell line was established in vitro from postvaccination lymphocytes of a non-small cell lung carcinoma patient whose primary tumor contained a Cys12 mutation when cultured on the immunizing peptide. Moreover, CD4+ proliferation was inducible against the corresponding mutant K-ras protein, suggesting productive T cell receptor recognition of exogenously processed Ag. Second, an Ag-specific, MHC class I (HLA-A2)-restricted CD8+ cytotoxic T lymphocyte (CTL) line was established in vitro from postvaccination lymphocytes of a colon carcinoma patient whose primary tumor contained an Asp12 mutation. To that end, a 10-mer peptide, nested within the 13-mer immunizing peptide, was identified [i.e., ras5-14(Asp12)], which was shown to bind to HLA-A2 and display specific functional capacity for expansion of the in vivo primed CD8+ CTL precursors. Third, both Ag-specific, MHC class II (DQ)-restricted CD4+ and MHC class I-restricted (HLA-A2) CD8+ T cell lines were generated from a single patient with duodenal carcinoma whose primary tumor contained a Val12 mutation when cultured on the immunizing 13-mer peptide or a nested 10-mer peptide [i.e., ras5-14(Val12)], respectively. Evidence is thus provided that vaccination with mutant ras oncogene peptides in adjuvant may induce specific anti-ras cellular immune responses, with no detectable cross-reactivity toward normal proto-ras sequences. Moreover, we have identified for the first time human HLA-A2-restricted, CD8+ CTL epitopes reflecting specific point mutations in the K-ras oncogenes at codon 12 which, in concert with the activation of the CD4+ T cell response, may have important implications for both active and passive immunotherapies in selected cancer patients.

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Crossref · 10.1006/cimm.1997.1224

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  • Adham et al. validated the KRAS G12 mutation peptide as a bona fide epitope promoting the development of immunotherapy directed against this oncoprotein.

    “Adham et al. validated the KRAS G12 mutation peptide as a bona fide epitope promoting the development of immunotherapy directed against this oncoprotein [91].”

    From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [91]

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Authors
Abrams, S. I., Khleif, S. N., Bergmann-Leitner, E. S., Kantor, J. A., Chung, Y., Hamilton, J. M., & Schlom, J.
Affiliations
National Institutes of Health (US)
Corresponding author
Schlom, Jeffrey
ORCID
Venue
Cellular Immunology
Publisher
Elsevier BV
Published
1997-12
Volume
182
Issue
2
Pages
137-151
ISSN
0008-8749 (ISSN-L)
DOI
10.1006/cimm.1997.1224
OpenAlex
W1983739608
Cited by
91
References
39
Citations by year
2026: 1 · 2025: 2 · 2024: 3 · 2023: 2 · 2022: 2 · 2021: 3 · 2020: 5 · 2019: 4 · 2018: 2 · 2017: 4 · 2016: 2 · 2015: 2 · 2014: 3 · 2013: 1 · 2012: 3
FWCI
2.62
Type
journal article
Language
en
Open access
closed
Licence
Locations
  • Cellular Immunology (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Keywords
K-ras codon 12 mutation, CD4+ T cell lines, CD8+ cytotoxic T lymphocytes, MHC class II restriction, MHC class I restriction, HLA-A2, HLA-DP, HLA-DQ, T cell receptor recognition, non-small cell lung cancer, colon cancer, duodenal cancer, metastatic carcinoma
MeSH terms
Adult, Amino Acid Sequence, Animals, Cell Line, Codon, Cytotoxicity, Immunologic, HLA-DQ Antigens, Humans, Immunization, Lymphocyte Activation, Male, Neoplasms, Genes, ras, CD4-Positive T-Lymphocytes, HLA-A2 Antigen, Point Mutation, CD8-Positive T-Lymphocytes, ras Proteins, Mice, In Vitro Techniques

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