A phase I vaccine trial with peptides reflecting ras oncogene mutations of solid tumors

Samir N. Khleif, Scott I. Abrams, J. Michael Hamilton, Elke Bergmann-Leitner, Alice Chen, Anne Bastian, Sarah Bernstein, Yoomie Chung, Carmen J. Allegra, Jeffrey Schlom

Research output: Contribution to journalArticle

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Abstract

Mutations in the ras genes occur in 20% of all human cancers. These genes, in turn, produce mutated proteins that are unique to cancer cells, rendering them distinguishable from normal cells by the immune system. Thus, mutated Ras proteins may form potential targets for immune therapy. We conducted a phase I/pilot clinical trial in patients with advanced cancers to test the toxicity and the ability to induce an immune response by vaccination with 13-mer mutated Ras peptides reflecting codon 12 mutations. These peptides corresponded to each of the patient’s own tumor Ras mutation. Patients were vaccinated monthly × 3 subcutaneously with the specific Ras peptide along with Detox adjuvant (RiBi ImmunoChem Research, Inc., Hamilton, MT, U.S.A.) at one of five different peptide dose levels (100, 500, 1,000, 1,500, and 5,000 µg). Three out of 10 evaluable patients generated a mutant Ras specific CD4+ and/or CD8+ T-cell immune response. The CD8+ cytotoxic cells specific for Gly to Val mutation at codon 12 were capable of lysing an HLA-A2-matched tumor cell line carrying the corresponding mutant but not the wild-type ras gene. The treatment has been well tolerated with no evidence of serious acute or delayed systemic side effects on any of the five dose levels. We demonstrated that we can generate in cancer patients specific T-lymphocyte responses that detect single amino acid differences in Ras oncoproteins. Neither the immune responses nor the minor side effects seen were found to be dose dependent. This approach may provide a unique opportunity for generating a tumor-directed therapy. Also, in vitro stimulation of these cells with the corresponding peptide generated specific T-cell lines that could be used for adoptive immune therapy.

Original languageEnglish (US)
Pages (from-to)155-165
Number of pages11
JournalJournal of Immunotherapy
Volume22
Issue number2
DOIs
StatePublished - Jan 1 1999

Fingerprint

ras Genes
Vaccines
Peptides
Mutation
Neoplasms
T-Lymphocytes
Codon
HLA-A2 Antigen
ras Proteins
Toxicity Tests
Clinical Trials, Phase I
Oncogene Proteins
Therapeutics
Tumor Cell Line
Immune System
Vaccination
Amino Acids
Cell Line
Research
Genes

Keywords

  • Ras oncogene mutations
  • Ras peptides
  • Ras vaccination

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Pharmacology
  • Cancer Research

Cite this

Khleif, S. N., Abrams, S. I., Hamilton, J. M., Bergmann-Leitner, E., Chen, A., Bastian, A., ... Schlom, J. (1999). A phase I vaccine trial with peptides reflecting ras oncogene mutations of solid tumors. Journal of Immunotherapy, 22(2), 155-165. https://doi.org/10.1097/00002371-199903000-00007

A phase I vaccine trial with peptides reflecting ras oncogene mutations of solid tumors. / Khleif, Samir N.; Abrams, Scott I.; Hamilton, J. Michael; Bergmann-Leitner, Elke; Chen, Alice; Bastian, Anne; Bernstein, Sarah; Chung, Yoomie; Allegra, Carmen J.; Schlom, Jeffrey.

In: Journal of Immunotherapy, Vol. 22, No. 2, 01.01.1999, p. 155-165.

Research output: Contribution to journalArticle

Khleif, SN, Abrams, SI, Hamilton, JM, Bergmann-Leitner, E, Chen, A, Bastian, A, Bernstein, S, Chung, Y, Allegra, CJ & Schlom, J 1999, 'A phase I vaccine trial with peptides reflecting ras oncogene mutations of solid tumors', Journal of Immunotherapy, vol. 22, no. 2, pp. 155-165. https://doi.org/10.1097/00002371-199903000-00007
Khleif SN, Abrams SI, Hamilton JM, Bergmann-Leitner E, Chen A, Bastian A et al. A phase I vaccine trial with peptides reflecting ras oncogene mutations of solid tumors. Journal of Immunotherapy. 1999 Jan 1;22(2):155-165. https://doi.org/10.1097/00002371-199903000-00007
Khleif, Samir N. ; Abrams, Scott I. ; Hamilton, J. Michael ; Bergmann-Leitner, Elke ; Chen, Alice ; Bastian, Anne ; Bernstein, Sarah ; Chung, Yoomie ; Allegra, Carmen J. ; Schlom, Jeffrey. / A phase I vaccine trial with peptides reflecting ras oncogene mutations of solid tumors. In: Journal of Immunotherapy. 1999 ; Vol. 22, No. 2. pp. 155-165.
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