Skip to main content
PMC home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1996 Dec;74(11):1828–1833. doi: 10.1038/bjc.1996.638

Characterisation of immune responses in pancreatic carcinoma patients after mutant p21 ras peptide vaccination.

M K Gjertsen 1, I Saeterdal 1, E Thorsby 1, G Gaudernack 1
PMCID: PMC2077214  PMID: 8956801

Abstract

This is a study of immune responses generated by mutant ras peptide vaccination of patients with pancreatic adenocarcinoma. Responding T cells from one patient were cloned and two CD4+ T-lymphocyte clones (TLC) specific for the 12 Val peptide and restricted by HLA-DR6 or DQ2 were obtained. These class II molecules have not previously been found to bind or present mutant ras peptides to T cells. The DR6-restricted TLC showed marked cytotoxicity against autologous target cells pulsed with the 12 Val peptide. Target cells pulsed with the control peptide were not killed. Responding T cells from another patient showed cross-reactivity towards the homologous ras peptides. Investigation by limiting dilution analysis (LDA) revealed different T-cell precursor frequencies for the immunising, mutant ras peptide (1:28000), compared with the normal ras peptide (1:110000).

Full text

PDF
1832

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Almoguera C., Shibata D., Forrester K., Martin J., Arnheim N., Perucho M. Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell. 1988 May 20;53(4):549–554. doi: 10.1016/0092-8674(88)90571-5. [DOI] [PubMed] [Google Scholar]
  2. Boon T., Cerottini J. C., Van den Eynde B., van der Bruggen P., Van Pel A. Tumor antigens recognized by T lymphocytes. Annu Rev Immunol. 1994;12:337–365. doi: 10.1146/annurev.iy.12.040194.002005. [DOI] [PubMed] [Google Scholar]
  3. Capella G., Cronauer-Mitra S., Pienado M. A., Perucho M. Frequency and spectrum of mutations at codons 12 and 13 of the c-K-ras gene in human tumors. Environ Health Perspect. 1991 Jun;93:125–131. doi: 10.1289/ehp.9193125. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Der C. J., Finkel T., Cooper G. M. Biological and biochemical properties of human rasH genes mutated at codon 61. Cell. 1986 Jan 17;44(1):167–176. doi: 10.1016/0092-8674(86)90495-2. [DOI] [PubMed] [Google Scholar]
  5. Fossum B., Gedde-Dahl T., 3rd, Breivik J., Eriksen J. A., Spurkland A., Thorsby E., Gaudernack G. p21-ras-peptide-specific T-cell responses in a patient with colorectal cancer. CD4+ and CD8+ T cells recognize a peptide corresponding to a common mutation (13Gly-->Asp). Int J Cancer. 1994 Jan 2;56(1):40–45. doi: 10.1002/ijc.2910560108. [DOI] [PubMed] [Google Scholar]
  6. Fossum B., Gedde-Dahl T., 3rd, Hansen T., Eriksen J. A., Thorsby E., Gaudernack G. Overlapping epitopes encompassing a point mutation (12 Gly-->Arg) in p21 ras can be recognized by HLA-DR, -DP and -DQ restricted T cells. Eur J Immunol. 1993 Oct;23(10):2687–2691. doi: 10.1002/eji.1830231045. [DOI] [PubMed] [Google Scholar]
  7. Fossum B., Olsen A. C., Thorsby E., Gaudernack G. CD8+ T cells from a patient with colon carcinoma, specific for a mutant p21-Ras-derived peptide (Gly13-->Asp), are cytotoxic towards a carcinoma cell line harbouring the same mutation. Cancer Immunol Immunother. 1995 Mar;40(3):165–172. doi: 10.1007/BF01517348. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Gaudernack G., Lundin K. E. Rapid immunomagnetic phenotyping of cells. J Immunogenet. 1989 Apr;16(2):169–175. doi: 10.1111/j.1744-313x.1989.tb00459.x. [DOI] [PubMed] [Google Scholar]
  9. Gedde-Dahl T., 3rd, Eriksen J. A., Thorsby E., Gaudernack G. T-cell responses against products of oncogenes: generation and characterization of human T-cell clones specific for p21 ras-derived synthetic peptides. Hum Immunol. 1992 Apr;33(4):266–274. doi: 10.1016/0198-8859(92)90334-j. [DOI] [PubMed] [Google Scholar]
  10. Gedde-Dahl T., 3rd, Fossum B., Eriksen J. A., Thorsby E., Gaudernack G. T cell clones specific for p21 ras-derived peptides: characterization of their fine specificity and HLA restriction. Eur J Immunol. 1993 Mar;23(3):754–760. doi: 10.1002/eji.1830230328. [DOI] [PubMed] [Google Scholar]
  11. Gedde-Dahl T., 3rd, Spurkland A., Eriksen J. A., Thorsby E., Gaudernack G. Memory T cells of a patient with follicular thyroid carcinoma recognize peptides derived from mutated p21 ras (Gln-->Leu61). Int Immunol. 1992 Nov;4(11):1331–1337. doi: 10.1093/intimm/4.11.1331. [DOI] [PubMed] [Google Scholar]
  12. Gedde-Dahl T., 3rd, Spurkland A., Fossum B., Wittinghofer A., Thorsby E., Gaudernack G. T cell epitopes encompassing the mutational hot spot position 61 of p21 ras. Promiscuity in ras peptide binding to HLA. Eur J Immunol. 1994 Feb;24(2):410–414. doi: 10.1002/eji.1830240221. [DOI] [PubMed] [Google Scholar]
  13. Gillis S., Ferm M. M., Ou W., Smith K. A. T cell growth factor: parameters of production and a quantitative microassay for activity. J Immunol. 1978 Jun;120(6):2027–2032. [PubMed] [Google Scholar]
  14. Gjertsen M. K., Bakka A., Breivik J., Saeterdal I., Gedde-Dahl T., 3rd, Stokke K. T., Sølheim B. G., Egge T. S., Søreide O., Thorsby E. Ex vivo ras peptide vaccination in patients with advanced pancreatic cancer: results of a phase I/II study. Int J Cancer. 1996 Feb 8;65(4):450–453. doi: 10.1002/(SICI)1097-0215(19960208)65:4<450::AID-IJC10>3.0.CO;2-E. [DOI] [PubMed] [Google Scholar]
  15. Gjertsen M. K., Bakka A., Breivik J., Saeterdal I., Solheim B. G., Søreide O., Thorsby E., Gaudernack G. Vaccination with mutant ras peptides and induction of T-cell responsiveness in pancreatic carcinoma patients carrying the corresponding RAS mutation. Lancet. 1995 Nov 25;346(8987):1399–1400. doi: 10.1016/s0140-6736(95)92408-6. [DOI] [PubMed] [Google Scholar]
  16. Johansen B. H., Gedde-Dahl T., 3rd, Sollid L. M., Vartdal F., Thorsby E., Gaudernack G. Binding of ras oncogene peptides to purified HLA-DQ(alpha 1*0102,beta 1*0602) and -DR(alpha,beta 1*0101) molecules. Scand J Immunol. 1994 Jun;39(6):607–612. doi: 10.1111/j.1365-3083.1994.tb03420.x. [DOI] [PubMed] [Google Scholar]
  17. Jung S., Schluesener H. J. Human T lymphocytes recognize a peptide of single point-mutated, oncogenic ras proteins. J Exp Med. 1991 Jan 1;173(1):273–276. doi: 10.1084/jem.173.1.273. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Kahn S. M., Jiang W., Culbertson T. A., Weinstein I. B., Williams G. M., Tomita N., Ronai Z. Rapid and sensitive nonradioactive detection of mutant K-ras genes via 'enriched' PCR amplification. Oncogene. 1991 Jun;6(6):1079–1083. [PubMed] [Google Scholar]
  19. Mukherji B., Chakraborty N. G., Yamasaki S., Okino T., Yamase H., Sporn J. R., Kurtzman S. K., Ergin M. T., Ozols J., Meehan J. Induction of antigen-specific cytolytic T cells in situ in human melanoma by immunization with synthetic peptide-pulsed autologous antigen presenting cells. Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):8078–8082. doi: 10.1073/pnas.92.17.8078. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Orosz C. G., Adams P. W., Ferguson R. M. Frequency of human alloantigen-reactive T lymphocytes. II. Method for limiting dilution analysis of alloantigen-reactive helper T cells in human peripheral blood. Transplantation. 1987 May;43(5):718–724. [PubMed] [Google Scholar]
  21. Seeburg P. H., Colby W. W., Capon D. J., Goeddel D. V., Levinson A. D. Biological properties of human c-Ha-ras1 genes mutated at codon 12. Nature. 1984 Nov 1;312(5989):71–75. doi: 10.1038/312071a0. [DOI] [PubMed] [Google Scholar]
  22. Skipper J., Stauss H. J. Identification of two cytotoxic T lymphocyte-recognized epitopes in the Ras protein. J Exp Med. 1993 May 1;177(5):1493–1498. doi: 10.1084/jem.177.5.1493. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Slamon D. J., deKernion J. B., Verma I. M., Cline M. J. Expression of cellular oncogenes in human malignancies. Science. 1984 Apr 20;224(4646):256–262. doi: 10.1126/science.6538699. [DOI] [PubMed] [Google Scholar]
  24. Spandidos D. A., Kerr I. B. Elevated expression of the human ras oncogene family in premalignant and malignant tumours of the colorectum. Br J Cancer. 1984 Jun;49(6):681–688. doi: 10.1038/bjc.1984.108. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Taswell C. Limiting dilution assays for the determination of immunocompetent cell frequencies. I. Data analysis. J Immunol. 1981 Apr;126(4):1614–1619. [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES