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. 1996 Apr 1;183(4):1357–1365. doi: 10.1084/jem.183.4.1357

Therapy of murine tumors with p53 wild-type and mutant sequence peptide- based vaccines

PMCID: PMC2192493  PMID: 8666894

Abstract

The BALB/c Meth A sarcoma carries a p53 missense mutation at codon 234, which occurs in a peptide, termed 234CM, capable of being presented to cytotoxic T lymphocytes (CTL) by H-2Kd molecules (Noguchi, Y., E.C. Richards, Y.-T. Chen, and L.J. Old. 1994. Proc. Natl. Acad. Sci. USA. 91:3171-3175). Immunization of BALB/c mice with bone marrow-derived dendritic cells (DC), generated in the presence of granulocyte macrophage colony-stimulating factor and interleukin 4, and prepulsed with the Meth A p53 mutant peptide, induced CTL that specifically recognized peptide-pulsed P815 cells, as well as Meth A cells naturally expressing this epitope. Immunization with this vaccine also protected naive mice from a subsequent tumor challenge, and it inhibited tumor growth in mice bearing day 7 subcutaneous Meth A tumors. We additionally determined that immunization of BALB/c mice with DC pulsed with the p53 peptide containing the wild-type residue at position 234, 234CW, induced peptide-specific CTL that reacted against several methylcholanthrene-induced BALB/c sarcomas, including CMS4 sarcoma, and rejection of CMS4 sarcoma in vaccination and therapy (day 7) protocols. These results support the efficacy of DC-based, p53-derived peptide vaccines for the immunotherapy of cancer. The translational potential of this strategy is enhanced by previous reports showing that DC can readily be generated from human peripheral blood lymphocytes.

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Selected References

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  1. Appasamy P. M., Kenniston T. W., Jr, Weng Y., Holt E. C., Kost J., Chambers W. H. Interleukin 7-induced expression of specific T cell receptor gamma variable region genes in murine fetal liver cultures. J Exp Med. 1993 Dec 1;178(6):2201–2206. doi: 10.1084/jem.178.6.2201. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Arai N., Nomura D., Yokota K., Wolf D., Brill E., Shohat O., Rotter V. Immunologically distinct p53 molecules generated by alternative splicing. Mol Cell Biol. 1986 Sep;6(9):3232–3239. doi: 10.1128/mcb.6.9.3232. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Castelli C., Storkus W. J., Maeurer M. J., Martin D. M., Huang E. C., Pramanik B. N., Nagabhushan T. L., Parmiani G., Lotze M. T. Mass spectrometric identification of a naturally processed melanoma peptide recognized by CD8+ cytotoxic T lymphocytes. J Exp Med. 1995 Jan 1;181(1):363–368. doi: 10.1084/jem.181.1.363. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Celluzzi C. M., Mayordomo J. I., Storkus W. J., Lotze M. T., Falo L. D., Jr Peptide-pulsed dendritic cells induce antigen-specific CTL-mediated protective tumor immunity. J Exp Med. 1996 Jan 1;183(1):283–287. doi: 10.1084/jem.183.1.283. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Coulie P. G., Brichard V., Van Pel A., Wölfel T., Schneider J., Traversari C., Mattei S., De Plaen E., Lurquin C., Szikora J. P. A new gene coding for a differentiation antigen recognized by autologous cytolytic T lymphocytes on HLA-A2 melanomas. J Exp Med. 1994 Jul 1;180(1):35–42. doi: 10.1084/jem.180.1.35. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Coulie P. G., Lehmann F., Lethé B., Herman J., Lurquin C., Andrawiss M., Boon T. A mutated intron sequence codes for an antigenic peptide recognized by cytolytic T lymphocytes on a human melanoma. Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):7976–7980. doi: 10.1073/pnas.92.17.7976. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cox A. L., Skipper J., Chen Y., Henderson R. A., Darrow T. L., Shabanowitz J., Engelhard V. H., Hunt D. F., Slingluff C. L., Jr Identification of a peptide recognized by five melanoma-specific human cytotoxic T cell lines. Science. 1994 Apr 29;264(5159):716–719. doi: 10.1126/science.7513441. [DOI] [PubMed] [Google Scholar]
  8. DeLeo A. B., Jay G., Appella E., Dubois G. C., Law L. W., Old L. J. Detection of a transformation-related antigen in chemically induced sarcomas and other transformed cells of the mouse. Proc Natl Acad Sci U S A. 1979 May;76(5):2420–2424. doi: 10.1073/pnas.76.5.2420. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. DeLeo A. B., Shiku H., Takahashi T., John M., Old L. J. Cell surface antigens of chemically induced sarcomas of the mouse. I. Murine leukemia virus-related antigens and alloantigens on cultured fibroblasts and sarcoma cells: description of a unique antigen on BALB/c Meth A sarcoma. J Exp Med. 1977 Sep 1;146(3):720–734. doi: 10.1084/jem.146.3.720. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Halevy O., Rodel J., Peled A., Oren M. Frequent p53 mutations in chemically induced murine fibrosarcoma. Oncogene. 1991 Sep;6(9):1593–1600. [PubMed] [Google Scholar]
  11. Hollstein M., Sidransky D., Vogelstein B., Harris C. C. p53 mutations in human cancers. Science. 1991 Jul 5;253(5015):49–53. doi: 10.1126/science.1905840. [DOI] [PubMed] [Google Scholar]
  12. Houbiers J. G., Nijman H. W., van der Burg S. H., Drijfhout J. W., Kenemans P., van de Velde C. J., Brand A., Momburg F., Kast W. M., Melief C. J. In vitro induction of human cytotoxic T lymphocyte responses against peptides of mutant and wild-type p53. Eur J Immunol. 1993 Sep;23(9):2072–2077. doi: 10.1002/eji.1830230905. [DOI] [PubMed] [Google Scholar]
  13. Houghton A. N. Cancer antigens: immune recognition of self and altered self. J Exp Med. 1994 Jul 1;180(1):1–4. doi: 10.1084/jem.180.1.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Inaba K., Inaba M., Romani N., Aya H., Deguchi M., Ikehara S., Muramatsu S., Steinman R. M. Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte/macrophage colony-stimulating factor. J Exp Med. 1992 Dec 1;176(6):1693–1702. doi: 10.1084/jem.176.6.1693. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Inaba K., Young J. W., Steinman R. M. Direct activation of CD8+ cytotoxic T lymphocytes by dendritic cells. J Exp Med. 1987 Jul 1;166(1):182–194. doi: 10.1084/jem.166.1.182. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Jay G., DeLeo A. B., Appella E., Dubois G. C., Law L. W., Khoury G., Old L. J. A common transformation-related protein in murine sarcomas and leukemias. Cold Spring Harb Symp Quant Biol. 1980;44(Pt 1):659–664. doi: 10.1101/sqb.1980.044.01.069. [DOI] [PubMed] [Google Scholar]
  17. Kawakami Y., Eliyahu S., Delgado C. H., Robbins P. F., Sakaguchi K., Appella E., Yannelli J. R., Adema G. J., Miki T., Rosenberg S. A. Identification of a human melanoma antigen recognized by tumor-infiltrating lymphocytes associated with in vivo tumor rejection. Proc Natl Acad Sci U S A. 1994 Jul 5;91(14):6458–6462. doi: 10.1073/pnas.91.14.6458. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Kawakami Y., Eliyahu S., Sakaguchi K., Robbins P. F., Rivoltini L., Yannelli J. R., Appella E., Rosenberg S. A. Identification of the immunodominant peptides of the MART-1 human melanoma antigen recognized by the majority of HLA-A2-restricted tumor infiltrating lymphocytes. J Exp Med. 1994 Jul 1;180(1):347–352. doi: 10.1084/jem.180.1.347. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Kubo R. T., Sette A., Grey H. M., Appella E., Sakaguchi K., Zhu N. Z., Arnott D., Sherman N., Shabanowitz J., Michel H. Definition of specific peptide motifs for four major HLA-A alleles. J Immunol. 1994 Apr 15;152(8):3913–3924. [PubMed] [Google Scholar]
  20. Mayordomo J. I., Zorina T., Storkus W. J., Zitvogel L., Celluzzi C., Falo L. D., Melief C. J., Ildstad S. T., Kast W. M., Deleo A. B. Bone marrow-derived dendritic cells pulsed with synthetic tumour peptides elicit protective and therapeutic antitumour immunity. Nat Med. 1995 Dec;1(12):1297–1302. doi: 10.1038/nm1295-1297. [DOI] [PubMed] [Google Scholar]
  21. Noguchi Y., Chen Y. T., Old L. J. A mouse mutant p53 product recognized by CD4+ and CD8+ T cells. Proc Natl Acad Sci U S A. 1994 Apr 12;91(8):3171–3175. doi: 10.1073/pnas.91.8.3171. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Pardoll D. M. Tumour antigens. A new look for the 1990s. Nature. 1994 Jun 2;369(6479):357–357. doi: 10.1038/369357a0. [DOI] [PubMed] [Google Scholar]
  23. Parmiani G. Tumor immunity as autoimmunity: tumor antigens include normal self proteins which stimulate anergic peripheral T cells. Immunol Today. 1993 Nov;14(11):536–538. doi: 10.1016/0167-5699(93)90183-L. [DOI] [PubMed] [Google Scholar]
  24. Peterson S. R., Kurimasa A., Oshimura M., Dynan W. S., Bradbury E. M., Chen D. J. Loss of the catalytic subunit of the DNA-dependent protein kinase in DNA double-strand-break-repair mutant mammalian cells. Proc Natl Acad Sci U S A. 1995 Apr 11;92(8):3171–3174. doi: 10.1073/pnas.92.8.3171. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Porgador A., Gilboa E. Bone marrow-generated dendritic cells pulsed with a class I-restricted peptide are potent inducers of cytotoxic T lymphocytes. J Exp Med. 1995 Jul 1;182(1):255–260. doi: 10.1084/jem.182.1.255. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Ruppert J., Sidney J., Celis E., Kubo R. T., Grey H. M., Sette A. Prominent role of secondary anchor residues in peptide binding to HLA-A2.1 molecules. Cell. 1993 Sep 10;74(5):929–937. doi: 10.1016/0092-8674(93)90472-3. [DOI] [PubMed] [Google Scholar]
  27. Sallusto F., Lanzavecchia A. Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor alpha. J Exp Med. 1994 Apr 1;179(4):1109–1118. doi: 10.1084/jem.179.4.1109. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Sette A., Sidney J., del Guercio M. F., Southwood S., Ruppert J., Dahlberg C., Grey H. M., Kubo R. T. Peptide binding to the most frequent HLA-A class I alleles measured by quantitative molecular binding assays. Mol Immunol. 1994 Aug;31(11):813–822. doi: 10.1016/0161-5890(94)90019-1. [DOI] [PubMed] [Google Scholar]
  29. Speiser D. E., Kyburz D., Stübi U., Hengartner H., Zinkernagel R. M. Discrepancy between in vitro measurable and in vivo virus neutralizing cytotoxic T cell reactivities. Low T cell receptor specificity and avidity sufficient for in vitro proliferation or cytotoxicity to peptide-coated target cells but not for in vivo protection. J Immunol. 1992 Aug 1;149(3):972–980. [PubMed] [Google Scholar]
  30. Steinman R. M. The dendritic cell system and its role in immunogenicity. Annu Rev Immunol. 1991;9:271–296. doi: 10.1146/annurev.iy.09.040191.001415. [DOI] [PubMed] [Google Scholar]
  31. Takahashi H., Nakagawa Y., Yokomuro K., Berzofsky J. A. Induction of CD8+ cytotoxic T lymphocytes by immunization with syngeneic irradiated HIV-1 envelope derived peptide-pulsed dendritic cells. Int Immunol. 1993 Aug;5(8):849–857. doi: 10.1093/intimm/5.8.849. [DOI] [PubMed] [Google Scholar]
  32. Widmann C., Romero P., Maryanski J. L., Corradin G., Valmori D. T helper epitopes enhance the cytotoxic response of mice immunized with MHC class I-restricted malaria peptides. J Immunol Methods. 1992 Oct 19;155(1):95–99. doi: 10.1016/0022-1759(92)90275-x. [DOI] [PubMed] [Google Scholar]
  33. Wipke B. T., Jameson S. C., Bevan M. J., Pamer E. G. Variable binding affinities of listeriolysin O peptides for the H-2Kd class I molecule. Eur J Immunol. 1993 Aug;23(8):2005–2010. doi: 10.1002/eji.1830230842. [DOI] [PubMed] [Google Scholar]
  34. Wölfel T., Hauer M., Schneider J., Serrano M., Wölfel C., Klehmann-Hieb E., De Plaen E., Hankeln T., Meyer zum Büschenfelde K. H., Beach D. A p16INK4a-insensitive CDK4 mutant targeted by cytolytic T lymphocytes in a human melanoma. Science. 1995 Sep 1;269(5228):1281–1284. doi: 10.1126/science.7652577. [DOI] [PubMed] [Google Scholar]
  35. Zakut-Houri R., Oren M., Bienz B., Lavie V., Hazum S., Givol D. A single gene and a pseudogene for the cellular tumour antigen p53. Nature. 1983 Dec 8;306(5943):594–597. doi: 10.1038/306594a0. [DOI] [PubMed] [Google Scholar]
  36. Zeh H. J., 3rd, Leder G. H., Lotze M. T., Salter R. D., Tector M., Stuber G., Modrow S., Storkus W. J. Flow-cytometric determination of peptide-class I complex formation. Identification of p53 peptides that bind to HLA-A2. Hum Immunol. 1994 Feb;39(2):79–86. doi: 10.1016/0198-8859(94)90105-8. [DOI] [PubMed] [Google Scholar]
  37. Zitvogel L., Mayordomo J. I., Tjandrawan T., DeLeo A. B., Clarke M. R., Lotze M. T., Storkus W. J. Therapy of murine tumors with tumor peptide-pulsed dendritic cells: dependence on T cells, B7 costimulation, and T helper cell 1-associated cytokines. J Exp Med. 1996 Jan 1;183(1):87–97. doi: 10.1084/jem.183.1.87. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. del Guercio M. F., Sidney J., Hermanson G., Perez C., Grey H. M., Kubo R. T., Sette A. Binding of a peptide antigen to multiple HLA alleles allows definition of an A2-like supertype. J Immunol. 1995 Jan 15;154(2):685–693. [PubMed] [Google Scholar]

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