Skip to main content

Advertisement

SpringerLink
Log in

Therapeutic vaccination with tumor cells that engage CD137

  • Review
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

Therapeutic cancer vaccination is based on the finding that tumors in both humans and experimental animals, such as mice, express potential immunological targets, some of which have high selectivity for cancer cells. In contrast to the successful vaccination against some infectious diseases, where most vaccines induce neutralizing antibodies that act prophylactically, the aim of therapeutic cancer vaccines is to treat established tumors (primarily micrometastases). Since most tumor-destructive immune responses are cell-mediated, therapeutic cancer vaccination needs to induce and expand such responses and also to overcome "escape" mechanisms that allow tumors to evade immunological destruction. Tumor antigens (as with other antigens) are presented by "professional" antigen-presenting cells, most notably dendritic cells (DC). Therefore DC that have been transfected or "pulsed" to present antigen provide a logical source of tumor vaccines, and some encouraging results have been obtained clinically as well as in preclinical models. An alternative and more physiological approach is to develop vaccines that deliver tumor antigen for in vivo uptake and presentation by the DC. Vaccines of the latter type include tumor cells that have been modified to produce certain lymphokines or express costimulatory molecules, as well as cDNAs, recombinant viruses, proteins, peptides and glycolipids which are often given together with an adjuvant. Several studies over the past 5 years have demonstrated dramatic therapeutic responses against established mouse tumors as a result of repeated injections of agonistic monoclonal antibodies (MAbs) to the costimulatory molecule CD137 (4-1BB). However, the clinical use of such MAbs may be problematic since they depress antibody formation, for example, to infectious agents. The alternative approach to transfect tumor cells to express the CD137 ligand (CD137L) increases their immunogenicity, but vaccination with tumor cells expressing CD137L is ineffective in several systems where injection of anti-CD137 MAb produces tumor regression. Recent findings indicate that a more effective way to engage CD137 towards tumor destruction is to transfect tumor cells to express a cell-bound form of anti-CD137 single-chain Fv fragments (scFv). Notably, tumors from melanoma K1735, growing either subcutaneously or in the lung, could be eradicated following vaccination with K1735 cells that expressed anti-CD137 scFv. This was in spite of the fact that K1735, as with many human neoplasms, expresses very low levels of MHC class I and has low immunogenicity. Similar results were subsequently obtained with other tumors of low immunogenicity, including sarcoma Ag104. We hypothesize that the concomitant expression of tumor antigen and anti-CD137 scFv effectively engages NK cells, monocytes and dendritic cells, as well as activated CD4+ and CD8+ T cells (all of which express CD137) so as to induce and expand a tumor-destructive Th1 response. While vaccines in the form of transfected tumor cells can be effective, at least in mouse models, the logical next step is to construct vaccines that combine genes that encode molecularly defined tumor antigens with a gene that encodes anti-CD137 scFv. Before planning any clinical trials, vaccines that engage CD137 via scFv need to be compared in demanding mouse models for efficacy and side effects with vaccines that are already being tested clinically, including transfected DC and tumor cells producing granulocyte-macrophage colony-stimulating factor.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1.
Fig. 2.

Similar content being viewed by others

Abbreviations

APC :

Antigen-presenting cell

CT :

Cancer/testis

CTL :

Cytotoxic T-lymphocyte

DC :

Dendritic cell

IFN :

Interferon

IL :

Interleukin

MAb :

Monoclonal antibody

NK :

Natural killer

scFv :

Single-chain Fv

TCR :

T cell receptor

TGF :

Transforming growth factor

TNF :

Tumor necrosis factor

WT :

Wild type

References

  1. Hellstrom I, Hellstrom KE, Pierce GE, Bill AH (1968) Demonstration of cell-bound and humoral immunity against neuroblastoma cells. Proc Natl Acad Sci U S A 60:1231–1238

    CAS  PubMed  Google Scholar 

  2. Hellstrom I, Hellstrom KE, Pierce GE, Yang JP (1968) Cellular and humoral immunity to different types of human neoplasms. Nature 220:1352–1354

    CAS  PubMed  Google Scholar 

  3. Bubenik J, Perlmann P, Helmstein K, Moberger G (1970) Cellular and humoral immune responses to human urinary bladder carcinomas. Int J Cancer 5:310–319

    CAS  PubMed  Google Scholar 

  4. Baldwin RW, Embleton MJ, Jones JS, Langman MJS (1973) Cell mediated and humoral immune reactions to human tumors. Int J Cancer 12:73–83

    CAS  PubMed  Google Scholar 

  5. Cochran AJ, Grant RM, Spilg WG, et al (1974) Sensitization to tumour-associated antigens in human breast carcinoma. Int J Cancer 14:19–25

    CAS  PubMed  Google Scholar 

  6. Herberman RB (1974) Cell-mediated immunity to tumor cells. Adv Cancer Res 19:207–263

    CAS  PubMed  Google Scholar 

  7. McCoy JL, Jerome LF, Dean JH, et al (1975) Inhibition of leukocyte migration by tumor-associated antigens in soluble extracts of human malignant melanoma. J Natl Cancer Inst 55:19–23

    CAS  PubMed  Google Scholar 

  8. McCoy JL, Jerome LF, Cannon GB, Weese JL, Herberman RB (1977) Reactivity of lung cancer patients in leukocyte migration inhibition assays to 3-M potassium chloride extracts of fresh tumor and tissue-cultured cells derived from lung cancer. J Natl Cancer Inst 59:1413–1418

    CAS  PubMed  Google Scholar 

  9. de Vries JE, Rumke P (1976) Tumour-associated lymphocyte cytotoxicity superimposed on "spontaneous" cytotoxicity in melanoma patients. Int J Cancer 17:182–190

    PubMed  Google Scholar 

  10. de Vries JE, Spits H (1984) Cloned human cytotoxic T lymphocyte (CTL) lines reactive with autologous melanoma cells. I. In vitro generation, isolation, and analysis to phenotype and specificity. J Immunol 132:510–519

    PubMed  Google Scholar 

  11. Cannon GB, Bonnard GD, Djeu J, West WH, Herberman RB (1977) Relationship of human natural lymphocyte-mediated cytotoxicity to cytotoxicity of breast-cancer-derived target cells. Int J Cancer 19:487–497

    CAS  PubMed  Google Scholar 

  12. Hellstrom I, Hellstrom KE (1998) Tumor vaccines—a reality at last? J Immunother 21:119–126

    CAS  PubMed  Google Scholar 

  13. Wallack MK, Bash J (1992) Vaccinia oncosylates as melanoma vaccines. In: Balch CM (ed) Cutaneous melanoma. Lippincott, Philadelphia, pp 548–550

  14. Boon T, Cerottini JC, Van den Eynde B, van der Bruggen P, Van Pel A (1994) Tumor antigens recognized by T lymphocytes. Annu Rev Immunol 12:337–365

    Article  CAS  PubMed  Google Scholar 

  15. Melief CJ, Kast WM (1994) Prospects for T cell immunotherapy of tumours by vaccination with immunodominant and subdominant peptides. Ciba Found Symp 187:97–104

    CAS  PubMed  Google Scholar 

  16. Hellstrom KE, Hellstrom I, Chen L (1995) Can co-stimulated tumor immunity be therapeutically efficacious? Immunol Rev 145:123–145

    CAS  PubMed  Google Scholar 

  17. Pardoll DM (2000) Therapeutic vaccination for cancer. Clin Immunol 95:S44–S62

    CAS  PubMed  Google Scholar 

  18. Boon T (1992) Toward a genetic analysis of tumor rejection antigens. Adv Cancer Res 58:177–210

    CAS  PubMed  Google Scholar 

  19. Rosenberg SA (1992) Karnofsky Memorial Lecture. The immunotherapy and gene therapy of cancer. J Clin Oncol 10:180–199

    CAS  PubMed  Google Scholar 

  20. Cheever MA, Disis ML, Bernhard H, et al (1995) Immunity to oncogenic proteins. Immunol Rev 145:33–59

    CAS  PubMed  Google Scholar 

  21. Old LJ, Chen YT (1998) New paths in human cancer serology. J Exp Med 187:1163–1167

    CAS  PubMed  Google Scholar 

  22. Rosenberg SA (2001) Progress in human tumour immunology and immunotherapy. Nature 411:380–384

    CAS  PubMed  Google Scholar 

  23. Scanlan MJ, Chen YT, Williamson B, et al (1998) Characterization of human colon cancer antigens recognized by autologous antibodies. Int J Cancer 76:652–658

    CAS  PubMed  Google Scholar 

  24. Nishikawa H, Tanida K, Ikeda H, et al (2001) Role of SEREX-defined immunogenic wild-type cellular molecules in the development of tumor-specific immunity. Proc Natl Acad Sci U S A 98:14571–14576

    Article  CAS  PubMed  Google Scholar 

  25. Ye C, Savage PA, Lee PP, Davis MM, Greenberg PD (1999) Isolation of high avidity melanoma-reactive CTL from heterogeneous populations using peptide-MHC tetramers. J Immunol 162

  26. Boon T, Coulie PG, Van den Eynde B (1997) Tumor antigens recognized by T cells. Immunol Today 18:267–268

    CAS  PubMed  Google Scholar 

  27. Pardoll DM (1996) Cancer vaccines: a road map for the next decade. Curr Opin Immunol 8:619–621

    Article  CAS  PubMed  Google Scholar 

  28. Hellstrom KE, Hellstrom I (1999) Cancer Vaccines. In: Perlmann P, Wigzell H (eds) Handbook of experimental pharmacology. Springer, Berlin Heidelberg New York, pp 463–478

  29. Steinman RM, Dhodapkar M (2001) Active immunization against cancer with dendritic cells: the near future. Int J Cancer 94:459–473

    CAS  PubMed  Google Scholar 

  30. Nestle FO, Alijagic S, Gilliet M, et al (1998) Vaccination of melanoma patients with peptide- or tumor lysate-pulsed dendritic cells. Nat Med 4:328–332

    CAS  PubMed  Google Scholar 

  31. Rosenberg SA, Yang JC, Schwartzentruber DJ, et al (1998) Immunologic and therapeutic evaluation of a synthetic peptide vaccine for the treatment of patients with metastatic melanoma. Nat Med 4:321–327

    CAS  PubMed  Google Scholar 

  32. Gross L (1943) Intradermal immunization of C3H mice against a sarcoma that originated in an animal of the same line. Cancer Res 3:326–333

    Google Scholar 

  33. Foley EJ (1953) Antigenic properties of methylcholanthrene-induced tumor in mice of the strain of origin. Cancer Res 13:835–837

    CAS  Google Scholar 

  34. Prehn R, Main D (1957) Immunity to methylcholanthrene-induced sarcomas. J Natl Cancer Inst 18:769–778

    CAS  Google Scholar 

  35. Klein G, Sjögren HO, Klein E, Hellström KE (1960) Demonstration of resistance against methylcholanthrene-induced sarcomas in the primary autochthonous host. Cancer Res 20:1561–1572

    CAS  Google Scholar 

  36. Hewitt HB, Blake ER, Walder AS (1976) A critique of the evidence for active host defence against cancer, based on personal studies of 27 murine tumours of spontaneous origin. Br J Cancer 33:241–259

    CAS  PubMed  Google Scholar 

  37. Malins DC, Polissar NL, Gunselman SJ (1996) Progression of human breast cancers to the metastatic state is linked to hydroxyl radical-induced DNA damage. Proc Natl Acad Sci USA 93:2557–2563

    Article  CAS  PubMed  Google Scholar 

  38. Vaage J (1968) Nonvirus-associated antigens in virus-induced mouse mammary tumors. Cancer Res 28:2477–2483

    CAS  PubMed  Google Scholar 

  39. Shiku H, Takahashi T, Oettgen HF (1976) Cell surface antigens of human malignant melanoma. II. Serological typing with immune adherence assays and definition of two new surface antigens. J Exp Med 144:873–881

    CAS  PubMed  Google Scholar 

  40. Hsu FJ, Benike C, Fagnoni F, et al (1996) Vaccination of patients with B-cell lymphoma using autologous antigen-pulsed dendritic cells. Nat Med 2:52–58

    CAS  PubMed  Google Scholar 

  41. Noguchi Y, Chen Y-T, Old LJ (1994) A mouse mutant p53 product recognized by CD4+ and CD8+ T cells. Proc Natl Acad Sci U S A 91:3171–3175

    CAS  PubMed  Google Scholar 

  42. Wolfel T, Hauer M, Schneider J, et al (1995) A p16INK4a-insensitive CDK4 mutant targeted by cytolytic T lymphocytes in a human melanoma. Science 269:1281–1284

    CAS  PubMed  Google Scholar 

  43. Hellstrom KE, Hellstrom I (1989) Oncogene-associated tumor antigens as targets for immunotherapy. FASEB J 3:1715–1722

    CAS  PubMed  Google Scholar 

  44. Sjogren HL, Hellstrom I, Klein G (1961) Transplantation of polyoma virus-induced tumors in mice. Cancer Res 21:329–337

    Google Scholar 

  45. Habel K (1962) Immunological determinants of polyoma virus oncogenesis. J Exp Med 115:181–193

    CAS  Google Scholar 

  46. Sjogren HO (1965) Transplantation methods as a tool for detection of tumor-specific antigens. Prog Exp Tumor Res 6:289–322

    CAS  PubMed  Google Scholar 

  47. Chen LP, Thomas EK, Hu SL, Hellström I, Hellström KE (1991) Human papillomavirus type 16 nucleoprotein E7 is a tumor rejection antigen. Proc Natl Acad Sci U S A 88:110–114

    CAS  PubMed  Google Scholar 

  48. Chen L, Mizuno MT, Singhal MC, et al (1992) Induction of cytotoxic T lymphocytes specific for a syngeneic tumor expressing the E6 oncoprotein of human papilloma virus type 16. J Immunol 148:2617–2621

    CAS  PubMed  Google Scholar 

  49. Bruggen P van der, Traversari C, Chomez P, et al (1991) A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science 254:1643–1647

    PubMed  Google Scholar 

  50. Boon T, van der Bruggen P (1996) Human tumor antigens recognized by T lymphocytes. J Exp Med 183:725–729

    CAS  PubMed  Google Scholar 

  51. Rosenberg SA (2000) Identification of cancer antigens: impact on development of cancer immunotherapies. Cancer J Sci Am 6 [Suppl 3]:S200–S207

    Google Scholar 

  52. Gold P, Freedman SO (1965) Specific carcinoembryonic antigens of the human digestive system. J Exp Med 122:467–481

    CAS  PubMed  Google Scholar 

  53. Greiner JW, Zeytin H, Anver MR, Schlom J (2002) Vaccine-based therapy directed against carcinoembryonic antigen demonstrates antitumor activity on spontaneous intestinal tumors in the absence of autoimmunity. Cancer Res 62:6944–6951

    CAS  PubMed  Google Scholar 

  54. Finn OJ, Jerome KR, Henderson RA, et al (1995) MUC-1 epithelial tumor mucin-based immunity and cancer vaccines. Immunol Rev 145:61–89

    CAS  PubMed  Google Scholar 

  55. Rosenberg SA (2000) The identification of cancer antigens: impact on the development of cancer vaccines. Cancer J Sci Am 6 [Suppl 2]:S142–s149

  56. Kahn M, Sugawara H, McGowan P, et al (1991) CD4+ T cell clones specific for the human p97 melanoma-associated antigen can eradicate pulmonary metastases from a murine tumor expressing the p97 antigen. J Immunol 146:3235–3241

    CAS  PubMed  Google Scholar 

  57. Hellstrom I, Hellstrom KE, Sjogren HO, Werner GA (1971) Demonstration of cell-mediated immunity to human neoplasms of various histological types. Int J Cancer 7:1–16

    CAS  PubMed  Google Scholar 

  58. Kadish AS, Marcus DM, Bloom BR (1976) Inhibition of leukocyte migration inhibitin by human breast cancer-associated antigens. Int J Cancer 18:581–586

    CAS  PubMed  Google Scholar 

  59. Morton DL, Malmgren RA, Holmes EC, Ketcham A (1968) Demonstration of antibodies against human malignant melanoma by immunofluorescence. Surgery 64:233–240

    CAS  PubMed  Google Scholar 

  60. Petricoin III EF, Ardekani AM, Hitt BA, et al (2002) Use of proteomic patterns in serum to identify ovarian cancer. The Lancet 359:572–577

    Article  CAS  Google Scholar 

  61. Hellstrom KE, Hellstrom I (1969) Cellular immunity against tumor specific antigens. Adv Cancer Res 12:167–223

    CAS  PubMed  Google Scholar 

  62. Greenberg PD (1991) Adoptive T cell therapy of tumors: mechanisms operative in the recognition and elimination of tumor cells. Adv Immunol 49:281–355

    CAS  PubMed  Google Scholar 

  63. Melief CJ, Kast WM (1995) T-cell immunotherapy of tumors by adoptive transfer of cytotoxic T lymphocytes and by vaccination with minimal essential epitopes. Immunol Rev 145:167–177

    CAS  PubMed  Google Scholar 

  64. Yee C, Thompson JA, Byrd D, Riddell SR, Roche P, Celis E, Greenberg PD (2002) Adoptive T cell therapy using antigen-specific CD8+ T cell clones for the treatment of patients with metastatic melanoma: In vivo persistence, migration, and antitumor effect of transferred T cells. Proc Natl Acad Sci USA 11:11

    Google Scholar 

  65. Ye Z, Hellstrom I, Hayden-Ledbetter M, Dahlin A, Ledbetter JA, Hellstrom KE (2002) Gene therapy for cancer using single-chain Fv fragments specific for 4-1BB. Nat Med 8:343–348

    Article  CAS  PubMed  Google Scholar 

  66. Schwartz RH (1989) Acquisition of immunologic self-tolerance. Cell 57:1073–1081

    CAS  PubMed  Google Scholar 

  67. Linsley PS, Ledbetter JA (1993) The role of the CD28 receptor during T cell responses to antigen. Annu Rev Immunol 11:191–212

    Article  CAS  PubMed  Google Scholar 

  68. Thompson CB, Lindsten T, Ledbetter JA, et al (1989) CD28 activation pathway regulates the production of multiple T-cell-derived lymphokines/cytokines. Proc Natl Acad Sci U S A 86:1333–1337

    CAS  PubMed  Google Scholar 

  69. Chen L, Ashe S, Brady WA, et al (1992) Costimulation of antitumor immunity by the B7 counterreceptor for the T lymphocyte molecules CD28 and CTLA-4. Cell 71:1093–1102

    CAS  PubMed  Google Scholar 

  70. Yang G, Hellström KE, Hellström I, Chen L (1995) Antitumor immunity elicited by tumor cells transfected with B7–2, a second ligand for CD28/CTLA-4 costimulatory molecules. J Immunol 154:2794–2800

    CAS  PubMed  Google Scholar 

  71. Huang AY, Golumbek P, Ahmadzadeh M, Jaffee E, Pardoll D, Levitsky H (1994) Role of bone marrow-derived cells in presenting MHC class I-restricted tumor antigens. Science 264:961–965

    CAS  PubMed  Google Scholar 

  72. Yang G, Mizuno MT, Hellström KE, Chen L (1997) B7-negative versus B7-positive P815 tumor: differential requirements for priming of an antitumor immune response in lymph nodes. J Immunol 158:851–858

    CAS  PubMed  Google Scholar 

  73. Ochsenbein AF, Sierro S, Odermatt B, et al (2001) Roles of tumour localization, second signals and cross priming in cytotoxic T-cell induction. Nature 411:1058–1064

    CAS  PubMed  Google Scholar 

  74. Melero I, Singhal MC, McGowan P, et al (1997) Immunological ignorance of an E7-encoded cytolytic T-lymphocyte epitope in transgenic mice expressing the E7 and E6 oncogenes of human papillomavirus type 16. J Virol 71:3998–4004

    CAS  PubMed  Google Scholar 

  75. Old LJ, Boyse EA (1964) Immunology of experimental tumors. Annu Rev Med 15:167–186

    CAS  Google Scholar 

  76. Fields RC, Shimizu J, Mule' JJ (1998) Murine dendritic cells pulsed with whole tumor lysates mediate potent antitumor immune responses in vitro and in vivo. Proc Natl Acad Sci U S A 95:9482–9487

    Article  CAS  PubMed  Google Scholar 

  77. Geiger JD, Hutchinson RJ, Hohenkirk LF, et al (2001) Vaccination of pediatric solid tumor patients with tumor-lysate pulsed dendritic cells can expand specific T cells and mediate tumor regression. Cancer Res 61:8513–8519

    PubMed  Google Scholar 

  78. Chen L, McGowan P, Ashe S, et al (1994) Tumor immunogenicity determines the effect of B7 costimulation on T cell-mediated tumor immunity. J Exp Med 179:523–532

    CAS  PubMed  Google Scholar 

  79. Townsend SE, Su FW, Atherton JM, Allison JP (1994) Specificity and longevity of antitumor immune responses induced by B7– transfected tumors. Cancer Res 54:6477–6483

    CAS  PubMed  Google Scholar 

  80. Clark EA, Ledbetter JA (1994) How B and T cells talk to each other Nature 367:425–428

    Google Scholar 

  81. Cayabyab M, Phillips JH, Lanier LL (1994) CD40 preferentially costimulates activation of CD4+ T lymphocytes. J Immunol 152:1523–1531

    CAS  PubMed  Google Scholar 

  82. Grewal IS, Flavell RA (1998) CD40 and CD154 in cell-mediated immunity. Annu Rev Immunol 16:111–135

    CAS  PubMed  Google Scholar 

  83. French RR, Chan HT, Tutt AL, Glennie MJ (1999) cD40 antibody evokes a cytotoxic T-cell response that eradicates lymphoma and bypasses T-cell help. Nat Med 5:548–553

    Article  CAS  PubMed  Google Scholar 

  84. Diehl L, den Boer AT, Schoenberger SP, et al (1999) CD40 activation in vivo overcomes peptide-induced periphereal cytotoxic T-lymphocyte tolerance and augments anti-tumor vaccine efficacy. Nat Med 5:774–779

    CAS  PubMed  Google Scholar 

  85. Schoenberger SP, Jonges LE, Mooijaart RJ, et al (1998) Efficient direct priming of tumor-specific cytotoxic T lymphocyte in vivo by an engineered APC. Cancer Res 58:3094–3100

    CAS  PubMed  Google Scholar 

  86. Todryk SM, Tutt AL, Green HA, et al (2001) CD40 ligation for immunotherapy of solid tumors. J Immunol Methods 248:139–147

    CAS  PubMed  Google Scholar 

  87. Li Y, Hellström KE, Ashe Newby S, Chen L (1996) Costimulation by CD48 and B7–1 induces immunity against poorly immunogenic tumors. J Exp Med 183:639–644

    CAS  PubMed  Google Scholar 

  88. Liu X, Bai XF, Wen J, et al (2001) B7H costimulates clonal expansion of, and cognate destruction of tumor cells by, CD8 (+) T lymphocytes in vivo. J Exp Med 194:1339–1348

    Article  CAS  PubMed  Google Scholar 

  89. Loetze MT, Hellerstedt B, Stolinski L, et al (1997) The role of interleukin-2, interleukin-12, and dendritic cells in cancer therapy. Cancer J Sci Am [Suppl 1]:S109–S114

  90. Walunas TL, Lenschow DJ, Bakker CY, et al (1994) CTLA-4 can function as a negative regulator of T cell activation. Immunity 1:405–413

    CAS  PubMed  Google Scholar 

  91. Krummel MF, Allison JP (1996) CTLA-4 engagement inhibits IL-2 accumulation and cell cycle progression upon activation of resting T cells. J Exp Med 183:2533–2540

    CAS  PubMed  Google Scholar 

  92. Leach DR, Krummel MF, Allison JP (1996) Enhancement of antitumor immunity by CTLA-4 blockade. Science 271:1734–1736

    CAS  PubMed  Google Scholar 

  93. Egen JG, Kuhns MS, Allison JP (2002) CTLA-4: new insights into its biological function and use in tumor immunotherapy. Nat Immunol 3:611–618

    Article  CAS  PubMed  Google Scholar 

  94. Winberg G, Grosmaire LS, Klussman K, et al (1996) Surface expression of CD28 single chain Fv for costimulation by tumor cells. Immunol Rev 153:209–223

    CAS  PubMed  Google Scholar 

  95. Hayden MS, Gilliland LK, Ledbetter JA (1997) Antibody engineering. Curr Opin Immunol 9:201–212

    Article  CAS  PubMed  Google Scholar 

  96. Hayden MS, Grosmaire LS, Norris NA, et al (1996) Costimulation by CD28 sFv expressed on the tumor cell surface or as a soluble bispecific molecule targeted to the L6 carcinoma antigen. Tissue Antigens 48:242–254

    CAS  PubMed  Google Scholar 

  97. Kiessling R, Wasserman K, Horiguchi S, et al (1999) Tumor-induced immune dysfunction. Cancer Immunol Immunother 48:353–362

    Article  CAS  PubMed  Google Scholar 

  98. Mizoguchi H, O'Shea JJ, Longo DL, Loeffler CM, McVicar DW, Ochoa AC (1992) Alterations in signal transduction molecules in T lymphocytes from tumor-bearing mice. Science 258:1795–1798

    CAS  PubMed  Google Scholar 

  99. Nakagomi H, Petersson M, Magnusson I, et al (1993) Decreased expression of the signal-transducing z chains in tumor-infiltrating T cells and NK cells of patients with colorectal carcinoma. Cancer Res 53:5610–5612

    CAS  PubMed  Google Scholar 

  100. Hellstrom I, Hellstrom KE, Evans CA, Heppner GH, Pierce GE, Yang JP (1969) Serum-mediated protection of neoplastic cells from inhibition by lymphocytes immune to their tumor-specific antigens. Proc Natl Acad Sci U S A 62:362–369

    CAS  PubMed  Google Scholar 

  101. Hellstrom KE, Hellstrom I (1974) Lymphocyte-mediated cytotoxicity and blocking serum activity to tumor antigens. Adv Immunol 18:209–277

    CAS  PubMed  Google Scholar 

  102. Hellstrom KE, Hellstrom I (1979) Enhancement of tumor outgrowth by tumor-associated blocking factors. Int J Cancer 23:366–373

    CAS  PubMed  Google Scholar 

  103. Sjogren HO, Hellstrom I, Bansal SC, Hellstrom KE (1971) Suggestive evidence that the "blocking antibodies" of tumor-bearing individuals may be antigen-antibody complexes. Proc Natl Acad Sci U S A 68:1372–1375

    CAS  PubMed  Google Scholar 

  104. Vaage J (1972) Specific desensitizationof resistance against a syngeneic methylcholanthrene-induced sarcoma in C3Hf mice. Cancer Res 32:193––199

    CAS  PubMed  Google Scholar 

  105. Alexander P (1974) Escape from immune destruction by the host through shedding of surface antigens: is this a characteristic shared by malignant and embryonic cells? Cancer Res 34:2077–2082

    CAS  PubMed  Google Scholar 

  106. Gabathuler R, Alimonti J, Zhang QJ, Kolaitis G, Reid G, Jefferies WA (1998) Surrogate antigen processing mediated by TAP-dependent antigenic peptide secretion. J Cell Biol 140:17–27

    Article  CAS  PubMed  Google Scholar 

  107. Nelson MB, Nyhus JK, Oravecz-Wilson KI, Barbera-Guillem E (2001) Tumor cells express FcgammaRI which contributes to tumor cell growth and a metastatic phenotype. Neoplasia 3:115–124

    Article  CAS  PubMed  Google Scholar 

  108. Barrionuevo P, Beigier-Bompadre M, De La Barrera S, et al (2001) Immune complexes (IC) down-regulate the basal and interferon-gamma-induced expression of MHC class II on human monocytes. Clin Exp Immunol 125:251–257

    Article  CAS  PubMed  Google Scholar 

  109. Gabrilovich DI, Ciernik IF, Carbone DP (1996) Dendritic cells in antitumor immune responses. I. defective antigen presentation in tumor-bearing hosts. Cell Immunol 170:101–110

    Article  CAS  PubMed  Google Scholar 

  110. Gabrilovich DI, Nadaf S, Corak J, Berzofsky JA, Carbone DP (1996) Dendritic cells in anti-tumor immune responses. II. Dendritic cells grown from bone marrow precursors, but not mature DC from tumor-bearing mice are effective antigen carriers in the therapy of established tumors. Cell Immunol 170:111–119

    Article  CAS  PubMed  Google Scholar 

  111. Gershon RK, Mokyr MB, Mitchell MS (1974) Activation of suppressor T cells by tumour cells and specific antibody. Nature 250:594–596

    CAS  PubMed  Google Scholar 

  112. Hellstrom KE, Hellstrom I (1978) Evidence that tumor antigens enhance tumor growth in vivo by interacting with a radiosensitive (suppressor?) cell population. Proc Natl Acad Sci U S A 74:4605–4609

    Google Scholar 

  113. North RJ (1985) Down-regulation of the antitumor immune response. Adv Cancer Res 45:1–43

    CAS  PubMed  Google Scholar 

  114. Hellstrom KE, Hellstrom I (1981) Cell-mediated suppression of tumor immunity has a nonspecific component. I. Evidence from transplantation tests. Int J Cancer 27:481–485

    CAS  PubMed  Google Scholar 

  115. Coggin JH Jr (1986) The implications of embryonic gene expression in neoplasia. Crit Rev Oncol Hematol 5:37–55

    PubMed  Google Scholar 

  116. Shimizu J, Yamazaki S, Sakaguchi M (1999) Induction of tumor immunity by removing CD25+CD4+ T cells: a common basis between tumor immunity and autoimmunity. J Immunol 163:5211–5218

    CAS  PubMed  Google Scholar 

  117. Shimizu J, Yamazaki S, Takahashi T, Ishida Y, Sakaguchi S (2002) Stimulation of CD25+CD4+ regulatory T cells through GITR breaks immunological self-tolerance. Nat Immunol 3:135–142

    Article  CAS  Google Scholar 

  118. Liyanage UK, Moore TT, Joo H-G, et al (2002) Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J Immunol 169:2756–2761

    CAS  PubMed  Google Scholar 

  119. Wilbanks GA, Mammolenti M, Streilein JW (1992) Studies on the induction of anterior chamber-associated immune deviation (ACAID). III. Induction of ACAID depends upon intraocular transforming growth factor-beta. Eur J Immunol 22:165–173

    CAS  PubMed  Google Scholar 

  120. D'Orazio TJ, Niederkorn JY (1998) A novel role for TGF-beta and IL-10 in the induction of immune privilege. J Immunol 160:2089–2098

    CAS  PubMed  Google Scholar 

  121. Chen W, Jin W, Wahl SM (1998) Engagement of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) induces transforming growth factor beta (TGF-beta) production by murine CD4 (+) T cells. J Exp Med 188:1849–1857

    Article  CAS  PubMed  Google Scholar 

  122. Allison JP, Chambers C, Hurwitz A, et al (1998) A role for CTLA-4-mediated inhibitory signals in peripheral T cell tolerance? Novartis Found Symp 215:92–98

    CAS  PubMed  Google Scholar 

  123. Nakamura K, Kitani A, Strober W (2001) Cell contact-dependent immunosuppression by CD4 (+) CD25 (+) regulatory T cells is mediated by cell surface-bound transforming growth factor beta. J Exp Med 194:629–644

    Article  CAS  PubMed  Google Scholar 

  124. Gorelik L, Flavell RA (2001) Immune-mediated eradication of tumors through the blockade of transforming growth factor-beta signaling in T cells. Nat Med 7:1118–1122

    Article  CAS  PubMed  Google Scholar 

  125. Goodwin JS, Bankhurst AD, Messner RP (1977) Suppression of human T-cell mitogenesis by prostaglandin. Existence of a prostaglandin-producing suppressor cell. J Exp Med 146:1719–1734

    CAS  PubMed  Google Scholar 

  126. Hegardt P, Widegren B, Sjogren HO (2000) Nitric-oxide-dependent systemic immunosuppression in animals with progressively growing malignant gliomas. Cell Immunol 200:116–127

    Article  CAS  PubMed  Google Scholar 

  127. Hahne M, Rimoldi D, Schroter M, et al (1996) Melanoma cell expression of Fas (Apo-1/CD95) ligand: implications for tumor immune escape. Science 274:1363–1366

    CAS  PubMed  Google Scholar 

  128. Kume T, Oshima K, Yamashita Y, Shirakusa T, Kikuchi M (1999) Relationship between Fas-ligand expression on carcinoma cell and cytotoxic T-lymphocyte response in lymphoepithelioma-like cancer of the stomach. Int J Cancer 84:339–343

    Google Scholar 

  129. Bennett MW, O'Connell J, O'Sullivan GC, et al (1998) The Fas counterattack in vivo: apoptotic depletion of tumor-infiltrating lymphocytes associated with Fas ligand expression by human esophageal carcinoma. J Immunol 160:5669–5675

    CAS  PubMed  Google Scholar 

  130. Shiraki K, Tsuji N, Shioda T, Isselbacher KJ, Takahashi H (1997) Expression of Fas ligand in liver metastases of human colonic adenocarcinomas. Proc Natl Acad Sci U S A 94:6420–6425

    Article  CAS  PubMed  Google Scholar 

  131. Chappell DB, Zaks TZ, Rosenberg SA, Restifo NP (1999) Human melanoma cells do not express Fas (Apo-1/CD95) ligand. Cancer Res 59:59–62

    Google Scholar 

  132. Dong H, Strome SE, Salomao D, et al (2002) Tumor-associated By-H1 promotes T-cell apoptosis. A potential mechanism of immune-evasion. Nat Med 8:793–800

    Google Scholar 

  133. Groh V, Wu J, Yee C, Spies T (2002) Tumour-derived soluble MIC ligands impair expression of NKG2D and T-cell metastases of human colonic adenocarcinomas. Nature 419:734–738

    Google Scholar 

  134. Maeurer MJ, Gollin SM, Martin D, et al (1996) Tumor escape from immune recognition: lethal recurrent melanoma in a patient associated with downregulation of the peptide transporter protein TAP-1 and loss of expression of the immunodominant MART-1/Melan-A antigen. J Clin Invest 98:1633–1641

    CAS  PubMed  Google Scholar 

  135. Jefferies WA, Kolaitis G, Gabathuler R (1993) The interferon-gamma-induced recognition of the antigen—processing variant CMT.64 by cytolytic T cells can be replaced by sequential addition of beta2 microglobulin and antigenic peptides. J Immunol 151:2974–2985

    CAS  PubMed  Google Scholar 

  136. Restifo NP, Esquivel F, Kawakami Y, et al (1993) Identification of human cancers deficient in antigen processing. J Exp Med 177:265–272

    CAS  PubMed  Google Scholar 

  137. Garrido F, Ruiz-Cabello F, Cabrera T, et al (1997) Implications for immunosurveillance of altered HLA class I phenotypes in human tumors. Immunol Today 18:89–95

    CAS  PubMed  Google Scholar 

  138. Johnsen A, France J, Sy MS, Harding CV (1998) Down-regulation of the transporter for antigen presentation, proteasome subunits, and class I major histocompatibility complex in tumor cell lines. Cancer Res 58:3660–3667

    CAS  PubMed  Google Scholar 

  139. Seliger B, Maeurer MJ, Ferrone S (2000) Antigen-processing machinery breakdown and tumor growth. Immunol Today 21:455–464

    Article  CAS  PubMed  Google Scholar 

  140. Porgador A, Tzehoval E, Vadai E, Feldman M, Eisenbach L (1995) Combined vaccination with major histocompatibility class I and interleukin 2 gene-transduced melanoma cells synergizes the cure of postsurgical established lung metastases. Cancer Res 55:4941–4949

    CAS  PubMed  Google Scholar 

  141. Hellstrom KE, Gladstone P, Hellstrom I (1997) Cancer vaccines: challenges and potential solutions. Mol Med Today 3:286–290

    Article  CAS  PubMed  Google Scholar 

  142. Kärre K (1995) Express yourself or die: peptides, MHC molecules, and NK cells. Science 267:978–979

    PubMed  Google Scholar 

  143. Gabathuler R, Reid G, Kolaitis G, Driscoll J, Jefferies WA (1994) Comparison of cell lines deficient in antigen presentation reveals a functional role for TAP-1 alone in antigen processing. J Exp Med 180:1415–1425

    CAS  PubMed  Google Scholar 

  144. Chen HL, Gabrilovich DI, Tampe R, Girgis KR, Nadaf S, Carbone DP (1996) A functionally defective allele of TAP1 results in loss of MHC class I antigen presentation in a human lung cancer. Nat Genet 13:210–213

    CAS  PubMed  Google Scholar 

  145. Alimonti J, Zhang QJ, Gabathuler R, Reid G, Chen S, Jefferies WA (2000) TAP expression provides a general method for improving the recognition of malignant cells in vivo. Nat Biotechnol 18:515–520

    CAS  PubMed  Google Scholar 

  146. Coley W (1896) Further observations upon the treatment of malignant tumors with the toxins of erysipelas and Bacillus prodigiosus with a report of 160 cases. Bull Johns Hopkins Hosp 7:157

    Google Scholar 

  147. Wilson RE, Hager EB, Hampers CL, Corson JM, Merrill JP, Murray JE (1968) Immunologic rejection of human cancer transplanted with a renal allograft. N Engl J Med 278:479–483

    CAS  PubMed  Google Scholar 

  148. Matter B, Zukoski CF, Killen DA, Ginn E (1970) Transplanted carcinoma in an immunosuppressed patient. Transplantation 9:71–74

    CAS  PubMed  Google Scholar 

  149. McSweeney PA, et al (2001) Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood 97:3390–3400

    CAS  PubMed  Google Scholar 

  150. Childs et al (2000) Regression of metastatic renal cell carcinoma after nonmyeloablative allogeneic peripheral blood stem cell transplantation. N Engl J Med 343:750–758

    CAS  PubMed  Google Scholar 

  151. Mihich E (1987) Modulation of antitumor immune responses. Cancer Detect Prev Suppl 1:399–407

    CAS  PubMed  Google Scholar 

  152. Hellstrom KE, Hellstrom I, Kant JA, Tamerius JD (1978) Regression and inhibition of sarcoma growth by interference with a radiosensitive T cell population. J Exp Med 148:799–804

    CAS  PubMed  Google Scholar 

  153. North RJ (1986) Radiation-induced, immunologically mediated regression of an established tumor as an example of successful therapeutic immunomanipulation. Preferential elimination of suppressor T cells allows sustained production of effector T cells. J Exp Med 164:1652–1666

    CAS  PubMed  Google Scholar 

  154. Askenase PW, Hayden BJ, Gershon RK (1975) Augmentation of delayed-type hypersensitivity by doses of cyclophosphamide which do not affect antibody responses. J Exp Med 141:697–702

    CAS  PubMed  Google Scholar 

  155. Einhorn LH, Donohue JP (1998) Advanced testicular cancer: update for urologists. J Urol 160:1964–1969

    CAS  PubMed  Google Scholar 

  156. Bhatia S, Abonour R, Porcu P, et al (2000) High-dose chemotherapy as initial salvage chemotherapy in patients with relapsed testicular cancer. J Clin Oncol 18:3346–3351

    CAS  PubMed  Google Scholar 

  157. Aubry F, Satie AP, Rioux-Leclercq N, et al (2001) MAGE-A4, a germ cell specific marker, is expressed differentially in testicular tumors. Cancer 92:2778–2785

    Article  CAS  PubMed  Google Scholar 

  158. Yuasa T, Okamoto K, Kawakami T, Mishina M, Ogawa O, Okada Y (2001) Expression patterns of cancer testis antigens in testicular germ cell tumors and adjacent testicular tissue. J Urol 165:1790–1794

    CAS  PubMed  Google Scholar 

  159. Hara I, Hara S, Miyake H, et al (1999) Expression of MAGE genes in testicular germ cell tumors. Urology 53:843–847

    Article  CAS  PubMed  Google Scholar 

  160. Marks A, Sutherland DR, Bailey D, et al (1999) Characterization and distribution of an oncofetal antigen (M2A antigen) expressed on testicular germ cell tumoours. Br J Cancer 80:569–578

    Article  CAS  PubMed  Google Scholar 

  161. Kendall A, Gilmore R, Newlands E (2002) Chemotherapy for trophoblastic disease: current standards. Curr Opin Obstet Gynecol 14:33–38

    Article  PubMed  Google Scholar 

  162. Lurain JR (2002) Advances in management of high-risk gestational trophoblastic tumors. J Reprod Med 47:451–459

    CAS  PubMed  Google Scholar 

  163. Hellstrom I, Ledbetter JA, Scholler N, et al (2001) CD3-mediated activation of tumor-reactive lymphocytes from patients with advanced cancer. Proc Natl Acad Sci U S A 98:6783–6788

    Article  CAS  PubMed  Google Scholar 

  164. Gerosa F, Baldani-Guerra B, Nisii C, Marchesini V, Carra G, Trinchieri G (2002) Reciprocal activating interaction between natural killer cells and dendritic cells. J Exp Med 195:327–333

    Article  CAS  PubMed  Google Scholar 

  165. Piccioli D, Sbrana S, Melandri E, Valiante NM (2002) Contact-dependent stimulation and inhibition of dendritic cells by natural killer cells. J Exp Med 195:335–341

    Article  CAS  PubMed  Google Scholar 

  166. Zitvogel L (2002) Dendritic and natural killer cells cooperate in the control/switch of innate immunity. J Exp Med 195:F9–F14

    Article  CAS  PubMed  Google Scholar 

  167. Levine BL, Bernstein WB, Connors M, et al (1997) Effects of CD28 costimulation on long-term proliferation of CD4+ T cells in the absence of exogenous feeder cells. J Immunol 159:5921–5930

    CAS  PubMed  Google Scholar 

  168. Garlie NK, LeFever AV, Siebenlist RE, Levine BL, June CH, Lum LG (1999) T cells coactivated with immobilized anti-CD3 and anti-CD28 as potential immunotherapy for cancer. J Immunother 22:336–345

    CAS  PubMed  Google Scholar 

  169. Niethammer AG, Xiang R, Becker JC, et al (2002) A DNA vaccine against VEGF receptor 2 prevents effective angiogenesis and inhibits tumor growth. Nat Med 8:1369–1375

    Article  CAS  PubMed  Google Scholar 

  170. Folkman J (1998) Antiangiogenic gene therapy. Proc Natl Acad Sci U S A 95:9064–9066

    CAS  PubMed  Google Scholar 

  171. Shibagaki N, Udey MC (2002) Dendritic cells transduced with protein antigens induce cytotoxic lymphocytes and elicit antitumor immunity. J Immunol 168:2393–2401

    CAS  PubMed  Google Scholar 

  172. Min WP, Gorczynski R, Huang XY, et al (2000) Dendritic cells genetically engineered to express Fas ligand induce donor-specific hyporesponsiveness and prolong allograft survival. J Immunol 164:161–167

    CAS  PubMed  Google Scholar 

  173. Gabrilovich DI, Chen HL, Girgis KR, et al (1996) Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat Med 2:1096–1103

    CAS  PubMed  Google Scholar 

  174. Srivastava PK (1993) Peptide-binding heat shock proteins in the endoplasmic reticulum: role in immune response to cancer and in antigen presentation. Adv Cancer Res 62:153–177

    CAS  PubMed  Google Scholar 

  175. Srivastava P (2002) Roles of heat-shock proteins in innate and adoptive immunity. Nat Rev Immunol 2:185–194

    Article  CAS  PubMed  Google Scholar 

  176. Kao JH, Chen DS (2002) Global control of hepatitis B virus infection. Lancet Infect Dis 2:395–403

    Article  PubMed  Google Scholar 

  177. Hausen H zur (1987) Papillomaviruses in human cancer. Cancer 59:1692–1696

    PubMed  Google Scholar 

  178. Sparkes AH (1997) Feline leukaemia virus: a review of immunity and vaccination. J Small Anim Pract 38:187–194

    CAS  PubMed  Google Scholar 

  179. Kwon BS et al (1997) A newly identified member of the tumor necrosis factor receptor superfamily with a wide tissue distribution and involvement in lymphocyte activation. J Biol Chem 272:14272–14276

    Article  CAS  PubMed  Google Scholar 

  180. DeBenedette MA, Chu NR, Pollok KE, et al (1995) Role of 4-1BB ligand in costimulation of T lymphocyte growth and its upregulation on M12 B lymphomas by cAMP. J Exp Med 181:985–992

    CAS  PubMed  Google Scholar 

  181. Shuford WW, Klussman K, Tritchler DD, et al (1997) 4-1BB costimulatory signals preferentially induce CD8+ T cell proliferation and lead to the amplification in vivo of cytotoxic T cell responses. J Exp Med 186:47–55

    Article  CAS  PubMed  Google Scholar 

  182. Melero I, Johnston JV, Shufford WW, Mittler RS, Chen L (1998) NK1.1 cells express 4-1BB (CDw137) costimulatory molecule and are required for tumor immunity elicited by anti-4-1BB monoclonal antibodies. Cell Immunol 190:167–172

    Article  CAS  PubMed  Google Scholar 

  183. Kienzle G, von Kempis J (2000) CD137 (ILA/4–4-1BB), expressed by primary human monocytes, induces monocyte activation and apoptosis of B lymphocytes. Int Immunol 12:73–82

    Article  CAS  PubMed  Google Scholar 

  184. Langstein J, Schwartz H (1999) Identification of CD137 as a potent monocyte survival factor. J Leukoc Biol 65:829–833

    CAS  PubMed  Google Scholar 

  185. Futagawa T, Akiba H, Kodama T, et al (2002) Expression and function of 4-1BB and 4-1BB ligand on murine dendritic cells. Int Immunol 14:275–286

    Article  CAS  PubMed  Google Scholar 

  186. Kim YJ, Kim SH, Mantel P, Kwon BS (1998) Human 4-1BB regulates CD28 co-stimulation to promote Th1 cell responses. Eur J Immunol 28:881–890

    Article  CAS  PubMed  Google Scholar 

  187. Hurtado JC, Kim YJ, Kwon BS (1997) Signals through 4-1BB are costimulatory to previously activated splenic T cells and inhibit activation-induced cell death. J Immunol 158:2600–2609

    CAS  PubMed  Google Scholar 

  188. Takahashi C, Mittler RS, Vella AT (1999) Cutting edge: 4-1BB is a bona fide CD8 T cell survival signal. J Immunol 162:5037–5040

    CAS  PubMed  Google Scholar 

  189. Tsushima H, Imaizumi Y, Imanishi D, Fuchigami K, Tomonaga M (1999) Fas antigen (CD95) in pure erythroid cell line AS-E2 is induced by interferon-gamma and tumor necrosis factor-alpha and potentiates apoptotic death. Exp Hematol 27:433–440

    Article  CAS  PubMed  Google Scholar 

  190. Natoli G, Costanzo A, Guido F, Moretti F, Levrero M (1998) Apoptotic, non-apoptotic, and anti-apoptotic pathways of tumor necrosis factor signalling. Biochem Pharmacol 56:915–920

    CAS  PubMed  Google Scholar 

  191. Zhu G, Flies DB, Tamada K, et al (2001) Progressive depletion of peripheral B lymphocytes in 4-1BB (CD137) ligand/I-Ealpha-transgenic mice. J Immunol 167:2671–2676

    CAS  PubMed  Google Scholar 

  192. Mittler RS, Bailey TS, Klussman K, Trailsmith MD, Hoffman MK (1999) Anti-4-1BB monoclonal antibodies abrogate T cell-dependent humoral immune responses in vivo through the induction of helper T cell anergy. J Exp Med 190:1535–1540

    Article  CAS  PubMed  Google Scholar 

  193. Hong HJ et al (2000) A humanized anti-4-1-BB monoclonal antibody suppresses antigen-induced humoral immune response in nonhuman primates. J Immunother 23:613–621

    Article  CAS  PubMed  Google Scholar 

  194. Melero I, Shuford WW, Newby SA, et al (1997) Monoclonal antibodies against the 4-1BB T-cell activation molecule eradicate established tumors. Nat Med 3:682–685

    CAS  PubMed  Google Scholar 

  195. Wilcox RA, Flies DB, Zhu G, et al (2002) Provision of antigen and CD137 signaling breaks immunological ignorance, promoting regression of poorly immunogenic tumors. J Clin Invest 109:651–659

    Article  CAS  PubMed  Google Scholar 

  196. Kim JA, Averbook BJ, Chambers K, et al (2001) Divergent effects of 4-1BB antibodies on antitumor immunity and on tumor-reactive T-cell generation. Cancer Res 61:2031–2037

    CAS  PubMed  Google Scholar 

  197. Cannons JL, Lau P, Ghumman B, et al (2001) 4-1BB ligand induces cell division, sustains survival, and enhances effector function of CD4 and CD8 T cells with similar efficacy. J Immunol 167:1313–1324

    CAS  PubMed  Google Scholar 

  198. Blazar BR, Kwon BS, Panoskaltsis-Mortari A, Kwak KB, Peschon JJ, Taylor PA (2001) Ligation of 4-1BB (CDw137) regulates graft-versus-host disease, graft-versus-leukemia, and graft rejection in allogeneic bone marrow transplant recipients. J Immunol 166:3174–3183

    CAS  PubMed  Google Scholar 

  199. Melero I, Bach N, Hellstrom KE, Aruffo A, Mittler RS, Chen L (1998) Amplification of tumor immunity by gene transfer of the co-stimulatory 4-1BB ligand: synergy with the CD28 co-stimulatory pathway. Eur J Immunol 28:1116–1121

    Article  CAS  PubMed  Google Scholar 

  200. Chen SH, Pham-Nguyen KB, Martinet O, et al (2000) Rejection of disseminated metastases of colon carcinoma by synergism of IL-12 gene therapy and 4-1BB costimulation. Mol Ther 2:39–46

    CAS  PubMed  Google Scholar 

  201. Guinn BA, Bertram EM, DeBenedette MA, Berinstein NL, Watts TH (2001) 4-1BBL enhances anti-tumor responses in the presence or absence of CD28 but CD28 is required for protective immunity against parental tumors. Cell Immunol 210:56–65

    Article  CAS  PubMed  Google Scholar 

  202. Salih HR, Kosowski SG, Haluska VF, et al (2000) Constitutive expression of functional 4-1BB (CD137) ligand on carcinoma cells. J Immunol 165:2903–2910

    CAS  PubMed  Google Scholar 

  203. Langstein J, Becke FM, Sollner L, et al (2000) Comparative analysis of CD137 and LPS effects on monocyte activation, survival, and proliferation. Biochem Biophys Res Commun 273:117–122

    Article  CAS  PubMed  Google Scholar 

  204. Gallucci S, Matzinger P (2001) Danger signals: SOS to the immune system. Curr Opin Immunol 13:114–119

    Article  CAS  PubMed  Google Scholar 

  205. Ferrone S, Marincola FM (1995) Loss of HLA class I antigens by melanoma cells: molecular mechanisms, functional significance and clinical relevance. Immunol Today 16:487–494

    CAS  PubMed  Google Scholar 

  206. Pardoll DM (1993) Genetically engineered tumor vaccines. Ann N Y Acad Sci 690:301–310

    CAS  PubMed  Google Scholar 

  207. Nestle FO (2000) Dendritic cell vaccination for cancer therapy. Oncogene 19:6673–6679

    CAS  PubMed  Google Scholar 

  208. Steinman RM, Pope M (2002) Exploiting dendritic cells to improve vaccine efficacy. J Clin Invest 109:1519–1526

    Article  CAS  PubMed  Google Scholar 

  209. Filippova GN, Fagerlie S, Klenova EM, et al (1996) An exceptionally conserved transcriptional repressor, CTCF, employs different combinations of zinc fingers to bind diverged promoter sequences of avian and mammalian c-myc oncogenes. Mol Cell Biol 16:2802–2813

    CAS  PubMed  Google Scholar 

  210. Filippova GN, Lindblom A, Meincke LJ, et al (1998) A widely expressed transcription factor with multiple DNA sequence specificity, CTCF, is localized at chromosome segment 16q22.1 within one of the smallest regions of overlap for common deletions in breast and prostate cancers. Genes Chromosomes Cancer 22:26–36

    Article  CAS  PubMed  Google Scholar 

  211. Loukinov DI, Pugacheva E, Vatolin S, et al (2002) BORIS, a novel male germ-line-specific protein associated with epigenetic reprogramming events, shares the same 11-zinc-finger domain with CTCF, the insulator protein involved in reading imprinting marks in the soma. Proc Natl Acad Sci U S A 99:6806–6811

    Article  CAS  PubMed  Google Scholar 

  212. Chomez P, De Backer O, Bertrand M, De Plaen E, Boon T, Lucas S (2001) An overview of the MAGE gene family with the identification of all human members of the family. Cancer Res 61:5544–5551

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The work of the authors has been supported by CA79490, 1 P50 CA83636, CA85780 and the Pacific Northwest Research Institute. The authors thank J.A. Ledbetter, M. Hayden-Ledbetter, Z. Ye, G. Filippova, and Y. Guo for collaboration and discussions and Dr. D. Malins for both discussions and helpful comments on the manuscript.

Author information

Authors and Affiliations

  1. Pacific Northwest Research Institute, Seattle, WA, 98122, USA

    Karl Erik Hellstrom & Ingegerd Hellstrom

Authors
  1. Karl Erik Hellstrom
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ingegerd Hellstrom
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Karl Erik Hellstrom.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hellstrom, K.E., Hellstrom, I. Therapeutic vaccination with tumor cells that engage CD137. J Mol Med 81, 71–86 (2003). https://doi.org/10.1007/s00109-002-0413-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-002-0413-8

Keywords

Search

Navigation