Application of T Cell lmmunotherapy for Human Viral and Malignant Diseases

  • S. R. Riddell
  • E. H. Warren
  • D. Lewinsohn
  • H. Mutimer
  • M. Topp
  • L. Cooper
  • R. de Fries
  • P. D. Greenberg
Conference paper
Part of the Ernst Schering Research Foundation Workshop book series (SCHERING FOUND, volume 30)


Improvements in our understanding of the molecular basis for T cell recognition of virus-infected cells and tumors, and of the signals involved in eliciting and maintaining a competent immune response has led to new efforts to bolster host T cell immunity in settings where deficient responses permit disease progression. The identification of viral antigens and antigens expressed by tumors has led to efforts to develop adoptive immunotherapy with T cell clones as a therapeutic approach to restore or augment host responses (Riddell and Greenberg 1995). The early results of clinical studies of T cell therapy for viral diseases have been encouraging and this approach is now being developed for the treatment of patients with leukemia that recurs after allogeneic bone marrow transplant (BMT) and patients with solid tumors.


Graft Versus Host Disease Major Histocompatibility Complex Molecule Adoptive Immunotherapy Bone Marrow Transplant Recipient Immediate Early 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. Appelbaum FR (1997) Allogeneic hematopoietic stem cell transplantation for acute leukemia. Semin Oncol 24: 114–123PubMedGoogle Scholar
  2. Arnold D, Faath S, Rammensee H, Schild H (1995) Cross-priming of minor histocompatibility antigen-specific cytotoxic T cells upon immunization with the heat shock protein gp96. J Exp Med 182: 885–889PubMedCrossRefGoogle Scholar
  3. Biron CA, Byron KS, Sullivan JL (1989) Severe herpesvirus infections in an adolescent without natural killer cells. N Engl J Med 320: 1731–1735PubMedCrossRefGoogle Scholar
  4. Boeckh MRS, Cunningham T, Myerson D, Flowers M, Bowden R (1996) Increased risk of late CMV infection and disease in allogeneic marrow transplant recipients after ganciclovir prophylaxis is due to a lack of CMV-specific T cell responses. Blood (suppl): 1195AGoogle Scholar
  5. Bonini C, Ferrari G, Verzeletti S, Servida P, Zappone E, Ruggieri L, et al (1997) HSV-TK gene transfer into donor lymphocytes for control of allogeneic graft-versus-leukemia. Science 276: 1719–1724PubMedCrossRefGoogle Scholar
  6. Bonnet D, Dick JE (1997) Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 3: 730–737PubMedCrossRefGoogle Scholar
  7. Bonnet D, Warren EH, Greenberg PD, Dick J, Riddell SR (1999) CD8+ minor histocompatibility antigen-specific cytotoxic T lymphocyte clones eliminate AML skin cells. Proc Natl Acad Sci USA 3: 730–737Google Scholar
  8. Boon T, Cerottini JC, Van den Eynde B, Bruggen P van der, Van Pel A (1994) Tumor antigens recognized by T lymphocytes. Annu Rev Immunol 12: 337–365PubMedCrossRefGoogle Scholar
  9. Borrow P, Lewicki H, Hahn BH, Shaw GM, Oldstone MB (1994) Virus-specific CD8+ cytotoxic T-lymphocyte activity associated with control of vire-mia in primary human immunodeficiency virus type 1 infection. J Virol 68: 6103–6110PubMedGoogle Scholar
  10. Brodie SJ, Lewinsohn DA, Patterson BK, Jiyamapa D, Krieger J, Corey L, et al (1999) In vivo migration and function of transferred HIV-1-specific cytotoxic T cells. Nat Med 5: 34–41PubMedCrossRefGoogle Scholar
  11. Bueger M de, Bakker A, Van Rood JJ, Van der Woude F, Goulmy E (1992) Tissue distribution of human minor histocompatibility antigens. Ubiquitous versus restricted tissue distribution indicates heterogeneity among human cytotoxic T lymphocyte-defined non-MHC antigens. J Immunol 149: 1788–1794Google Scholar
  12. Dolstra H, Fredrix H, Preijers F, Goulmy E, Figdor CG, Witte TM de, et al (1997) Recognition of a B cell leukemia-associated minor histocompatibility antigen by CTL. J Immunol 158: 560–565PubMedGoogle Scholar
  13. Dolstra H, Fredrix H, Maas F, Coulie PG, Brasseur F, Mensink E, et al (1999) A human minor histocompatibility antigen specific for B cell acute lymphoblastic leukemia. J Exp Med 189: 301–308PubMedCrossRefGoogle Scholar
  14. Els CA van, D’Amaro J, Pool J, Blokland E, Bakker A, Elsen PJ van, et al (1992) Immunogenetics of human minor histocompatibility antigens: their polymorphism and immunodominance. Immunogenetics 35: 161–165Google Scholar
  15. Emanuel D, Cunningham I, Jules-Elysee K, Brochstein JA, Kernan NA, Laver J, et al (1988) Cytomegalovirus pneumonia after bone marrow transplantation successfully treated with the combination of ganciclovir and high-dose intravenous immune globulin. Ann Intern Med 109: 777–782PubMedGoogle Scholar
  16. Evans LS, Witte PR, Feldhaus AL, et al (1999) Expression of a GM-CSF/IL-2 chimeric receptor in human CTL clones results in GM-CSF dependent growth. Hum Gene Ther 10: 1942–1951Google Scholar
  17. Falkenburg JH, Goselink HM, Harst D van der, Luxemburg-Heijs SA van, Kooy-Winkelaar YM, Faber LM, et al (1991) Growth inhibition of clono-genic leukemic precursor cells by minor histocompatibility antigen-specific cytotoxic T lymphocytes. J Exp Med 174: 27–33PubMedCrossRefGoogle Scholar
  18. Forman SJ, Zaia JA, Clark BR, Wright CL, Mills BJ, Pottathil R, et al (1985) A 64,000 dalton matrix protein of human cytomegalovirus induces in vitro immune responses similar to those of whole viral antigen. J Immunol 134: 3391–3395PubMedGoogle Scholar
  19. Goldman JM, Gale RP, Horowitz MM, Biggs JC, Champlin RE, Gluckman E, et al (1988) Bone marrow transplantation for chronic myelogenous leukemia in chronic phase. Increased risk for relapse associated with T-cell depletion. Ann Intern Med 108: 806–814Google Scholar
  20. Goodrich JM, Bowden RA, Fisher L, Keller C, Schoch G, Meyers JD (1993) Ganciclovir prophylaxis to prevent cytomegalovirus disease after allogeneic marrow transplant. Ann Intern Med 118: 173–178PubMedGoogle Scholar
  21. Goulmy E (1997a) Human minor histocompatibility antigens: new concepts for marrow transplantation and adoptive immunotherapy. Immunol Rev 157: 125–140PubMedCrossRefGoogle Scholar
  22. Goulmy E (1997b) Minor histocompatibility antigens: from T cell recognition to peptide identification (editorial). Hum Immunol 54: 8–14PubMedCrossRefGoogle Scholar
  23. Gubarev MI, Jenkin JC, Leppert MF, Buchanan GS, Otterud BE, Guilbert DA, et al (1996) Localization to chromosome 22 of a gene encoding a human minor histocompatibility antigen. J Immunol 157: 5448–5454PubMedGoogle Scholar
  24. Haan JM den, Sherman NE, Blokland E, Huczko E, Koning F, Drijfhout JW, et al (1995) Identification of a graft versus host disease-associated human minor histocompatibility antigen. Science 268: 1476–1480CrossRefGoogle Scholar
  25. Haan JM den, Meadows LM, Wang W, Pool J, Blokland E, Bishop TL, et al (1998) The minor histocompatibility antigen HA-1: a diallelic gene with a single amino acid polymorphism. Science 279: 1054–1057CrossRefGoogle Scholar
  26. Harst D van der, Goulmy E, Falkenburg JH, Kooij-Winkelaar YM, Luxemburg-Heijs SA van, Goselink HM, et al (1994) Recognition of minor histocompatibility antigens on lymphocytic and myeloid leukemic cells by cytotoxic T-cell clones. Blood 83: 1060–1066PubMedGoogle Scholar
  27. Hopkins JI, Fiander AN, Evans AS, Delchambre M, Gheysen D, Borysiewicz LK (1996) Cytotoxic T cell immunity to human cytomegalovirus glycoprotein B. J Med Virol 49: 124–131PubMedCrossRefGoogle Scholar
  28. Horowitz MM, Gale RP, Sondel PM, Goldman JM, Kersey J, Kolb HJ, et al (1990) Graft-versus-leukemia reactions after bone marrow transplantation. Blood 75: 555–562PubMedGoogle Scholar
  29. Hunt DF, Henderson RA, Shabanowitz J, Sakaguchi K, Michel H, Sevilir N, et al (1992) Characterization of peptides bound to the class I MHC molecule HLA-A2.1 by mass spectrometry. Science 255: 1261–1263PubMedCrossRefGoogle Scholar
  30. Klein MR, Baalen CA van, Holwerda AM, Kerkhof Garde SR, Bende RJ, Keet IP, et al (1995) Kinetics of Gag-specific cytotoxic T lymphocyte responses during the clinical course of HIV-1 infection: a longitudinal analysis of rapid progressors and long-term asymptomatics. J Exp Med 181: 1365–1372PubMedCrossRefGoogle Scholar
  31. Koup RA (1994) Virus escape from CTL recognition. J Exp Med 180: 779–782PubMedCrossRefGoogle Scholar
  32. Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J, et al (1994) A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 367: 645–648PubMedCrossRefGoogle Scholar
  33. Li CR, Greenberg PD, Gilbert MJ, Goodrich JM, Riddell SR (1994) Recovery of HLA-restricted cytomegalovirus (CMV)-specific T-cell responses after allogeneic bone marrow transplant: correlation with CMV disease and effect of ganciclovir prophylaxis. Blood 83: 1971–1979PubMedGoogle Scholar
  34. McKinney DM, Lewinsohn DA, Riddell SR, et al (1999) The antiviral activity of HIV-specific CD8+ CTL clones is limited by elimination due to encounter with HIV-infected targets. J Immunol 163: 861–867PubMedGoogle Scholar
  35. McLaughlin-Taylor E, Pande H, Forman SJ, Tanamachi B, Li CR, Zaia JA, et al (1994) Identification of the major late human cytomegalovirus matrix protein pp65 as a target antigen for CD8+ virus-specific cytotoxic T lymphocytes. J Med Virol 43: 103–110PubMedCrossRefGoogle Scholar
  36. Meadows L, Wang W, Haan JM den, Blokland E, Reinhardus C, Drijfhout JW, et al (1997) The HLA-A*0201-restricted H-Y antigen contains a posttranslationally modified cysteine that significantly affects T cell recognition. Immunity 6: 273–281PubMedCrossRefGoogle Scholar
  37. Meyers JD, Flournoy N, Thomas ED (1986) Risk factors for cytomegalovirus infection after human marrow transplantation. J Infect Dis 153: 478–488PubMedCrossRefGoogle Scholar
  38. Musey L, Hughes J, Schacker T, Shea T, Corey L, McElrath MJ (1997) Cytotoxic-T-cell responses, viral load, and disease progression in early human immunodeficiency virus type 1 infection. N Engl J Med 337: 1267–1274PubMedCrossRefGoogle Scholar
  39. Mutis T, Verdijk R, Schrama E, Esendam B, Brand A, Goulmy E (1999) Feasibility of immunotherapy of relapsed leukemia with ex vivo-generated cytotoxic T lymphocytes specific for hematopoietic system-restricted minor histocompatibility antigens. Blood 93: 2336–2341PubMedGoogle Scholar
  40. Nelson BH, Lord JD, Greenberg PD (1994) Cytoplasmic domains of the interleukin-2 receptor beta and gamma chains mediate the signal for T-cell proliferation. Nature 369: 333–336PubMedCrossRefGoogle Scholar
  41. Ogg GS, Jin X, Bonhoeffer S, Dunbar PR, Nowak MA, Monard S, et al (1998) Quantitation of HIV-1-specific cytotoxic T lymphocytes and plasma load of viral RNA. Science 279: 2103–2106PubMedCrossRefGoogle Scholar
  42. Pitcher CJ, Quittner C, Peterson DM, Connors M, Koup RA, Maino VC, et al (1999) HIV-1-specific CD4+ T cells are detectable in most individuals with active HIV-1 infection, but decline with prolonged viral suppression. Nat Med 5: 518–525PubMedCrossRefGoogle Scholar
  43. Ploegh HL (1998) Viral strategies of immune evasion. Science 280: 248–253PubMedCrossRefGoogle Scholar
  44. Quinnan GV Jr, Kirmani N, Rook AH, Manischewitz JF, Jackson L, Moreschi G, et al (1982) Cytotoxic T cells in cytomegalovirus infection: HLA-restricted T-lymphocyte and non-T-lymphocyte cytotoxic responses correlate with recovery from cytomegalovirus infection in bone-marrow-transplant recipients. N Engl J Med 307: 7–13Google Scholar
  45. Reddehase MJ, Weiland F, Munch K, Jonjic S, Luske A, Koszinowski UH (1985) Interstitial murine cytomegalovirus pneumonia after irradiation: characterization of cells that limit viral replication during established infection of the lungs. J Virol 55: 264–273PubMedGoogle Scholar
  46. Reddehase MJ, Mutter W, Munch K, Buhring HJ, Koszinowski UH (1987) CD8-positive T lymphocytes specific for murine cytomegalovirus immediate-early antigens mediate protective immunity. J Virol 61: 3102–3108PubMedGoogle Scholar
  47. Reusser P, Riddell SR, Meyers JD, Greenberg PD (1991) Cytotoxic T-lymphocyte response to cytomegalovirus after human allogeneic bone marrow transplantation: pattern of recovery and correlation with cytomegalovirus infection and disease. Blood 78: 1373–1380PubMedGoogle Scholar
  48. Rhee F van, Kolb HJ (1995) Donor leukocyte transfusions for leukemic relapse. Curr Opin Hematol 2: 423–430PubMedCrossRefGoogle Scholar
  49. Riddell SR, Greenberg PD (1995) Principles for adoptive T cell therapy of human viral diseases. Annu Rev Immunol 13: 545–586PubMedCrossRefGoogle Scholar
  50. Riddell SR, Greenberg PD (1997) T cell therapy of human CMV and EBV in-fections in immunocompromised hosts. Rev Med Virol 7: 181–192PubMedCrossRefGoogle Scholar
  51. Riddell SR, Rabin M, Geballe AP et al (1991) Class I MHC-restricted cyto-toxic T lymphocyte recognition of cells infected with human cytomega-lovirus does not require endogenous viral gene expression. J Immunol 146: 2795–2804PubMedGoogle Scholar
  52. Riddell SR, Watanabe KS, Goodrich JM, Li CR, Agha ME, Greenberg PD (1992) Restoration of viral immunity in immunodeficient humans by the adoptive transfer of T cell clones. Science 257: 238–241PubMedCrossRefGoogle Scholar
  53. Riddell SR, Elliott M, Lewinsohn DA, Gilbert MJ, Wilson L, Manley SA, et al (1996) T-cell mediated rejection of gene-modified HIV-specific cytotoxic T lymphocytes in HIV-infected patients. Nat Med 2: 216–223PubMedCrossRefGoogle Scholar
  54. Rodgers B, Borysiewicz L, Mundin J, Graham S, Sissons P (1987) Immunoaffinity purification of a 72 K early antigen of human cytomegalovirus: analysis of humoral and cell-mediated immunity to the purified polypeptide. J Gen Virol 68: 2371–2378PubMedCrossRefGoogle Scholar
  55. Rosenberg SA (1999) A new era for cancer immunotherapy based on the genes that encode cancer antigens. Immunity 10: 281–287PubMedCrossRefGoogle Scholar
  56. Rosenberg ES, Billingsley JM, Caliendo AM, Boswell SL, Sax PE, Kalams SA, et al (1997) Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia. Science 278: 1447–1450PubMedCrossRefGoogle Scholar
  57. Tomazin R, Boname J, Hegde NR, Lewinsohn DA, Altschuler Y, Jones TR, et al (1999) Cytomegalovirus US2 destroys two components of the MHC class II pathway preventing recognition by CD4+ T cells. Nat Med 5: 1039–1043PubMedCrossRefGoogle Scholar
  58. Walter EA, Greenberg PD, Gilbert MJ, Finch RJ, Watanabe KS, Thomas ED, et al (1995) Reconstitution of cellular immunity against cytomegalovirus in recipients of allogeneic bone marrow by transfer of T-cell clones from the donor. N Engl J Med 333: 1038–1044PubMedCrossRefGoogle Scholar
  59. Wang W, Meadows LR, Haan JM den, Sherman NE, Chen Y, Blokland E, et al (1995) Human H-Y: a male-specific histocompatibility antigen derived from the SMCY protein. Science 269: 1588–1590PubMedCrossRefGoogle Scholar
  60. Warren EH, Gavin M, Greenberg PD, Riddell SR (1998a) Minor histocompatibility antigens as targets for T-cell therapy after bone marrow transplantation. Cuff Opin Hematol 5: 429–433CrossRefGoogle Scholar
  61. Warren EH, Greenberg PD, Riddell SR (1998b) Cytotoxic T-lymphocyte-defined human minor histocompatibility antigens with a restricted tissue distribution. Blood 91: 2197–2207PubMedGoogle Scholar
  62. Wills MR, Carmichael AJ, Mynard K, Jin X, Weekes MP, Plachter B, et al. (1996) The human cytotoxic T-lymphocyte (CTL) response to cytomegalovirus is dominated by structural protein pp65: frequency, specificity, and T-cell receptor usage of pp65-specific CTL. J Virol 70: 7569–7579PubMedGoogle Scholar
  63. Zajac AJ, Blattman JN, Murali-Krishna K, Sourdive DJ, Suresh M, Altman JD, et al (1998) Viral immune evasion due to persistence of activated T cells without effector function. J Exp Med 188: 2205–2213PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2000

Authors and Affiliations

  • S. R. Riddell
  • E. H. Warren
  • D. Lewinsohn
  • H. Mutimer
  • M. Topp
  • L. Cooper
  • R. de Fries
  • P. D. Greenberg

There are no affiliations available

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