Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

Biology of the graft-versus-tumor effect following hematopoietic cell transplantation

Robert S Negrin, MD
Section Editor
Nelson J Chao, MD
Deputy Editor
Alan G Rosmarin, MD


The majority of patients with malignancy who undergo hematopoietic cell transplantation (HCT) are effectively treated, thereby resulting in minimal residual disease. However, this response is frequently not maintained since relapse ultimately occurs in 40 to 75 percent of patients who undergo an autologous transplant and 10 to 40 percent of those who undergo an allogeneic transplant. Further, with the development of non-myeloablative or reduced intensity allogeneic transplantation there is increased reliance on immune-mediated effects to control the underlying disease.

The rationale for using immunotherapy to prevent and/or treat the reemergence of malignancy is based upon the following observations:

Evidence indicates that the graft-versus-tumor (GVT) effect plays a major role in reducing the risk of relapse following an allogeneic transplant.

Significant advances have been made in our basic understanding of both the cellular populations responsible for potential antitumor activity and the cellular interactions and cytokines required for their activation and expansion.

The cell populations capable of recognizing and lysing malignant targets can be divided into two broad categories based upon the mechanism of cellular recognition: cytotoxic T cells (CTLs) and natural killer (NK) cells. Significant insights have been made into the functional mechanisms of these two populations.


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Sep 2016. | This topic last updated: Jul 20, 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2016 UpToDate, Inc.
  1. Clark EA, Ledbetter JA. How B and T cells talk to each other. Nature 1994; 367:425.
  2. Jenkins MK. The ups and downs of T cell costimulation. Immunity 1994; 1:443.
  3. Sayegh MH, Turka LA. T cell costimulatory pathways: promising novel targets for immunosuppression and tolerance induction. J Am Soc Nephrol 1995; 6:1143.
  4. Schwartz RH. Costimulation of T lymphocytes: the role of CD28, CTLA-4, and B7/BB1 in interleukin-2 production and immunotherapy. Cell 1992; 71:1065.
  5. Lanzavecchia A. Immunology. Licence to kill. Nature 1998; 393:413.
  6. Shevach EM. Certified professionals: CD4(+)CD25(+) suppressor T cells. J Exp Med 2001; 193:F41.
  7. Hoffmann P, Ermann J, Edinger M, et al. Donor-type CD4(+)CD25(+) regulatory T cells suppress lethal acute graft-versus-host disease after allogeneic bone marrow transplantation. J Exp Med 2002; 196:389.
  8. Rezvani K, Mielke S, Ahmadzadeh M, et al. High donor FOXP3-positive regulatory T-cell (Treg) content is associated with a low risk of GVHD following HLA-matched allogeneic SCT. Blood 2006; 108:1291.
  9. Edinger M, Hoffmann P, Ermann J, et al. CD4+CD25+ regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation. Nat Med 2003; 9:1144.
  10. Trenado A, Charlotte F, Fisson S, et al. Recipient-type specific CD4+CD25+ regulatory T cells favor immune reconstitution and control graft-versus-host disease while maintaining graft-versus-leukemia. J Clin Invest 2003; 112:1688.
  11. Martelli MF, Di Ianni M, Ruggeri L, et al. "Designed" grafts for HLA-haploidentical stem cell transplantation. Blood 2014; 123:967.
  12. Ofran Y, Ritz J. Targets of tumor immunity after allogeneic hematopoietic stem cell transplantation. Clin Cancer Res 2008; 14:4997.
  13. Randolph SS, Gooley TA, Warren EH, et al. Female donors contribute to a selective graft-versus-leukemia effect in male recipients of HLA-matched, related hematopoietic stem cell transplants. Blood 2004; 103:347.
  14. Meyer EH, Hsu AR, Liliental J, et al. A distinct evolution of the T-cell repertoire categorizes treatment refractory gastrointestinal acute graft-versus-host disease. Blood 2013; 121:4955.
  15. Thomas ED, Clift RA, Fefer A, et al. Marrow transplantation for the treatment of chronic myelogenous leukemia. Ann Intern Med 1986; 104:155.
  16. Horowitz MM, Gale RP, Sondel PM, et al. Graft-versus-leukemia reactions after bone marrow transplantation. Blood 1990; 75:555.
  17. Gale RP, Horowitz MM, Ash RC, et al. Identical-twin bone marrow transplants for leukemia. Ann Intern Med 1994; 120:646.
  18. Boon T, van der Bruggen P. Human tumor antigens recognized by T lymphocytes. J Exp Med 1996; 183:725.
  19. Nishida T, Hudecek M, Kostic A, et al. Development of tumor-reactive T cells after nonmyeloablative allogeneic hematopoietic stem cell transplant for chronic lymphocytic leukemia. Clin Cancer Res 2009; 15:4759.
  20. Hsu FJ, Benike C, Fagnoni F, et al. Vaccination of patients with B-cell lymphoma using autologous antigen-pulsed dendritic cells. Nat Med 1996; 2:52.
  21. Van den Eynde BJ, van der Bruggen P. T cell defined tumor antigens. Curr Opin Immunol 1997; 9:684.
  22. Bocchia M, Korontsvit T, Xu Q, et al. Specific human cellular immunity to bcr-abl oncogene-derived peptides. Blood 1996; 87:3587.
  23. Bosch GJ, Joosten AM, Kessler JH, et al. Recognition of BCR-ABL positive leukemic blasts by human CD4+ T cells elicited by primary in vitro immunization with a BCR-ABL breakpoint peptide. Blood 1996; 88:3522.
  24. Engleman EG. Dendritic cells in the treatment of cancer. Biol Blood Marrow Transplant 1996; 2:115.
  25. Choudhury A, Gajewski JL, Liang JC, et al. Use of leukemic dendritic cells for the generation of antileukemic cellular cytotoxicity against Philadelphia chromosome-positive chronic myelogenous leukemia. Blood 1997; 89:1133.
  26. Laport GG, Levine BL, Stadtmauer EA, et al. Adoptive transfer of costimulated T cells induces lymphocytosis in patients with relapsed/refractory non-Hodgkin lymphoma following CD34+-selected hematopoietic cell transplantation. Blood 2003; 102:2004.
  27. Rapoport AP, Stadtmauer EA, Aqui N, et al. Restoration of immunity in lymphopenic individuals with cancer by vaccination and adoptive T-cell transfer. Nat Med 2005; 11:1230.
  28. Zheng Z, Takahashi M, Aoki S, et al. Expression patterns of costimulatory molecules on cells derived from human hematological malignancies. J Exp Clin Cancer Res 1998; 17:251.
  29. Schultze JL, Seamon MJ, Michalak S, et al. Autologous tumor infiltrating T cells cytotoxic for follicular lymphoma cells can be expanded in vitro. Blood 1997; 89:3806.
  30. Dunussi-Joannopoulos K, Weinstein HJ, Nickerson PW, et al. Irradiated B7-1 transduced primary acute myelogenous leukemia (AML) cells can be used as therapeutic vaccines in murine AML. Blood 1996; 87:2938.
  31. Townsend SE, Allison JP. Tumor rejection after direct costimulation of CD8+ T cells by B7-transfected melanoma cells. Science 1993; 259:368.
  32. Davids MS, Kim HT, Bachireddy P, et al. Ipilimumab for Patients with Relapse after Allogeneic Transplantation. N Engl J Med 2016; 375:143.
  33. Phillips JH, Lanier LL. Dissection of the lymphokine-activated killer phenomenon. Relative contribution of peripheral blood natural killer cells and T lymphocytes to cytolysis. J Exp Med 1986; 164:814.
  34. Grimm EA, Mazumder A, Zhang HZ, Rosenberg SA. Lymphokine-activated killer cell phenomenon. Lysis of natural killer-resistant fresh solid tumor cells by interleukin 2-activated autologous human peripheral blood lymphocytes. J Exp Med 1982; 155:1823.
  35. Gumperz JE, Parham P. The enigma of the natural killer cell. Nature 1995; 378:245.
  36. Döhring C, Scheidegger D, Samaridis J, et al. A human killer inhibitory receptor specific for HLA-A1,2. J Immunol 1996; 156:3098.
  37. Litwin V, Gumperz J, Parham P, et al. NKB1: a natural killer cell receptor involved in the recognition of polymorphic HLA-B molecules. J Exp Med 1994; 180:537.
  38. Moretta A, Vitale M, Bottino C, et al. P58 molecules as putative receptors for major histocompatibility complex (MHC) class I molecules in human natural killer (NK) cells. Anti-p58 antibodies reconstitute lysis of MHC class I-protected cells in NK clones displaying different specificities. J Exp Med 1993; 178:597.
  39. Pende D, Biassoni R, Cantoni C, et al. The natural killer cell receptor specific for HLA-A allotypes: a novel member of the p58/p70 family of inhibitory receptors that is characterized by three immunoglobulin-like domains and is expressed as a 140-kD disulphide-linked dimer. J Exp Med 1996; 184:505.
  40. Boyington JC, Riaz AN, Patamawenu A, et al. Structure of CD94 reveals a novel C-type lectin fold: implications for the NK cell-associated CD94/NKG2 receptors. Immunity 1999; 10:75.
  41. Brooks AG, Borrego F, Posch PE, et al. Specific recognition of HLA-E, but not classical, HLA class I molecules by soluble CD94/NKG2A and NK cells. J Immunol 1999; 162:305.
  42. Raulet DH. Roles of the NKG2D immunoreceptor and its ligands. Nat Rev Immunol 2003; 3:781.
  43. Kärre K. Express yourself or die: peptides, MHC molecules, and NK cells. Science 1995; 267:978.
  44. Uhrberg M, Valiante NM, Shum BP, et al. Human diversity in killer cell inhibitory receptor genes. Immunity 1997; 7:753.
  45. Weng WK, Levy R. Two immunoglobulin G fragment C receptor polymorphisms independently predict response to rituximab in patients with follicular lymphoma. J Clin Oncol 2003; 21:3940.
  46. Weng WK, Negrin RS, Lavori P, Horning SJ. Immunoglobulin G Fc receptor FcgammaRIIIa 158 V/F polymorphism correlates with rituximab-induced neutropenia after autologous transplantation in patients with non-Hodgkin's lymphoma. J Clin Oncol 2010; 28:279.
  47. Aversa F, Tabilio A, Velardi A, et al. Treatment of high-risk acute leukemia with T-cell-depleted stem cells from related donors with one fully mismatched HLA haplotype. N Engl J Med 1998; 339:1186.
  48. Ruggeri L, Capanni M, Casucci M, et al. Role of natural killer cell alloreactivity in HLA-mismatched hematopoietic stem cell transplantation. Blood 1999; 94:333.
  49. Ruggeri L, Capanni M, Urbani E, et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 2002; 295:2097.
  50. Hsu KC, Keever-Taylor CA, Wilton A, et al. Improved outcome in HLA-identical sibling hematopoietic stem-cell transplantation for acute myelogenous leukemia predicted by KIR and HLA genotypes. Blood 2005; 105:4878.
  51. Miller JS, Soignier Y, Panoskaltsis-Mortari A, et al. Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. Blood 2005; 105:3051.
  52. Perussia B, Chan SH, D'Andrea A, et al. Natural killer (NK) cell stimulatory factor or IL-12 has differential effects on the proliferation of TCR-alpha beta+, TCR-gamma delta+ T lymphocytes, and NK cells. J Immunol 1992; 149:3495.
  53. Kobayashi M, Fitz L, Ryan M, et al. Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes. J Exp Med 1989; 170:827.
  54. Siegel JP, Puri RK. Interleukin-2 toxicity. J Clin Oncol 1991; 9:694.
  55. Benyunes MC, Massumoto C, York A, et al. Interleukin-2 with or without lymphokine-activated killer cells as consolidative immunotherapy after autologous bone marrow transplantation for acute myelogenous leukemia. Bone Marrow Transplant 1993; 12:159.
  56. Nagler A, Ackerstein A, Or R, et al. Immunotherapy with recombinant human interleukin-2 and recombinant interferon-alpha in lymphoma patients postautologous marrow or stem cell transplantation. Blood 1997; 89:3951.
  57. Miller JS, Tessmer-Tuck J, Pierson BA, et al. Low dose subcutaneous interleukin-2 after autologous transplantation generates sustained in vivo natural killer cell activity. Biol Blood Marrow Transplant 1997; 3:34.
  58. Thompson JA, Fisher RI, Leblanc M, et al. Total body irradiation, etoposide, cyclophosphamide, and autologous peripheral blood stem-cell transplantation followed by randomization to therapy with interleukin-2 versus observation for patients with non-Hodgkin lymphoma: results of a phase 3 randomized trial by the Southwest Oncology Group (SWOG 9438). Blood 2008; 111:4048.
  59. Yao X, Ahmadzadeh M, Lu YC, et al. Levels of peripheral CD4(+)FoxP3(+) regulatory T cells are negatively associated with clinical response to adoptive immunotherapy of human cancer. Blood 2012; 119:5688.
  60. Ahmadzadeh M, Rosenberg SA. IL-2 administration increases CD4+ CD25(hi) Foxp3+ regulatory T cells in cancer patients. Blood 2006; 107:2409.
  61. Charak BS, Brynes RK, Groshen S, et al. Bone marrow transplantation with interleukin-2-activated bone marrow followed by interleukin-2 therapy for acute myeloid leukemia in mice. Blood 1990; 76:2187.
  62. Agah R, Malloy B, Kerner M, Mazumder A. Generation and characterization of IL-2-activated bone marrow cells as a potent graft vs tumor effector in transplantation. J Immunol 1989; 143:3093.
  63. Ochoa AC, Gromo G, Alter BJ, et al. Long-term growth of lymphokine-activated killer (LAK) cells: role of anti-CD3, beta-IL 1, interferon-gamma and -beta. J Immunol 1987; 138:2728.
  64. Schmidt-Wolf IG, Negrin RS, Kiem HP, et al. Use of a SCID mouse/human lymphoma model to evaluate cytokine-induced killer cells with potent antitumor cell activity. J Exp Med 1991; 174:139.
  65. Lu PH, Negrin RS. A novel population of expanded human CD3+CD56+ cells derived from T cells with potent in vivo antitumor activity in mice with severe combined immunodeficiency. J Immunol 1994; 153:1687.
  66. Baker J, Verneris MR, Ito M, et al. Expansion of cytolytic CD8(+) natural killer T cells with limited capacity for graft-versus-host disease induction due to interferon gamma production. Blood 2001; 97:2923.
  67. Verneris MR, Karimi M, Baker J, et al. Role of NKG2D signaling in the cytotoxicity of activated and expanded CD8+ T cells. Blood 2004; 103:3065.
  68. Karimi M, Cao TM, Baker JA, et al. Silencing human NKG2D, DAP10, and DAP12 reduces cytotoxicity of activated CD8+ T cells and NK cells. J Immunol 2005; 175:7819.
  69. Hoyle C, Bangs CD, Chang P, et al. Expansion of Philadelphia chromosome-negative CD3(+)CD56(+) cytotoxic cells from chronic myeloid leukemia patients: in vitro and in vivo efficacy in severe combined immunodeficiency disease mice. Blood 1998; 92:3318.
  70. Leemhuis T, Wells S, Scheffold C, et al. A phase I trial of autologous cytokine-induced killer cells for the treatment of relapsed Hodgkin disease and non-Hodgkin lymphoma. Biol Blood Marrow Transplant 2005; 11:181.
  71. Laport GG, Sheehan K, Baker J, et al. Adoptive immunotherapy with cytokine-induced killer cells for patients with relapsed hematologic malignancies after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 2011; 17:1679.
  72. Takayama T, Sekine T, Makuuchi M, et al. Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial. Lancet 2000; 356:802.
  73. Thorne SH, Negrin RS, Contag CH. Synergistic antitumor effects of immune cell-viral biotherapy. Science 2006; 311:1780.
  74. Cesano A, Visonneau S, Pasquini S, et al. Antitumor efficacy of a human major histocompatibility complex nonrestricted cytotoxic T-cell line (TALL-104) in immunocompetent mice bearing syngeneic leukemia. Cancer Res 1996; 56:4444.
  75. Cesano A, Visonneau S, Jeglum KA, et al. Phase I clinical trial with a human major histocompatibility complex nonrestricted cytotoxic T-cell line (TALL-104) in dogs with advanced tumors. Cancer Res 1996; 56:3021.
  76. Gong JH, Maki G, Klingemann HG. Characterization of a human cell line (NK-92) with phenotypical and functional characteristics of activated natural killer cells. Leukemia 1994; 8:652.
  77. Klingemann HG, Wong E, Maki G. A cytotoxic NK-cell line (NK-92) for ex vivo purging of leukemia from blood. Biol Blood Marrow Transplant 1996; 2:68.
  78. Klingemann HG, Miyagawa B. Purging of malignant cells from blood after short ex vivo incubation with NK-92 cells. Blood 1996; 87:4913.
  79. Hambach L, Vermeij M, Buser A, et al. Targeting a single mismatched minor histocompatibility antigen with tumor-restricted expression eradicates human solid tumors. Blood 2008; 112:1844.
  80. Arai S, Meagher R, Swearingen M, et al. Infusion of the allogeneic cell line NK-92 in patients with advanced renal cell cancer or melanoma: a phase I trial. Cytotherapy 2008; 10:625.
  81. Porter DL, Levine BL, Kalos M, et al. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med 2011; 365:725.
  82. Porter DL, Kalos M, Zheng Z, et al. Chimeric Antigen Receptor Therapy for B-cell Malignancies. J Cancer 2011; 2:331.
  83. Henkart PA. Lymphocyte-mediated cytotoxicity: two pathways and multiple effector molecules. Immunity 1994; 1:343.
  84. Chung WH, Hung SI, Yang JY, et al. Granulysin is a key mediator for disseminated keratinocyte death in Stevens-Johnson syndrome and toxic epidermal necrolysis. Nat Med 2008; 14:1343.
  85. Nagasawa M, Isoda T, Itoh S, et al. Analysis of serum granulysin in patients with hematopoietic stem-cell transplantation: its usefulness as a marker of graft-versus-host reaction. Am J Hematol 2006; 81:340.
  86. Heusel JW, Wesselschmidt RL, Shresta S, et al. Cytotoxic lymphocytes require granzyme B for the rapid induction of DNA fragmentation and apoptosis in allogeneic target cells. Cell 1994; 76:977.
  87. Kägi D, Ledermann B, Bürki K, et al. Cytotoxicity mediated by T cells and natural killer cells is greatly impaired in perforin-deficient mice. Nature 1994; 369:31.
  88. Rouvier E, Luciani MF, Golstein P. Fas involvement in Ca(2+)-independent T cell-mediated cytotoxicity. J Exp Med 1993; 177:195.
  89. Oshimi Y, Oda S, Honda Y, et al. Involvement of Fas ligand and Fas-mediated pathway in the cytotoxicity of human natural killer cells. J Immunol 1996; 157:2909.
  90. Hahne M, Rimoldi D, Schröter M, et al. Melanoma cell expression of Fas(Apo-1/CD95) ligand: implications for tumor immune escape. Science 1996; 274:1363.
  91. Walker PR, Saas P, Dietrich PY. Role of Fas ligand (CD95L) in immune escape: the tumor cell strikes back. J Immunol 1997; 158:4521.
  92. Groh V, Wu J, Yee C, Spies T. Tumour-derived soluble MIC ligands impair expression of NKG2D and T-cell activation. Nature 2002; 419:734.
  93. Inamoto Y, Flowers ME, Lee SJ, et al. Influence of immunosuppressive treatment on risk of recurrent malignancy after allogeneic hematopoietic cell transplantation. Blood 2011; 118:456.
  94. Claret EJ, Alyea EP, Orsini E, et al. Characterization of T cell repertoire in patients with graft-versus-leukemia after donor lymphocyte infusion. J Clin Invest 1997; 100:855.
  95. Ringdén O, Labopin M, Gorin NC, et al. Is there a graft-versus-leukaemia effect in the absence of graft-versus-host disease in patients undergoing bone marrow transplantation for acute leukaemia? Br J Haematol 2000; 111:1130.
  96. Anderson LD Jr, Savary CA, Mullen CA. Immunization of allogeneic bone marrow transplant recipients with tumor cell vaccines enhances graft-versus-tumor activity without exacerbating graft-versus-host disease. Blood 2000; 95:2426.
  97. Nishimura R, Baker J, Beilhack A, et al. In vivo trafficking and survival of cytokine-induced killer cells resulting in minimal GVHD with retention of antitumor activity. Blood 2008; 112:2563.
  98. Choi J, Ritchey J, Prior JL, et al. In vivo administration of hypomethylating agents mitigate graft-versus-host disease without sacrificing graft-versus-leukemia. Blood 2010; 116:129.
  99. Sprangers B, Van Wijmeersch B, Fevery S, et al. Experimental and clinical approaches for optimization of the graft-versus-leukemia effect. Nat Clin Pract Oncol 2007; 4:404.
  100. Schmaltz C, Alpdogan O, Horndasch KJ, et al. Differential use of Fas ligand and perforin cytotoxic pathways by donor T cells in graft-versus-host disease and graft-versus-leukemia effect. Blood 2001; 97:2886.
  101. Fontaine P, Roy-Proulx G, Knafo L, et al. Adoptive transfer of minor histocompatibility antigen-specific T lymphocytes eradicates leukemia cells without causing graft-versus-host disease. Nat Med 2001; 7:789.
  102. Epperson DE, Margolis DA, McOlash L, et al. In vitro T-cell receptor V beta repertoire analysis may identify which T-cell V beta families mediate graft-versus-leukaemia and graft-versus-host responses after human leucocyte antigen-matched sibling stem cell transplantation. Br J Haematol 2001; 114:57.
  103. André-Schmutz I, Le Deist F, Hacein-Bey-Abina S, et al. Immune reconstitution without graft-versus-host disease after haemopoietic stem-cell transplantation: a phase 1/2 study. Lancet 2002; 360:130.
  104. Guimond M, Balassy A, Barrette M, et al. P-glycoprotein targeting: a unique strategy to selectively eliminate immunoreactive T cells. Blood 2002; 100:375.
  105. Morris ES, MacDonald KP, Hill GR. Stem cell mobilization with G-CSF analogs: a rational approach to separate GVHD and GVL? Blood 2006; 107:3430.
  106. Zeiser R, Nguyen VH, Beilhack A, et al. Inhibition of CD4+CD25+ regulatory T-cell function by calcineurin-dependent interleukin-2 production. Blood 2006; 108:390.
  107. Chakraverty R, Sykes M. The role of antigen-presenting cells in triggering graft-versus-host disease and graft-versus-leukemia. Blood 2007; 110:9.
  108. Barrett AJ. Understanding and harnessing the graft-versus-leukaemia effect. Br J Haematol 2008; 142:877.
  109. Boni A, Muranski P, Cassard L, et al. Adoptive transfer of allogeneic tumor-specific T cells mediates effective regression of large tumors across major histocompatibility barriers. Blood 2008; 112:4746.
  110. Cai SF, Cao X, Hassan A, et al. Granzyme B is not required for regulatory T cell-mediated suppression of graft-versus-host disease. Blood 2010; 115:1669.
  111. Goodyear OC, Dennis M, Jilani NY, et al. Azacitidine augments expansion of regulatory T cells after allogeneic stem cell transplantation in patients with acute myeloid leukemia (AML). Blood 2012; 119:3361.