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The basis of T-cell-mediated immunity to chronic myelogenous leukemia

Oncogene volume 21, pages 8668–8673 (2002)Cite this article

The most compelling evidence that lymphocytes meditate an anti-leukemia effect comes from studies where allogeneic donor lymphocyte infusions (DLI) have been used to treat relapse of myeloid leukemia after allogeneic BMT (Antin, 1993; Giralt and Kolb, 1996; Kolb and Holler, 1997; Kolb et al., 1995, 1996). Lymphocyte transfusion from the original bone marrow (BM) donor induces both hematological and cytogenetic responses in approximately 70–80% of patients with myelogenous leukemia in chronic phase (Kolb et al., 1996). A complete cytogenetic response is usually obtained between 1–4 months after DLI (van Rhee et al., 1994) and approximately 80% of responders will achieve reverse transcriptase-polymerase chain reaction (RT–PCR) negativity for the bcr–abl translocation (the fusion product of the t(9;22) translocation found in chronic myelogenous leukemia (CML)) within a mean of 6 months (van Rhee et al., 1994). Acute myelogenous leukemia (AML) is also susceptible to the graft-versus-leukemia (GVL) effect, with 15–40% of patients obtaining remission with DLI alone (Collins et al., 1997). While significant graft-versus-host disease (GVHD) occurs in 50% of patients treated with DLI, and disease response occurs in 90% of CML patients, 55% of patients who do not get GVHD also have disease response (Giralt and Kolb, 1996; Kolb and Holler, 1997). This demonstrates that GVL is separable from GVHD in some patients, although only a handful of antigens that drive the donor's lymphocyte response preferentially against the leukemia have been identified. Remissions after DLI for AML are generally not as durable as those obtained in CML, which may reflect the rapid kinetics of tumor growth outpacing the kinetics of the developing immune response. However, if more antigens could be determined, and if large numbers of antigen-specific cytotoxic T-lymphocytes (CTLs) could be obtained, it would allow for development of leukemia-specific therapies using the antigens as a targets for generating specific T-cells for use in adoptive immunotherapy.

To understand the nature of GVL and GVHD, we must review some of the principles of antigen recognition and highlight a recent discovery that has aided our ability to study T-cell interactions. T-cells recognize peptide antigens that are presented on the cell surface in combination with major histocompatibility complex (MHC) antigens. Peptides derived from cytoplasmic proteins that are 8 to 11 amino acids in length, bind in the groove of class I MHC molecules and are transported via the endoplasmic reticulum to the cell surface. Larger peptides, typically 12–18 amino acids in length, that are derived from cell processing of extracellular proteins, bind class II MHC molecules and are presented to T-cells on the cell surface. Both peptide/MHC-I and peptide/MHC-II are recognized by the heterodimeric T-cell receptor (TCR) on CD8 or CD4 T-lymphocytes, respectively, with rapid off rates and kD in the range of 10−4 to 10−5 M (Alam et al., 1996). Points of contact between the TCR and the peptide/MHC surface include surface amino acids contributed by the two alpha helical domains of the MHC molecule that flank the peptide antigen binding pocket, as well as amino acids from the peptide itself.

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References

  • Alam SM, Travers PJ, Wung JL, Nasholds W, Redpath S, Jameson SC, Gascoigne NR . 1996 Nature 381: 616–620

  • Altman JD, Moss PAH, Goulder PJR, Barouch DH, McHeyzer-Williams MG, Bell JI, McMichael AJ, Davis MM . 1996 Science 274: 94–96

  • Anderton SM, Wraith DC . 2002 Nat. Rev. Immunol. 2: 487–498

  • Antin JH . 1993 Blood 82: 2273–2277

  • Ballieux BE, van der Burg SH, Hagen EC, van der Woude FJ, Melief CJ, Daha MR . 1995 Clin. Exp. Immunol. 100: 186–193

  • Barrett AJ, Ringden O, Zhang MJ, Bashey A, Cahn JY, Cairo MS, Gale RP, Gratwohl A, Locatelli F, Martino R, Schultz KR, Tiberghien P . 2000 Blood 95: 3323–3327

  • Behre G, Zhang P, Zhang DE, Tenen DG . 1999 Methods 17: 231–237

  • Bocchia M, Korontsvit T, Xu Q, Mackinnon S, Yang SY, Sette A, Scheinberg DA . 1996 Blood 87: 3587–35892

  • Bocchia M, Wentworth PA, Southwood S, Sidney J, McGraw K, Scheinberg DA, Sette A . 1995 Blood 85: 2680–2684

  • Boon T, Coulie P, Marchand M, Weynants P, Wolfel T, Brichard V . 1994 Important Adv. Oncol. 53–69

  • Boon T, Coulie PG, Van den Eynde B . 1997 Immunol. Today 18: 267–268

  • Bories D, Raynal MC, Solomon DH, Darzynkiewicz Z, Cayre YE . 1989 Cell 59: 959

  • Borregaard N, Cowland JB . 1997 Blood 89: 3503–3521

  • Braunschweig I, Wang C, Molldrem J . 2000 Blood 96: 3291

  • Brouwer E, Stegeman CA, Huitema MG, Limburg PC, Kallenberg CG . 1994 Clin. Exp. Immunol. 98: 448–453

  • Callan MF, Tan L, Annels N, Ogg GS, Wilson JD, O'Callaghan CA, Steven N, McMichael AJ, Rickinson AB . 1998 J. Exp. Med. 187: 1395–1402

  • Celis E, Tsai V, Crimi C, DeMars R, Wentworth PA, Chesnut RW, Grey HM, Sette A, Serra HM . 1994 Proc. Natl. Acad. Sci. USA 91: 2105–2109

  • Chen T, Meier R, Ziemiecki A, Fey MF, Tobler A . 1994 Biochem. Biophys. Res. Commun. 200: 1130–1135

  • Clark RE, Dodi IA, Hill SC, Lill JR, Aubert G, Macintyre AR, Rojas J, Bourdon A, Bonner PL, Wang L, Christmas SE, Travers PJ, Creaser CS, Rees RC, Madrigal JA . 2001 Blood 98: 2887–2893

  • Collins Jr RH, Shpilberg O, Drobyski WR, Porter DL, Giralt S, Champlin R, Goodman SA, Wolff SN, Hu W, Verfaillie C, List A, Dalton W, Ognoskie N, Chetrit A, Antin JH, Nemunaitis J . 1997 J. Clin. Oncol. 15: 433–444

  • den Haan JMM, Sherman NE, Blokland E, Huczko E, Koning F, Drijfhout JW, Skipper J, Shabanowitz J, Hunt DF, Engelhard VH, Goulmy E . 1995 Science 268: 1476–1480

  • Dengler R, Munstermann U, al-Batran S, Hausner I, Faderl S, Nerl C, Emmerich B . 1995 Br. J. Haematol. 89: 250–257

  • Dermime S, Molldrem J, Parker KC, Jiang YZ, Mavroudis D, Hensel N, Couriel D, Mahoney M, Coligan JE, Barrett AJ . 1995 Blood 86: (Abstract) 620

  • Faber LM, van der Hoeven J, Goulmy E, Hooftman-den Otter AL, van Luxemburg-Heijs SA, Willemze R, Falkenburg JH . 1995a J. Clin. Invest. 96: 877–883

  • Faber LM, van Luxemburg-Heijs SA, Rijnbeek M, Willemze R, Falkenburg JH . 1996 Biol. Blood Marrow Transplant 2: 31–36

  • Faber LM, van Luxemburg-Heijs SA, Veenhof WF, Willemze R, Falkenburg JH . 1995b Blood 86: 2821–2828

  • Franssen CF, Cohen Tervaert JW, Stegeman CA, Kallenberg CG . 1996 Lancet 347: 116; Discussion 118

  • Franssen CF, Stegeman CA, Kallenberg CG, Gans RO, De Jong PE, Hoorntje SJ, Tervaert JW . 2000 Kidney Int. 57: 2195–2206

  • Gale RP, Horowitz MM, Ash RC, Champlin RE, Goldman JM, Rimm AA, Ringden O, Stone JA, Bortin MM . 1994 Ann. Intern. Med. 120: 646–652

  • Gaugler B, Van den Eynde B, Van der Bruggen P, Romero P, Gaforio JJ, De Plaen E, Lethe B, Brasseur F, Boon T . 1994 J. Exp. Med. 179: 921–930

  • Giralt SA, Kolb HJ . 1996 Curr. Opin. Oncol. 8: 96–102

  • Goulmy E, Schipper R, Pool J, Blokland E, Falkenburg JH, Vossen J, Grathwohl A, Vogelsang GB, van Houwelingen HC, van Rood JJ . 1996 N. Engl. J. Med. 334: 281–285

  • Jennette JC, Thomas DB, Falk RJ . 2001 Semin. Diagn. Pathol. 18: 3–13

  • Kochenderfer JN, Molldrem JJ . 2001 Curr. Oncol. Rep. 3: 193–200

  • Kolb HJ, Holler E . 1997 Curr. Opin. Oncol. 9: 139–145

  • Kolb HJ, Mittermuller J, Holler E, Thalmeier K, Bartram CR . 1996 Bone Marrow Transplant. 17: 449–452

  • Kolb HJ, Schattenberg A, Goldman JM, Hertenstein B, Jacobsen N, Arcese W, Ljungman P, Ferrant A, Verdonck L, Niederwieser D . 1995 Blood 86: 2041–2050

  • Komanduri KV, Donahoe SM, Moretto WJ, Schmidt DK, Gillespie G, Ogg GS, Roederer M, Nixon DF, McCune JM . 2001 Virology 279: 459–470

  • Komanduri KV, Viswanathan MN, Wieder ED, Schmidt DK, Bredt BM, Jacobson MA, McCune JM . 1998 Nat. Med. 4: 953–956

  • Lee PP, Yee C, Savage PA, Fong L, Brockstedt D, Weber JS, Johnson D, Swetter S, Thompson J, Greenberg PD, Roederer M, Davis MM . 1999 Nat. Med. 5: 677–685

  • Marchand M, Weynants P, Rankin E, Arienti F, Belli F, Parmiani G, Cascinelli N, Bourlond A, Vanwijck R, Humblet Y . 1995 Int. J. Cancer 63: 883–885

  • Molldrem J, Dermime S, Parker K, Jiang YZ, Mavroudis D, Hensel N, Fukushima P, Barrett AJ . 1996 Blood 88: 2450–2457

  • Molldrem JJ, Clave E, Jiang YZ, Mavroudis D, Raptis A, Hensel N, Agarwala V, Barrett AJ . 1997 Blood 90: 2529–2534

  • Molldrem JJ, Lee PP, Wang C, Champlin RE, Davis MM . 1999 Cancer Res. 59: 2675–2681

  • Molldrem JJ, Lee PP, Wang C, Felio K, Kantarjian HM, Champlin RE, Davis MM . 2000 Nat. Med. 6: 1018–1023

  • Muller-Berat N, Minowada J, Tsuji-Takayama K, Drexler H, Lanotte M, Wieslander J, Wiik A . 1994 Clin. Immunol. Immunopathol. 70: 51–59

  • Nanda NK, Sercarz EE . 1995 Cell 82: 13–17

  • Pardoll DM . 1994 Nature 369: 357

  • Pardoll DM . 2002 Nature Rev. Immunol. 2: 227–238

  • Rosenberg SA, White DE . 1996 J. Immunother. Emphasis Tumor Immunol. 19: 81–84

  • Savige J, Gillis D, Benson E, Davies D, Esnault V, Falk RJ, Hagen EC, Jayne D, Jennette JC, Paspaliaris B, Pollock W, Pusey C, Savage CO, Silvestrini R, van der Woude F, Wieslander J, Wiik A . 1999 Am. J. Clin. Pathol. 111: 507–513

  • Sturrock AB, Franklin KF, Rao G, Marshall BC, Rebentisch MB, Lemons RS, Hoidal JR . 1992 J. Biol. Chem. 267: 21193

  • Tanaka F, Fujie T, Tahara K, Mori M, Takesako K, Sette A, Celis E, Akiyoshi T . 1997 Cancer Res. 57: 4465–4468

  • van der Bruggen P, Bastin J, Gajewski T, Coulie PG, Boel P, De Smet C, Traversari C, Townsend A, Boon T . 1994 Eur. J. Immunol. 24: 3038–3043

  • van der Harst D, Goulmy E, Falkenburg JH, Kooij-Winkelaar YM, van Luxemburg-Heijs SA, Goselink HM, Brand A . 1994 Blood 83: 1060–1066

  • van Rhee F, Lin F, Cullis JO, Spencer A, Cross NC, Chase A, Garicochea BV, Bungey J, Barrett J, Goldman J . 1994 Blood 83: 3377–3383

  • Williams RC, Staud R, Malone CC, Payabyab J, Byres L, Underwood D . 1994 J. Immunol. 152: 4722–4732

  • Zarour H, De Smet C, Lehmann F, Marchand M, Lethe B, Romero P, Boon T, Renauld JC . 1996 J. Invest. Dermatol. 107: 63–67

  • Zhang P, Nelson E, Radomska HS, Iwasaki-Arai J, Akashi K, Friedman AD, Tenen DG . 2002 Blood 99: 4406–4412

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Acknowledgements

Supported by the US Public Health Service (CA81247 and CA85843 to JJ Molldrem) and by the Leukemia and Lymphoma Society of America (R6247-02 to JJ Molldrem).

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  1. Department of Blood and Marrow Transplantation, Transplantation Immunology Section, University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA

    Jeffrey J Molldrem, Shreya Kant, Weidong Jiang & Sijie Lu

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Correspondence to Jeffrey J Molldrem.

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Molldrem, J., Kant, S., Jiang, W. et al. The basis of T-cell-mediated immunity to chronic myelogenous leukemia. Oncogene 21, 8668–8673 (2002). https://doi.org/10.1038/sj.onc.1206093

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