Peptidselektive Isolierung unmanipulierter T-Zellen für die adoptive Immuntherapie

Zusammenfassung

Infektionen oder Reaktivierungen durch persistierende Viren, wie z. B. dem humanen Zytomegalievirus und dem Epstein-Barr-Virus, oder lytische Viren, wie z. B. dem Adenovirus, können sehr problematisch sein und durch teils schwere Verläufe zur Sterblichkeit nach Stammzell- und Organtransplantation beitragen. Es konnte gezeigt werden, dass der adoptive Transfer von antigen- bzw. virusspezifischen T-Lymphozyten des seropositiven Spenders die spezifische Immunität im Patienten rekonstituiert und das Risiko einer Graft-versus-Host-Erkrankung minimal ist. Bereits eine geringe Zahl dieser antigenspezifischen T-Zellen führt zu klinischen Ansprechraten. Effektive Verfahren zur Aufreinigung dieser Zellen und deren klinische Effizienz wurden gezeigt.

Abstract

Infection with and reactivation of human cytomegalovirus, Epstein-Barr virus, and adenovirus are frequent and can lead to severe complications in immunocompromised recipients after hematopoietic stem cell transplantation or solid organ transplantation. These serious adverse events are associated with a significant morbidity and mortality. Adoptive immunotherapy with virus-specific cytotoxic effector T cells derived from seropositive donors can rapidly reconstitute antiviral immunity of the patient with no acute toxicity or increased risk of GvHD following transplantation. Only small numbers of antigen-specific T cells are required to improve the transplantation outcome. Strategies to isolate the specific T cells are already established and the efficiency of adoptively transferred cells was shown.

Schlüsselwörter

adoptive T-Zelltherapie - Stammzell- und Organtransplantation - humanes Zytomegalievirus - pMHC-Multimere

Key words

adoptive T cell therapy - stem cell and organ transplantation - human cytomegalovirus - pMHC multimers

• Literatur

• 1 Ljungman P et al. Allogeneic and autologous transplantation for haematological diseases, solid tumours and immune disorders: current practice in Europe 2009. Bone Marrow Transplant 2010; 45: 219-234
• 2 Gooley TA et al. Reduced mortality after allogeneic hematopoietic-cell transplantation. N Engl J Med 2010; 363: 2091-2101
• 3 Barnes DW et al. Treatment of murine leukaemia with X rays and homologous bone marrow; preliminary communication. Br Med J 1956; 2: 626-627
• 4 Mathe G et al. Adoptive immunotherapy of acute leukemia: experimental and clinical results. Cancer Res 1965; 25: 1525-1531
• 5 Brestrich G et al. Adoptive T-cell therapy of a lung transplanted patient with severe CMV disease and resistance to antiviral therapy. Am J Transplant 2009; 9: 1679-1684
• 6 Doubrovina E et al. Adoptive immunotherapy with unselected or EBV-specific T cells for biopsy-proven EBV+ lymphomas after allogeneic hematopoietic cell transplantation. Blood 2012; 119: 2644-2656
• 7 Einsele H, Kapp M, Grigoleit GU. CMV-specific T cell therapy. Blood Cells Mol Dis 2008; 40: 71-75
• 8 Feuchtinger T et al. Safe adoptive transfer of virus-specific T-cell immunity for the treatment of systemic adenovirus infection after allogeneic stem cell transplantation. Br J Haematol 2006; 134: 64-76
• 9 Feuchtinger T et al. Adoptive transfer of pp 65-specific T cells for the treatment of chemorefractory cytomegalovirus disease or reactivation after haploidentical and matched unrelated stem cell transplantation. Blood 2010; 116: 4360-4367
• 10 Haque T et al. Allogeneic T-cell therapy for Epstein-Barr virus-positive posttransplant lymphoproliferative disease: long-term follow-up. Transplantation 2010; 90: 93-94
• 11 Heslop HE et al. Long-term outcome of EBV-specific T-cell infusions to prevent or treat EBV-related lymphoproliferative disease in transplant recipients. Blood 2010; 115: 925-935
• 12 Hoffman JA. Adenovirus infections in solid organ transplant recipients. Curr Opin Organ Transplant 2009; 14: 625-633
• 13 Mackinnon S et al. Adoptive cellular therapy for cytomegalovirus infection following allogeneic stem cell transplantation using virus-specific T cells. Blood Cells Mol Dis 2008; 40: 63-67
• 14 Moosmann A et al. Effective and long-term control of EBV PTLD after transfer of peptide-selected T cells. Blood 2010; 115: 2960-2970
• 15 Pagliara D, Savoldo B. Cytotoxic T lymphocytes for the treatment of viral infections and posttransplant lymphoproliferative disorders in transplant recipients. Curr Opin Infect Dis 2012; 25: 431-437
• 16 Peggs KS et al. Directly selected cytomegalovirus-reactive donor T cells confer rapid and safe systemic reconstitution of virus-specific immunity following stem cell transplantation. Clin Infect Dis 2011; 52: 49-57
• 17 Qasim W et al. Third-party virus-specific T cells eradicate adenoviraemia but trigger bystander graft-versus-host disease. Br J Haematol 2011; 154: 150-153
• 18 Walter EA et al. 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 1995; 333: 1038-1044
• 19 Zandvliet ML et al. Combined CD8+ and CD4+ adenovirus hexon-specific T cells associated with viral clearance after stem cell transplantation as treatment for adenovirus infection. Haematologica 2010; 95: 1943-1951
• 20 Casalegno-Garduno R et al. Wilmsʼ tumor 1 as a novel target for immunotherapy of leukemia. Transplant Proc 2010; 42: 3309-3311
• 21 Hofmann S, Greiner J. Adoptive Immunotherapy after Allogeneic Hematopoietic Progenitor Cell Transplantation: New Perspectives for Transfusion Medicine. Transfus Med Hemother 2011; 38: 173-182
• 22 June CH. Adoptive T cell therapy for cancer in the clinic. J Clin Invest 2007; 117: 1466-1476
• 23 Marijt WA et al. Hematopoiesis-restricted minor histocompatibility antigens HA-1- or HA-2-specific T cells can induce complete remissions of relapsed leukemia. Proc Natl Acad Sci U S A 2003; 100: 2742-2747
• 24 Rapoport AP et al. Combination immunotherapy using adoptive T-cell transfer and tumor antigen vaccination on the basis of hTERT and survivin after ASCT for myeloma. Blood 2011; 117: 788-797
• 25 Rosenberg SA, Dudley ME. Adoptive cell therapy for the treatment of patients with metastatic melanoma. Curr Opin Immunol 2009; 21: 233-240
• 26 Rosenberg SA et al. Adoptive cell transfer: a clinical path to effective cancer immunotherapy. Nat Rev Cancer 2008; 8: 299-308
• 27 Porter DL, June CH. T-cell reconstitution and expansion after hematopoietic stem cell transplantation: ‘T it up!. Bone Marrow Transplant 2005; 35: 935-942
• 28 Doubrovina E et al. Mapping of novel peptides of WT-1 and presenting HLA alleles that induce epitope-specific HLA-restricted T cells with cytotoxic activity against WT-1(+) leukemias. Blood 2012; 120: 1633-1646
• 29 Hobo W et al. Association of Disparities in Known Minor Histocompatibility Antigens with Relapse-Free Survival and Graft-versus-Host-Disease after Allogeneic Stem Cell Transplantation. Biol Blood Marrow Transplant 2012;
• 30 Katagiri T et al. Mismatch of minor histocompatibility antigen contributes to a graft-versus-leukemia effect rather than to acute GVHD, resulting in long-term survival after HLA-identical stem cell transplantation in Japan. Bone Marrow Transplant 2006; 38: 681-686
• 31 Kolb HJ et al. Donor leukocyte transfusions for treatment of recurrent chronic myelogenous leukemia in marrow transplant patients. Blood 1990; 76: 2462-2465
• 32 Porter DL et al. Treatment of relapsed leukemia after unrelated donor marrow transplantation with unrelated donor leukocyte infusions. Blood 2000; 95: 1214-1221
• 33 Einsele H et al. Risk factors for treatment failures in patients receiving PCR-based preemptive therapy for CMV infection. Bone Marrow Transplant 2000; 25: 757-763
• 34 Fujita Y, Rooney CM, Heslop HE. Adoptive cellular immunotherapy for viral diseases. Bone Marrow Transplant 2008; 41: 193-198
• 35 Lilleri D et al. Human cytomegalovirus-specific CD4+ and CD8+ T-cell reconstitution in adult allogeneic hematopoietic stem cell transplant recipients and immune control of viral infection. Haematologica 2008; 93: 248-256
• 36 Lilleri D et al. Monitoring of human cytomegalovirus and virus-specific T-cell response in young patients receiving allogeneic hematopoietic stem cell transplantation. PLoS One 2012; 7: e41648
• 37 Ugarte-Torres A et al. Donor serostatus has an impact on cytomegalovirus-specific immunity, cytomegaloviral disease incidence, and survival in seropositive hematopoietic cell transplant recipients. Biol Blood Marrow Transplant 2011; 17: 574-585
• 38 Zhou W et al. Impact of donor CMV status on viral infection and reconstitution of multifunction CMV-specific T cells in CMV-positive transplant recipients. Blood 2009; 113: 6465-6476
• 39 Borchers S et al. Tetramer monitoring to assess risk factors for recurrent cytomegalovirus reactivation and reconstitution of antiviral immunity post allogeneic hematopoietic stem cell transplantation. Transpl Infect Dis 2011; 13: 222-236
• 40 Sun Q et al. Simultaneous ex vivo expansion of cytomegalovirus and Epstein-Barr virus-specific cytotoxic T lymphocytes using B-lymphoblastoid cell lines expressing cytomegalovirus pp 65. Blood 1999; 94: 3242-3250
• 41 Maus MV et al. HLA tetramer-based artificial antigen-presenting cells for stimulation of CD4+ T cells. Clin Immunol 2003; 106: 16-22
• 42 Oelke M et al. Ex vivo induction and expansion of antigen-specific cytotoxic T cells by HLA-Ig-coated artificial antigen-presenting cells. Nat Med 2003; 9: 619-624
• 43 Paine A et al. Expansion of human cytomegalovirus-specific T lymphocytes from unfractionated peripheral blood mononuclear cells with artificial antigen-presenting cells. Transfusion 2007; 47: 2143-2152
• 44 Prakken B et al. Artificial antigen-presenting cells as a tool to exploit the immune ‘synapse . Nat Med 2000; 6: 1406-1410
• 45 Amidi M et al. Induction of humoral and cellular immune responses by antigen-expressing immunostimulatory liposomes. J Control Release 2012; 164: 323-330
• 46 Chaput N et al. Exosomes for immunotherapy of cancer. Adv Exp Med Biol 2003; 532: 215-221
• 47 Hsu DH et al. Exosomes as a tumor vaccine: enhancing potency through direct loading of antigenic peptides. J Immunother 2003; 26: 440-450
• 48 Levine BL et al. Large-scale production of CD4+ T cells from HIV-1-infected donors after CD3/CD28 costimulation. J Hematother 1998; 7: 437-448
• 49 Carlsson B et al. Ex vivo stimulation of cytomegalovirus (CMV)-specific T cells using CMV pp 65-modified dendritic cells as stimulators. Br J Haematol 2003; 121: 428-438
• 50 Lozza L et al. Simultaneous quantification of human cytomegalovirus (HCMV)-specific CD4+ and CD8+ T cells by a novel method using monocyte-derived HCMV-infected immature dendritic cells. Eur J Immunol 2005; 35: 1795-1804
• 51 Peggs K, Verfuerth S, Mackinnon S. Induction of cytomegalovirus (CMV)-specific T-cell responses using dendritic cells pulsed with CMV antigen: a novel culture system free of live CMV virions. Blood 2001; 97: 994-1000
• 52 Tischer S et al. Heat shock protein 70/peptide complexes: potent mediators for the generation of antiviral T cells particularly with regard to low precursor frequencies. J Transl Med 2011; 9: 175
• 53 Feuchtinger T et al. Clinical grade generation of hexon-specific T cells for adoptive T-cell transfer as a treatment of adenovirus infection after allogeneic stem cell transplantation. J Immunother 2008; 31: 199-206
• 54 Peggs KS et al. Cytomegalovirus-specific T cell immunotherapy promotes restoration of durable functional antiviral immunity following allogeneic stem cell transplantation. Clin Infect Dis 2009; 49: 1851-1860
• 55 Rauser G et al. Rapid generation of combined CMV-specific CD4+ and CD8+ T-cell lines for adoptive transfer into recipients of allogeneic stem cell transplants. Blood 2004; 103: 3565-3572
• 56 Casalegno-Garduno R et al. Multimer technologies for detection and adoptive transfer of antigen-specific T cells. Cancer Immunol Immunother 2010; 59: 195-202
• 57 Cobbold M et al. Adoptive transfer of cytomegalovirus-specific CTL to stem cell transplant patients after selection by HLA-peptide tetramers. J Exp Med 2005; 202: 379-386
• 58 Schmitt A et al. Adoptive transfer and selective reconstitution of streptamer-selected cytomegalovirus-specific CD8+ T cells leads to virus clearance in patients after allogeneic peripheral blood stem cell transplantation. Transfusion 2011; 51: 591-599
• 59 Yao J et al. Multimer staining of cytomegalovirus phosphoprotein 65-specific T cells for diagnosis and therapeutic purposes: a comparative study. Clin Infect Dis 2008; 46: e96-e105
• 60 Sarawar SR et al. Stimulation via CD40 can substitute for CD4 T cell function in preventing reactivation of a latent herpesvirus. Proc Natl Acad Sci U S A 2001; 98: 6325-6329
• 61 Schoenberger SP et al. T-cell help for cytotoxic T lymphocytes is mediated by CD40-CD40L interactions. Nature 1998; 393: 480-483
• 62 Matsui K et al. Kinetics of T-cell receptor binding to peptide/I-Ek complexes: correlation of the dissociation rate with T-cell responsiveness. Proc Natl Acad Sci U S A 1994; 91: 12862-12866
• 63 Altman JD et al. Phenotypic analysis of antigen-specific T lymphocytes. Science 1996; 274: 94-96
• 64 Batard P et al. Dextramers: new generation of fluorescent MHC class I/peptide multimers for visualization of antigen-specific CD8+ T cells. J Immunol Methods 2006; 310: 136-148
• 65 Dal Porto J et al. A soluble divalent class I major histocompatibility complex molecule inhibits alloreactive T cells at nanomolar concentrations. Proc Natl Acad Sci U S A 1993; 90: 6671-6675
• 66 Knabel M et al. Reversible MHC multimer staining for functional isolation of T-cell populations and effective adoptive transfer. Nat Med 2002; 8: 631-637
• 67 Tischer S et al. Establishment of the reversible peptide-major histocompatibility complex (pMHC) class I Histamer technology: tool for visualization and selection of functionally active antigen-specific CD8+ T lymphocytes. Int Immunol 2012; 24: 561-572
• 68 Duplan V et al. Tracking antigen-specific CD8+ T cells in the rat using MHC class I multimers. J Immunol Methods 2007; 320: 30-39
• 69 Neudorfer J et al. Reversible HLA multimers (Streptamers) for the isolation of human cytotoxic T lymphocytes functionally active against tumor- and virus-derived antigens. J Immunol Methods 2007; 320: 119-131
• 70 Paine A et al. Soluble recombinant CMVpp65 spanning multiple HLA alleles for reconstitution of antiviral CD4+ and CD8+ T-cell responses after allogeneic stem cell transplantation. J Immunother 2010; 33: 60-72
• 71 Egli A, Humar A, Kumar D. State-of-the-Art Monitoring of Cytomegalovirus-Specific Cell-Mediated Immunity After Organ Transplant: A Primer for the Clinician. Clin Infect Dis 2012; 55: 1678-1689
• 72 Moss P, Rickinson A. Cellular immunotherapy for viral infection after HSC transplantation. Nat Rev Immunol 2005; 5: 9-20