Infusion of Cytotoxic T Cells for the Prevention and Treatment of Epstein-Barr Virus–Induced Lymphoma in Allogeneic Transplant Recipients

Blood - Tập 92 Số 5 - Trang 1549-1555 - 1998
Cliona M. Rooney1, Colton A. Smith1, Catherine Y. Ng1, Susan K. Loftin1, John W. Sixbey1, Yan‐jun Gan1, Deo Kumar Srivastava1, Laura C. Bowman1, Robert A. Krance1, Malcolm K. Brenner1, Helen E. Heslop1
1From the Departments of Virology and Molecular Biology, Biostatistics, and the Division of Bone Marrow Transplantation, St Jude Children’s Research Hospital, Memphis, TN; and the Departments of Pathology and Pediatrics, University of Tennessee, Memphis, TN.

Tóm tắt

Abstract Epstein-Barr virus (EBV) causes potentially lethal immunoblastic lymphoma in up to 25% of children receiving bone marrow transplants from unrelated or HLA-mismatched donors. Because this complication appears to stem from a deficiency of EBV-specific cytotoxic T cells, we assessed the safety and efficacy of donor-derived polyclonal (CD4+ and CD8+) T-cell lines as immunoprophylaxis and treatment for EBV-related lymphoma. Thirty-nine patients considered to be at high risk for EBV-induced lymphoma each received 2 to 4 intravenous infusions of donor-derived EBV-specific T lymphocytes, after they had received T-cell–depleted bone marrow from HLA-matched unrelated donors (n = 33) or mismatched family members (n = 6). The immunologic effects of this therapy were monitored during and after the infusions. Infused cells were identified by detection of the neo marker gene. EBV-specific T cells bearing theneo marker were identified in all but 1 of the patients. Serial analysis of DNA detected the marker gene for as long as 18 weeks in unmanipulated peripheral blood mononuclear cells and for as long as 38 months in regenerated lines of EBV-specific cytotoxic T cells. Six patients (15.5%) had greatly increased amounts of EBV-DNA on study entry (>2,000 genome copies/106 mononuclear cells), indicating uncontrolled EBV replication, a complication that has had a high correlation with subsequent development of overt lymphoma. All of these patients showed 2 to 4 log decreases in viral DNA levels within 2 to 3 weeks after infusion and none developed lymphoma, confirming the antiviral activity of the donor-derived cells. There were no toxic effects that could be attributed to prophylactic T-cell therapy. Two additional patients who did not receive prophylaxis and developed overt immunoblastic lymphoma responded fully to T-cell infusion. Polyclonal donor-derived T-cell lines specific for EBV proteins can thus be used safely to prevent EBV-related immunoblastic lymphoma after allogeneic marrow transplantation and may also be effective in the treatment of established disease. © 1998 by The American Society of Hematology.

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Tài liệu tham khảo

Barber, 1993, Peptide binding to major histocompatibility complex molecules., Annu Rev Cell Biol, 9, 163, 10.1146/annurev.cb.09.110193.001115

Janeway, 1994, Signals and signs for lymphocyte responses., Cell, 76, 275, 10.1016/0092-8674(94)90335-2

Lanzavecchia, 1993, Identifying strategies for immune intervention., Science, 260, 937, 10.1126/science.8493532

Nanda, 1995, Induction of anti-self-immunity to cure cancer., Cell, 82, 13, 10.1016/0092-8674(95)90047-0

Cheever, 1995, Immunity to oncogenic proteins., Immunol Rev, 145, 33, 10.1111/j.1600-065X.1995.tb00076.x

Houghton, 1994, Cancer antigens: Immune recognition of self and altered self., J Exp Med, 180, 1, 10.1084/jem.180.1.1

Riddell, 1995, Principles for adoptive T cell therapy of human viral diseases., Annu Rev Immunol, 13, 545, 10.1146/annurev.iy.13.040195.002553

Walter, 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, 10.1056/NEJM199510193331603

Rickinson, 1997, Human cytotoxic T lymphocyte responses to Epstein-Barr virus infection., Annu Rev Immunol, 15, 405, 10.1146/annurev.immunol.15.1.405

Ambinder, 1993, Epstein-Barr virus and childhood Hodgkin’s disease in Honduras and the United States., Blood, 81, 462, 10.1182/blood.V81.2.462.462

Straus, 1992, Epstein-Barr virus infections: Biology, pathogenesis and management., Ann Intern Med, 118, 45, 10.7326/0003-4819-118-1-199301010-00009

Kieff, 1996, Epstein-Barr virus, Fields Virology., 2397

Skinner, 1988, B cell lymphoproliferative disorders following T cell depleted allogeneic bone marrow transplantation., Am J Pediatr Hematol Oncol, 10, 112, 10.1097/00043426-198822000-00005

Shapiro, 1988, Epstein-Barr virus associated B cell lymphoproliferative disorders following bone marrow transplantation., Blood, 71, 1234, 10.1182/blood.V71.5.1234.1234

Lucas, 1996, The development of cellular immunity to Epstein-Barr virus after allogeneic bone marrow transplantation., Blood, 87, 2594, 10.1182/blood.V87.6.2594.bloodjournal8762594

Zutter, 1988, Epstein-Barr virus lymphoproliferation after bone marrow transplantation., Blood, 72, 520, 10.1182/blood.V72.2.520.520

Gerritsen, 1996, Risk factors for developing EBV-related B cell lymphoproliferative disorders (BLPD) after non-HLA-identical BMT in children., Bone Marrow Transplant, 18, 377

Heslop, 1997, Adoptive immunotherapy of EBV lymphoproliferative diseases., Immunol Rev, 157, 217, 10.1111/j.1600-065X.1997.tb00984.x

Papadopoulos, 1994, Infusions of donor leukocytes to treat Epstein-Barr virus-associated lymphoproliferative disorders after allogeneic bone marrow transplantation., N Engl J Med, 330, 1185, 10.1056/NEJM199404283301703

Heslop, 1994, Donor T cells to treat EBV-associated lymphoma., N Engl J Med, 331, 679, 10.1056/NEJM199409083311017

Rooney, 1995, Use of gene-modified virus-specific T lymphocytes to control Epstein-Barr virus-related lymphoproliferation., Lancet, 345, 9, 10.1016/S0140-6736(95)91150-2

Heslop, 1996, Long-term restoration of immunity against Epstein-Barr virus infection by adoptive transfer of gene-modified virus-specific T lymphocytes., Nat Med, 2, 551, 10.1038/nm0596-551

Hongeng, 1997, Outcomes of transplantation with matched-sibling and unrelated-donor bone marrow in children with leukemia., Lancet, 350, 767, 10.1016/S0140-6736(97)03098-5

Heslop, 1994, Administration of neomycin-resistance-gene-marked EBV-specific cytotoxic T lymphocytes to recipients of mismatched-related or phenotypically similar unrelated donor marrow grafts., Hum Gene Ther, 5, 381, 10.1089/hum.1994.5.3-381

Smith, 1995, Production of genetically modified EBV-specific cytotoxic T cells for adoptive transfer to patients at high risk of EBV-associated lymphoproliferative disease., J Hematother, 4, 73, 10.1089/scd.1.1995.4.73

Brenner, 1993, Gene marking to determine whether autologous marrow infusion restores long-term haemopoiesis in cancer patients., Lancet, 342, 1134, 10.1016/0140-6736(93)92122-A

Bagasra, 1993, Polymerase chain reaction in situ: Intracellular amplification and detection of HIV-1 proviral DNA and other specific genes., J Immunol Methods, 158, 131, 10.1016/0022-1759(93)90265-9

Glucksberg, 1974, Clinical manifestations of graft-versus-host disease in human recipients of marrow from HLA-matched sibling donors., Transplantation, 18, 295, 10.1097/00007890-197410000-00001

Bourgault, 1991, Limiting-dilution analysis of the HLA restriction of anti-Epstein-Barr virus-specific cytolytic T lymphocytes., Clin Exp Immunol, 84, 501

Rooney, 1995, Early identification of Epstein-Barr virus-associated post-transplant lymphoproliferative disease., Br J Haematol, 89, 98, 10.1111/j.1365-2141.1995.tb08904.x

Savoie, 1994, Direct correlation between the load of Epstein-Barr virus-infected lymphocytes in the peripheral blood of pediatric transplant patients and risk of lymphoproliferative disease., Blood, 83, 2715, 10.1182/blood.V83.9.2715.2715

Riddler, 1994, Increased levels of circulating Epstein-Barr virus (EBV)-infected lymphocytes and decreased EBV nuclear antigen antibody responses are associated with the development of posttransplant lymphoproliferative disease in solid-organ transplant recipients., Blood, 84, 972, 10.1182/blood.V84.3.972.972

Riddell, 1992, Restoration of viral immunity in immunodeficient humans by the adoptive transfer of T cell clones., Science, 257, 238, 10.1126/science.1352912

Matloubian, 1994, CD4+ T cells are required to sustain CD8+ cytotoxic T cell responses during chronic viral infection., J Virol, 68, 8056, 10.1128/JVI.68.12.8056-8063.1994

Cardin, 1996, Progressive loss of CD8(+) T cell-mediated control of a gamma-herpesvirus in the absence of CD4(+) T cells., J Exp Med, 184, 863, 10.1084/jem.184.3.863

Romani, 1994, Proliferating dendritic cell progenitors in human blood., J Exp Med, 180, 83, 10.1084/jem.180.1.83

Banchereau, 1998, Dendritic cells and the control of immunity., Nature, 392, 245, 10.1038/32588

Roskrow, 1996, Genetically modified dendritic cells generate primary and memory tumor antigen-specific cytotoxic T lymphocytes., Blood, 10, 87a

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Blood

Tập 92 Số 5

1549-1555

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