Cytotoxic T lymphocytes as immune‐therapy in haematological practice

Viral infections are a significant cause of morbidity and mortality, particularly in pediatric allogeneic haematopoietic stem cell transplant recipients. Effective therapies are limited and often associated with significant side effects. Adoptive transfer of virus‐reactive T cells offers a means of reconstituting antiviral immunity and this approach has been successfully used to prevent and treat cytomegalovirus, Epstein‐Barr virus, and adenovirus infections in vivo. This review outlines the clinical trials that have been performed to date, and will describe future initiatives to (a) develop strategies that can increase the breadth of the viruses that can be targeted, and (b) simplify the process to extend this technology to more centers so that cellular therapy to reconstitute immunity can be more widely applied.

[1]  M. Schilham,et al.  Human CD4+ T cells stimulated by conserved adenovirus 5 hexon peptides recognize cells infected with different species of human adenovirus , 2006, European journal of immunology.

[2]  H. Heslop,et al.  Exploiting Cytokine Secretion to Rapidly Produce Multivirus-specific T Cells for Adoptive Immunotherapy , 2008, Journal of immunotherapy.

[3]  R. O'reilly,et al.  Adoptive transfer of antigen-specific T-cells of donor type for immunotherapy of viral infections following allogeneic hematopoietic cell transplants , 2007, Immunologic research.

[4]  C. Rooney,et al.  Fiber-modified adenoviruses generate subgroup cross-reactive, adenovirus-specific cytotoxic T lymphocytes for therapeutic applications. , 2004, Blood.

[5]  S. Riddell,et al.  Reconstitution of cellular immunity against cytomegalovirus in recipients of allogeneic bone marrow by transfer of T-cell clones from the donor. , 1995, The New England journal of medicine.

[6]  J. Sierra,et al.  Prospective study of the incidence, clinical features, and outcome of symptomatic upper and lower respiratory tract infections by respiratory viruses in adult recipients of hematopoietic stem cell transplants for hematologic malignancies. , 2005, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[7]  A. Fischer,et al.  Immune reconstitution without graft-versus-host disease after haemopoietic stem-cell transplantation: a phase 1/2 study , 2002, The Lancet.

[8]  L. Eisenlohr,et al.  Human CD8+ cytotoxic T cell responses to adenovirus capsid proteins. , 2006, Virology.

[9]  P. Ljungman,et al.  BK-viruria and haemorrhagic cystitis are more frequent in allogeneic haematopoietic stem cell transplant patients receiving full conditioning and unrelated-HLA-mismatched grafts , 2008, Bone Marrow Transplantation.

[10]  F. Baldanti,et al.  Preemptive Therapy of EBV‐Related Lymphoproliferative Disease after Pediatric Haploidentical Stem Cell Transplantation , 2007, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[11]  H. Einsele,et al.  Rapid generation of combined CMV-specific CD4+ and CD8+ T-cell lines for adoptive transfer into recipients of allogeneic stem cell transplants. , 2004, Blood.

[12]  M. Horowitz,et al.  Increasing incidence of adenovirus disease in bone marrow transplant recipients. , 1994, The Journal of infectious diseases.

[13]  P. Moss,et al.  Adoptive cellular therapy for early cytomegalovirus infection after allogeneic stem-cell transplantation with virus-specific T-cell lines , 2003, The Lancet.

[14]  M. Ladanyi,et al.  Infusions of donor leukocytes to treat Epstein-Barr virus-associated lymphoproliferative disorders after allogeneic bone marrow transplantation. , 1994, The New England journal of medicine.

[15]  Malcolm K. Brenner,et al.  Long–term restoration of immunity against Epstein–Barr virus infection by adoptive transfer of gene–modified virus–specific T lymphocytes , 1996, Nature Medicine.

[16]  P. Marrack,et al.  Cytokine-induced survival of activated T cells in vitro and in vivo. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[17]  L. Eisenlohr,et al.  Adenovirus hexon T-cell epitope is recognized by most adults and is restricted by HLA DP4, the most common class II allele , 2004, Gene Therapy.

[18]  J. Michálek,et al.  Optimized clinical-scale culture conditions for ex vivo selective depletion of host-reactive donor lymphocytes: a strategy for GvHD prophylaxis in allogeneic PBSC transplantation. , 2002, Cytotherapy.

[19]  T. Goto,et al.  Unsuccessful CTL transfusion in a case of post-BMT Epstein–Barr virus-associated lymphoproliferative disorder (EBV-LPD) , 1997, Bone Marrow Transplantation.

[20]  A. Rothman,et al.  Discordance between antibody and T cell responses in recipients of trivalent inactivated influenza vaccine. , 2008, Vaccine.

[21]  J. Kurtzberg,et al.  In vitro priming and expansion of cytomegalovirus-specific Th1 and Tc1 T cells from naive cord blood lymphocytes. , 2006, Blood.

[22]  R. Krance,et al.  Adoptive immunotherapy with allodepleted donor T-cells improves immune reconstitution after haploidentical stem cell transplantation. , 2006, Blood.

[23]  H. Heslop,et al.  In vivo expansion of LMP 1- and 2-specific T-cells in a patient who received donor-derived EBV-specific T-cells after allogeneic stem cell transplantation , 2006, Leukemia & lymphoma.

[24]  C. Fathman,et al.  Donor-type CD4+CD25+ Regulatory T Cells Suppress Lethal Acute Graft-Versus-Host Disease after Allogeneic Bone Marrow Transplantation , 2002, The Journal of experimental medicine.

[25]  R. Krance,et al.  Use of gene-modified virus-specific T lymphocytes to control Epstein-Barr-virus-related lymphoproliferation , 1995, The Lancet.

[26]  H. Heslop,et al.  Post-transplant lymphoproliferative disorders. , 2005, Annual review of medicine.

[27]  Nina Khanna,et al.  Cytomegalovirus and polyomavirus BK posttransplant. , 2007, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[28]  Peter Shaw,et al.  Ex vivo expansion and prophylactic infusion of CMV-pp65 peptide-specific cytotoxic T-lymphocytes following allogeneic hematopoietic stem cell transplantation. , 2007, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[29]  B. Moss,et al.  Identification of viral molecules recognized by influenza-specific human cytotoxic T lymphocytes , 1987, The Journal of experimental medicine.

[30]  D. Srivastava,et al.  Infusion of Cytotoxic T Cells for the Prevention and Treatment of Epstein-Barr Virus–Induced Lymphoma in Allogeneic Transplant Recipients , 1998 .

[31]  A. Fischer,et al.  Adenovirally transduced dendritic cells induce bispecific cytotoxic T lymphocyte responses against adenovirus and cytomegalovirus pp65 or against adenovirus and Epstein-Barr virus EBNA3C protein: a novel approach for immunotherapy. , 2002, Human Gene Therapy.

[32]  A. Enk,et al.  Identification and Functional Characterization of Human Cd4+Cd25+ T Cells with Regulatory Properties Isolated from Peripheral Blood , 2001, The Journal of experimental medicine.

[33]  J. Michálek,et al.  Selective depletion of donor alloreactive T cells without loss of antiviral or antileukemic responses. , 2003, Blood.

[34]  M. Boeckh,et al.  Emerging viral infections after hematopoietic cell transplantation , 2005, Pediatric transplantation.

[35]  P. Marrack,et al.  Interleukin 4 (IL-4) or IL-7 Prevents the Death of Resting T Cells: Stat6 Is Probably Not Required for the Effect of IL-4 , 1997, The Journal of experimental medicine.

[36]  U. Nater,et al.  Epstein-Barr virus. , 1991, The Journal of family practice.

[37]  F. Ruscetti,et al.  Induction of CD4+ T cell alloantigen-specific hyporesponsiveness by IL-10 and TGF-beta. , 1999, Journal of immunology.

[38]  Nitin J. Karandikar,et al.  In vitro methotrexate as a practical approach to selective allodepletion. , 2006, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[39]  V. Boussiotis,et al.  CD134-allodepletion allows selective elimination of alloreactive human T cells without loss of virus-specific and leukemia-specific effectors. , 2008, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[40]  C. Rooney,et al.  Adenovirus as an emerging pathogen in immunocompromised patients , 2005, British journal of haematology.

[41]  C. Rooney,et al.  Adenovirus-pulsed dendritic cells stimulate human virus-specific T-cell responses in vitro , 1996, Journal of virology.

[42]  J. Bell,et al.  Functional Heterogeneity and High Frequencies of Cytomegalovirus-Specific CD8+ T Lymphocytes in Healthy Seropositive Donors , 2000, Journal of Virology.

[43]  F. Baldanti,et al.  Successful In Vitro Priming of EBV‐Specific CD8+ T Cells Endowed with Strong Cytotoxic Function from T Cells of EBV‐Seronegative Children , 2006, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[44]  K. Cornetta,et al.  Donor leukocyte infusion as therapy of life-threatening adenoviral infections after T-cell-depleted bone marrow transplantation. , 1994, Blood.

[45]  C. Huber,et al.  Depletion of alloreactive T cells via CD69: implications on antiviral, antileukemic and immunoregulatory T lymphocytes , 2006, Bone Marrow Transplantation.

[46]  M. Roncarolo,et al.  Human Cd25+Cd4+ T Regulatory Cells Suppress Naive and Memory T Cell Proliferation and Can Be Expanded in Vitro without Loss of Function , 2001, The Journal of experimental medicine.

[47]  R. Truitt,et al.  Characterization of human proliferative T cell responses to adenovirus. , 1995, The Journal of infectious diseases.

[48]  Zhensheng Liu,et al.  CD20 monoclonal antibody (rituximab) for therapy of Epstein-Barr virus lymphoma after hemopoietic stem-cell transplantation. , 2000, Blood.

[49]  R. Webster,et al.  The human cytotoxic T cell response to influenza A vaccination. , 1981, Clinical and experimental immunology.

[50]  G. Papanicolaou,et al.  Cytomegalovirus in hematopoietic stem cell transplant recipients: Current status, known challenges, and future strategies. , 2003, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[51]  K. Rezvani,et al.  A clinical-scale selective allodepletion approach for the treatment of HLA-mismatched and matched donor-recipient pairs using expanded T lymphocytes as antigen-presenting cells and a TH9402-based photodepletion technique. , 2008, Blood.

[52]  H. Einsele,et al.  Isolation and expansion of human adenovirus-specific CD4+ and CD8+ T cells according to IFN-gamma secretion for adjuvant immunotherapy. , 2004, Experimental hematology.

[53]  C. Rooney,et al.  Conserved CTL epitopes on the adenovirus hexon protein expand subgroup cross-reactive and subgroup-specific CD8+ T cells. , 2004, Blood.

[54]  Chung-Che Chang,et al.  Monoculture-derived T lymphocytes specific for multiple viruses expand and produce clinically relevant effects in immunocompromised individuals , 2006, Nature Medicine.

[55]  G. Freeman,et al.  CD4+CD25high Regulatory Cells in Human Peripheral Blood1 , 2001, The Journal of Immunology.

[56]  C. Rooney,et al.  A comparison of gene transfer and antigen-loaded dendritic cells for the generation of CD4+ and CD8+ cytomegalovirus-specific T cells in HLA-A2+ and HLA-A2- donors. , 2004, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[57]  A. Tosti,et al.  Photodynamic purging of alloreactive T cells for adoptive immunotherapy after haploidentical stem cell transplantation. , 2008, Blood cells, molecules & diseases.

[58]  Shamsul A. Khan,et al.  Targeting the activation-induced antigen CD137 can selectively deplete alloreactive T cells from antileukemic and antitumor donor T-cell lines. , 2007, Blood.

[59]  K. Rezvani,et al.  High donor FOXP3-positive regulatory T-cell (Treg) content is associated with a low risk of GVHD following HLA-matched allogeneic SCT. , 2006, Blood.

[60]  H. Einsele,et al.  Induction of CMV-specific T-cell lines using Ag-presenting cells pulsed with CMV protein or peptide. , 2002, Cytotherapy.

[61]  M. Boeckh,et al.  Respiratory virus infection among hematopoietic cell transplant recipients: evidence for asymptomatic parainfluenza virus infection. , 2007, Blood.

[62]  S. Rowland-Jones,et al.  A re-evaluation of the frequency of CD8+ T cells specific for EBV in healthy virus carriers. , 1999, Journal of immunology.

[63]  R. Andreesen,et al.  Large-scale in vitro expansion of polyclonal human CD4+CD25high regulatory T cells , 2004 .

[64]  M. Karim,et al.  CD25+CD4+ Regulatory T Cells Prevent Graft Rejection: CTLA-4- and IL-10-Dependent Immunoregulation of Alloresponses1 , 2002, The Journal of Immunology.

[65]  A. Swerdlow,et al.  Treatment of Epstein-Barr-virus-positive post-transplantation lymphoproliferative disease with partly HLA-matched allogeneic cytotoxic T cells , 2002, The Lancet.

[66]  M. Boeckh,et al.  Clinical outcomes of human herpesvirus 6 reactivation after hematopoietic stem cell transplantation. , 2005, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[67]  H. Heslop,et al.  Donor T cells to treat EBV-associated lymphoma. , 1994, The New England journal of medicine.

[68]  A. Barrett,et al.  Selective depletion of alloreactive donor lymphocytes: a novel method to reduce the severity of graft-versus-host disease in older patients undergoing matched sibling donor stem cell transplantation. , 2005, Blood.

[69]  R. Krance,et al.  Adenovirus infection rates in pediatric recipients of alternate donor allogeneic bone marrow transplants receiving either antithymocyte globulin (ATG) or alemtuzumab (Campath) , 2005, Bone Marrow Transplantation.

[70]  D. Srivastava,et al.  Infusion of cytotoxic T cells for the prevention and treatment of Epstein-Barr virus-induced lymphoma in allogeneic transplant recipients. , 1998, Blood.

[71]  C. Sample,et al.  An Epstein-Barr virus deletion mutant associated with fatal lymphoproliferative disease unresponsive to therapy with virus-specific CTLs. , 2001, Blood.

[72]  C. Craddock,et al.  Direct visualization of cytomegalovirus-specific T-cell reconstitution after allogeneic stem cell transplantation. , 2001, Blood.

[73]  A. Swerdlow,et al.  Allogeneic cytotoxic T-cell therapy for EBV-positive posttransplantation lymphoproliferative disease: results of a phase 2 multicenter clinical trial. , 2007, Blood.

[74]  R. Noelle,et al.  Cd4+Cd25+ Immune Regulatory Cells Are Required for Induction of Tolerance to Alloantigen via Costimulatory Blockade , 2001, The Journal of experimental medicine.

[75]  T. Lion,et al.  Safe adoptive transfer of virus‐specific T‐cell immunity for the treatment of systemic adenovirus infection after allogeneic stem cell transplantation , 2006, British journal of haematology.

[76]  Hans-Georg Rammensee,et al.  Infusion of cytomegalovirus (CMV)-specific T cells for the treatment of CMV infection not responding to antiviral chemotherapy. , 2002, Blood.

[77]  I. Ernberg,et al.  Epstein-Barr virus (EBV) load in bone marrow transplant recipients at risk to develop posttransplant lymphoproliferative disease: prophylactic infusion of EBV-specific cytotoxic T cells. , 2000, Blood.

[78]  C. Craddock,et al.  Adoptive transfer of cytomegalovirus-specific CTL to stem cell transplant patients after selection by HLA–peptide tetramers , 2005, The Journal of experimental medicine.

[79]  S. Mackinnon,et al.  Adoptive immunotherapy using donor leukocytes following bone marrow transplantation for chronic myeloid leukemia: is T cell dose important in determining biological response? , 1995, Bone marrow transplantation.

[80]  R. Noelle,et al.  CD4(+) T cells tolerized ex vivo to host alloantigen by anti-CD40 ligand (CD40L:CD154) antibody lose their graft-versus-host disease lethality capacity but retain nominal antigen responses. , 1998, The Journal of clinical investigation.

[81]  Zhensheng Liu,et al.  Generation of EBV-Specific CD4+ Cytotoxic T Cells from Virus Naive Individuals1 , 2002, The Journal of Immunology.

[82]  Malcolm K. Brenner,et al.  Identification of Hexon-Specific CD4 and CD8 T-Cell Epitopes for Vaccine and Immunotherapy , 2007, Journal of Virology.

[83]  R. Handgretinger,et al.  Detection of adenovirus‐specific T cells in children with adenovirus infection after allogeneic stem cell transplantation , 2005, British journal of haematology.