title: Towards gene therapy for EBV-associated posttransplant lymphoma with genetically modified EBV-specific cytotoxic T cells.
abstract: Epstein-Barr virus (EBV)-associated posttransplant lymphoma (PTLD) is a major cause of morbidity/mortality after hematopoietic stem cell (SCT) or solid organ (SOT) transplant. Adoptive immunotherapy with EBV-specific cytotoxic lymphocytes (CTLs), although effective in SCT, is less successful after SOT where lifelong immunosuppression therapy is necessary. We have genetically engineered EBV-CTLs to render them resistant to calcineurin (CN) inhibitor FK506 through retroviral transfer of a calcineurin A mutant (CNA12). Here we examined whether or not FK506-resistant EBV-CTLs control EBV-driven tumor progression in the presence of immunosuppression in a xenogeneic mouse model. NOD/SCID/IL2rγ(null) mice bearing human B-cell lymphoma were injected with autologous CTLs transduced with either CNA12 or eGFP in the presence/absence of FK506. Adoptive transfer of autologous CNA12-CTLs induced dramatic lymphoma regression despite the presence of FK506, whereas eGFP-CTLs did not. CNA12-CTLs persisted longer, homed to the tumor, and expanded more than eGFP-CTLs in mice treated with FK506. Mice receiving CNA12-CTLs and treated with FK506 survived significantly longer than control-treated animals. Our results demonstrate that CNA12-CTL induce regression of EBV-associated tumors in vivo despite ongoing immunosuppression. Clinical application of this novel approach may enhance the efficacy of adoptive transfer of EBV-CTL in SOT patients developing PTLD without the need for reduction in immunosuppressive therapy.
authors.affiliation: Molecular and Cellular Immunology Unit, Institute of Child Health and Department of Haematology, Cancer Institute, University College London, London, United Kingdom; and.
authors.forename: Ida
authors.identifier: http://orcid.org/0000-0001-5780-6580
authors.initials: I
authors.lastname: Ricciardelli
authors.affiliation: Molecular and Cellular Immunology Unit, Institute of Child Health and.
authors.forename: Michael Patrick
authors.initials: MP
authors.lastname: Blundell
authors.affiliation: Molecular and Cellular Immunology Unit, Institute of Child Health and.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Brewin
authors.affiliation: Molecular and Cellular Immunology Unit, Institute of Child Health and.
authors.forename: Adrian
authors.initials: A
authors.lastname: Thrasher
authors.affiliation: Department of Haematology, Cancer Institute, University College London, London, United Kingdom; and.
authors.forename: Martin
authors.initials: M
authors.lastname: Pule
authors.affiliation: Molecular and Cellular Immunology Unit, Institute of Child Health and Department of Bone Marrow Transplantation, Great Ormond Street Hospital for Children National Health Service Trust, London, United Kingdom.
authors.forename: Persis J
authors.initials: PJ
authors.lastname: Amrolia
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000235:genetics; D065095:Calcineurin Inhibitors / Q000494:pharmacology; D004351:Drug Resistance; D020031:Epstein-Barr Virus Infections / Q000150:complications*; D005818:Genetic Engineering / Q000379:methods; D015316:Genetic Therapy / Q000379:methods; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000302:isolation & purification; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D016219:Immunotherapy, Adoptive / Q000379:methods; D008223:Lymphoma / Q000235:genetics / Q000473:pathology / Q000628:therapy* / Q000821:virology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009154:Mutation; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000378:metabolism / Q000637:transplantation* / Q000821:virology*; D016559:Tacrolimus / Q000494:pharmacology; D014161:Transduction, Genetic
chemical_list: D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D019703:Calcineurin; D016559:Tacrolimus