title: Effective treatment of refractory CMV reactivation after allogeneic stem cell transplantation with in vitro-generated CMV pp65-specific CD8+ T-cell lines.
abstract: To treat patients with refractory cytomegalovirus (CMV) reactivation after allogeneic stem cell transplantation, a phase I/II clinical study on adoptive transfer of in vitro-generated donor-derived or patient-derived CMV pp65-specific CD8* T-cell lines was performed. Peripheral blood mononuclear cells from CMV seropositive donors or patients were stimulated with HLA-A*0201-restricted and/or HLA-B*0702-restricted CMV pp65 peptides (NLV/TPR) and 1 day after stimulation interferon-γ)-producing cells were enriched using the CliniMACS Cytokine Capture System (interferon-γ), and cultured with autologous feeders and low-dose interluekin-2. After 7-14 days of culture, quality controls were performed and the CMV-specific T-cell lines were administered or cryopreserved. The T-cell lines generated contained 0.6-17 × 10(6) cells, comprising 54%-96% CMV pp65-specific CD8 T cells, and showed CMV-specific lysis of target cells. Fifteen CMV-specific T-cell lines were generated of which 8 were administered to patients with refractory CMV reactivation. After administration, no acute adverse events and no graft versus host disease were observed and CMV load disappeared. In several patients, a direct relation between administration of the T-cell line and the in vivo appearance of CMV pp65-specific T cells could be documented. In conclusion, administration of CMV pp65-specific CD8* T-cell lines was found to be feasible and safe, and enduring efficacy of administered CMV pp65-specific CD8* T-cell lines could be demonstrated.
authors.affiliation: Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands. p.meij@lumc.nl
authors.forename: Pauline
authors.initials: P
authors.lastname: Meij
authors.forename: Inge
authors.initials: I
authors.lastname: Jedema
authors.forename: Maarten L
authors.initials: ML
authors.lastname: Zandvliet
authors.forename: Pim L J
authors.initials: PL
authors.lastname: van der Heiden
authors.forename: Marian
authors.initials: M
authors.lastname: van de Meent
authors.forename: H M Esther
authors.initials: HM
authors.lastname: van Egmond
authors.forename: Ellis
authors.initials: E
authors.lastname: van Liempt
authors.forename: Conny
authors.initials: C
authors.lastname: Hoogstraten
authors.forename: Simone
authors.initials: S
authors.lastname: Kruithof
authors.forename: Sabrina
authors.initials: S
authors.lastname: Veld
authors.forename: Erik W A
authors.initials: EW
authors.lastname: Marijt
authors.forename: Peter A
authors.initials: PA
authors.lastname: von dem Borne
authors.forename: Arjan C
authors.initials: AC
authors.lastname: Lankester
authors.forename: Constantijn J M
authors.initials: CJ
authors.lastname: Halkes
authors.forename: J H Frederik
authors.initials: JH
authors.lastname: Falkenburg
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D002460:Cell Line; D003602:Cytotoxicity, Immunologic; D015789:HLA-A2 Antigen / Q000378:metabolism; D015793:HLA-B7 Antigen / Q000378:metabolism; D006561:Herpes Simplex / Q000209:etiology / Q000276:immunology / Q000628:therapy*; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism; D010750:Phosphoproteins / Q000276:immunology / Q000378:metabolism; D011183:Postoperative Complications; D011485:Protein Binding; D018139:Simplexvirus / Q000502:physiology*; D033581:Stem Cell Transplantation; D014184:Transplantation, Homologous; D019562:Viral Load / Q000276:immunology; D014763:Viral Matrix Proteins / Q000276:immunology / Q000378:metabolism; D014775:Virus Activation
chemical_list: C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; C477444:HLA-B*07:02 antigen; D015793:HLA-B7 Antigen; D007376:Interleukin-2; D010446:Peptide Fragments; D010750:Phosphoproteins; D014763:Viral Matrix Proteins; C065418:cytomegalovirus matrix protein 65kDa; D007371:Interferon-gamma