title: Adoptive immunotherapy with unselected or EBV-specific T cells for biopsy-proven EBV+ lymphomas after allogeneic hematopoietic cell transplantation.
abstract: We evaluated HLA-compatible donor leukocyte infusions (DLIs) and HLA-compatible or HLA-disparate EBV-specific T cells (EBV-CTLs) in 49 hematopoietic cell transplantation recipients with biopsy-proven EBV-lymphoproliferative disease (EBV-LPD). DLIs and EBV-CTLs each induced durable complete or partial remissions in 73% and 68% of treated patients including 74% and 72% of patients surviving ≥ 8 days after infusion, respectively. Reversible acute GVHD occurred in recipients of DLIs (17%) but not EBV-CTLs. The probability of complete response was significantly lower among patients with multiorgan involvement. In responders, DLIs and EBV-CTLs regularly induced exponential increases in EBV-specific CTL precursor (EBV-CTLp) frequencies within 7-14 days, with subsequent clearance of EBV viremia and resolution of disease. In nonresponders, EBV-CTLps did not increase and EBV viremia persisted. Treatment failures were correlated with impaired T-cell recognition of tumor targets. Either donor-derived EBV-CTLs that had been sensitized with autologous BLCLs transformed by EBV strain B95.8 could not lyse spontaneous donor-derived EBV-transformed BLCLs expanded from the patient's blood or biopsied tumor or they failed to lyse their targets because they were selectively restricted by HLA alleles not shared by the EBV-LPD. Therefore, either unselected DLIs or EBV-specific CTLs can eradicate both untreated and Rituxan-resistant lymphomatous EBV-LPD, with failures ascribable to impaired T-cell recognition of tumor-associated viral antigens or their presenting HLA alleles.
authors.affiliation: Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Doubrovina
authors.forename: Banu
authors.initials: B
authors.lastname: Oflaz-Sozmen
authors.forename: Susan E
authors.initials: SE
authors.lastname: Prockop
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Kernan
authors.forename: Sara
authors.initials: S
authors.lastname: Abramson
authors.forename: Julie
authors.initials: J
authors.lastname: Teruya-Feldstein
authors.forename: Cyrus
authors.initials: C
authors.lastname: Hedvat
authors.forename: Joanne F
authors.initials: JF
authors.lastname: Chou
authors.forename: Glenn
authors.initials: G
authors.lastname: Heller
authors.forename: Juliet N
authors.initials: JN
authors.lastname: Barker
authors.forename: Farid
authors.initials: F
authors.lastname: Boulad
authors.forename: Hugo
authors.initials: H
authors.lastname: Castro-Malaspina
authors.forename: Diane
authors.initials: D
authors.lastname: George
authors.forename: Ann
authors.initials: A
authors.lastname: Jakubowski
authors.forename: Guenther
authors.initials: G
authors.lastname: Koehne
authors.forename: Esperanza B
authors.initials: EB
authors.lastname: Papadopoulos
authors.forename: Andromachi
authors.initials: A
authors.lastname: Scaradavou
authors.forename: Trudy N
authors.initials: TN
authors.lastname: Small
authors.forename: Ramzi
authors.initials: R
authors.lastname: Khalaf
authors.forename: James W
authors.initials: JW
authors.lastname: Young
authors.forename: Richard J
authors.initials: RJ
authors.lastname: O'Reilly
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D004279:DNA, Viral / Q000235:genetics; D020031:Epstein-Barr Virus Infections / Q000209:etiology / Q000628:therapy*; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D004854:Herpesvirus 4, Human / Q000472:pathogenicity; D006801:Humans; D016219:Immunotherapy, Adoptive; D008223:Lymphoma / Q000209:etiology / Q000628:therapy*; D008232:Lymphoproliferative Disorders / Q000209:etiology / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000637:transplantation*; D014184:Transplantation, Homologous; D055815:Young Adult
chemical_list: D004279:DNA, Viral