title: Cell therapy of stage IV nasopharyngeal carcinoma with autologous Epstein-Barr virus-targeted cytotoxic T lymphocytes.
abstract: OBJECTIVE
  Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV)-related malignancy expressing EBV antigens that are possible targets of cell therapy, including latent membrane protein 2 (LMP2). We conducted a clinical trial of EBV-targeted cell therapy with autologous virus-specific cytotoxic T lymphocytes (CTLs) for NPC refractory to conventional treatments.
  
  
  METHODS
  Ten patients with EBV-related stage IV NPC in progression after conventional radiotherapy and chemotherapy received intravenously autologous EBV-specific CTLs reactivated and expanded ex vivo from peripheral blood lymphocytes through stimulation with EBV-transformed autologous B-lymphoblastoid cell lines (LCL). Toxicity, specific cellular immune responses, and clinical tumor responses were evaluated.
  
  
  RESULTS
  EBV-specific CTLs could be generated in all patients and were predominantly CD3+/CD8+ T lymphocytes displaying specific killing of autologous EBV-LCL, autologous NPC cells as well as autologous targets bearing the EBV antigen LMP2. Patients received two to 23 infusions of EBV-specific CTLs that were well tolerated with the exception of grade 1 to 2 inflammatory reactions at the tumor site in two cases. Control of disease progression was obtained in six of 10 patients (two with partial response and four with stable disease). Analysis of interferon-gamma-producing cells demonstrated an increased frequency of EBV-specific immunity, with appearance of LMP2-specific responses in four patients, of whom three had clinical benefit.
  
  
  CONCLUSIONS
  Cell therapy with EBV-targeted autologous CTLs is safe, induces LMP-2-specific immunologic responses, and is associated with objective responses and control of disease progression in patients with stage IV NPC resistant to conventional treatments.
authors.affiliation: Laboratorio di Ricerca Area Trapianti e Oncoematologia Pediatrica, IRCCS Policlinico S. Matteo, V.le Golgi 19, 27100 Pavia, Italy. pcomoli@smatteo.pv.it
authors.forename: Patrizia
authors.initials: P
authors.lastname: Comoli
authors.forename: Paolo
authors.initials: P
authors.lastname: Pedrazzoli
authors.forename: Rita
authors.initials: R
authors.lastname: Maccario
authors.forename: Sabrina
authors.initials: S
authors.lastname: Basso
authors.forename: Ornella
authors.initials: O
authors.lastname: Carminati
authors.forename: Massimo
authors.initials: M
authors.lastname: Labirio
authors.forename: Roberta
authors.initials: R
authors.lastname: Schiavo
authors.forename: Simona
authors.initials: S
authors.lastname: Secondino
authors.forename: Chiara
authors.initials: C
authors.lastname: Frasson
authors.forename: Cesare
authors.initials: C
authors.lastname: Perotti
authors.forename: Mauro
authors.initials: M
authors.lastname: Moroni
authors.forename: Franco
authors.initials: F
authors.lastname: Locatelli
authors.forename: Salvatore
authors.initials: S
authors.lastname: Siena
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000956:Antigens, Viral / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D004854:Herpesvirus 4, Human / Q000276:immunology*; D006801:Humans; D016219:Immunotherapy, Adoptive; D008297:Male; D008875:Middle Aged; D009303:Nasopharyngeal Neoplasms / Q000276:immunology / Q000628:therapy* / Q000821:virology; D009367:Neoplasm Staging; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000637:transplantation; D014182:Transplantation, Autologous; D016896:Treatment Outcome; D014763:Viral Matrix Proteins / Q000276:immunology
chemical_list: D000956:Antigens, Viral; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D014763:Viral Matrix Proteins