title: Sustained complete responses in patients with lymphoma receiving autologous cytotoxic T lymphocytes targeting Epstein-Barr virus latent membrane proteins.
abstract: OBJECTIVE
  Tumor cells from approximately 40% of patients with Hodgkin or non-Hodgkin lymphoma express the type II latency Epstein-Barr virus (EBV) antigens latent membrane protein 1 (LMP1) and LMP2, which represent attractive targets for immunotherapy. Because T cells specific for these antigens are present with low frequency and may be rendered anergic by the tumors that express them, we expanded LMP-cytotoxic T lymphocytes (CTLs) from patients with lymphoma using autologous dendritic cells and EBV-transformed B-lymphoblastoid cell lines transduced with an adenoviral vector expressing either LMP2 alone (n = 17) or both LMP2 and ΔLMP1 (n = 33).
  
  
  METHODS
  These genetically modified antigen-presenting cells expanded CTLs that were enriched for specificity against type II latency LMP antigens. When infused into 50 patients with EBV-associated lymphoma, the expanded CTLs did not produce infusional toxicities.
  
  
  RESULTS
  Twenty-eight of 29 high-risk or multiple-relapse patients receiving LMP-CTLs as adjuvant therapy remained in remission at a median of 3.1 years after CTL infusion. None subsequently died as a result of lymphoma, but nine succumbed to complications associated with extensive prior chemoradiotherapy, including myocardial infarction and secondary malignancies. Of 21 patients with relapsed or resistant disease at the time of CTL infusion, 13 had clinical responses, including 11 complete responses. T cells specific for LMP as well as nonviral tumor-associated antigens (epitope spreading) could be detected in the peripheral blood within 2 months after CTL infusion, but this evidence for epitope spreading was seen only in patients achieving clinical responses.
  
  
  CONCLUSIONS
  Autologous T cells directed to the LMP2 or LMP1 and LMP2 antigens can induce durable complete responses without significant toxicity. Their earlier use in the disease course may reduce delayed treatment-related mortality.
authors.affiliation: Catherine M. Bollard, Stephen Gottschalk, Vicky Torrano, Oumar Diouf, Stephanie Ku, Yasmin Hazrat, George Carrum, Carlos Ramos, Hao Liu, Meng-Fen Wu, Andrea M. Sheehan, Adrian P. Gee, Malcolm K. Brenner, Helen E. Heslop, and Cliona M. Rooney, Baylor College of Medicine and Texas Children's Hospital; Catherine M. Bollard, Stephen Gottschalk, Vicky Torrano, Oumar Diouf, Stephanie Ku, Yasmin Hazrat, George Carrum, Carlos Ramos, Hao Liu, Meng-Fen Wu, Daniel Lee, Andrea M. Sheehan, Youli Zu, Adrian P. Gee, Malcolm K. Brenner, Helen E. Heslop, and Cliona M. Rooney, Methodist Hospital; Luis Fayad, Elizabeth J. Shpall, and Barbara Pro, MD Anderson Cancer Center, Houston, TX; and Daniel Lee and Youli Zu, Weill Medical College of Cornell University, New York, NY.
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Bollard
authors.forename: Stephen
authors.initials: S
authors.lastname: Gottschalk
authors.forename: Vicky
authors.initials: V
authors.lastname: Torrano
authors.forename: Oumar
authors.initials: O
authors.lastname: Diouf
authors.forename: Stephanie
authors.initials: S
authors.lastname: Ku
authors.forename: Yasmin
authors.initials: Y
authors.lastname: Hazrat
authors.forename: George
authors.initials: G
authors.lastname: Carrum
authors.forename: Carlos
authors.initials: C
authors.lastname: Ramos
authors.forename: Luis
authors.initials: L
authors.lastname: Fayad
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Shpall
authors.forename: Barbara
authors.initials: B
authors.lastname: Pro
authors.forename: Hao
authors.initials: H
authors.lastname: Liu
authors.forename: Meng-Fen
authors.initials: MF
authors.lastname: Wu
authors.forename: Daniel
authors.initials: D
authors.lastname: Lee
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Sheehan
authors.forename: Youli
authors.initials: Y
authors.lastname: Zu
authors.forename: Adrian P
authors.initials: AP
authors.lastname: Gee
authors.forename: Malcolm K
authors.initials: MK
authors.lastname: Brenner
authors.forename: Helen E
authors.initials: HE
authors.lastname: Heslop
authors.forename: Cliona M
authors.initials: CM
authors.lastname: Rooney
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000368:Aged; D002460:Cell Line; D049109:Cell Proliferation; D002648:Child; D018572:Disease-Free Survival; D005260:Female; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods* / Q000401:mortality; D005822:Genetic Vectors; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000276:immunology*; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000009:adverse effects / Q000379:methods* / Q000401:mortality; D053208:Kaplan-Meier Estimate; D008223:Lymphoma / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000628:therapy* / Q000821:virology; D008297:Male; D008875:Middle Aged; D012008:Recurrence; D012074:Remission Induction; D012307:Risk Factors; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000637:transplantation*; D013781:Texas; D013997:Time Factors; D014161:Transduction, Genetic; D014182:Transplantation, Autologous; D016896:Treatment Outcome; D014763:Viral Matrix Proteins / Q000235:genetics / Q000276:immunology*; D055815:Young Adult
chemical_list: C037662:EBV-associated membrane antigen, Epstein-Barr virus; D014763:Viral Matrix Proteins