Sustained complete responses in patients with lymphoma receiving autologous cytotoxic T lymphocytes targeting Epstein-Barr virus latent membrane proteins

J Clin Oncol. 2014 Mar 10;32(8):798-808. doi: 10.1200/JCO.2013.51.5304. Epub 2013 Dec 16.


Purpose: 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).

Patients and 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.

Conclusion: 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.

Trial registration: NCT00671164.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural
  • Webcast

MeSH terms

  • Adenoviridae / genetics
  • Adolescent
  • Adult
  • Aged
  • Cell Line
  • Cell Proliferation
  • Child
  • Disease-Free Survival
  • Female
  • Genetic Therapy / adverse effects
  • Genetic Therapy / methods*
  • Genetic Therapy / mortality
  • Genetic Vectors
  • Herpesvirus 4, Human / genetics
  • Herpesvirus 4, Human / immunology*
  • Humans
  • Immunotherapy, Adoptive / adverse effects
  • Immunotherapy, Adoptive / methods*
  • Immunotherapy, Adoptive / mortality
  • Kaplan-Meier Estimate
  • Lymphoma / immunology
  • Lymphoma / mortality
  • Lymphoma / pathology
  • Lymphoma / therapy*
  • Lymphoma / virology
  • Male
  • Middle Aged
  • Recurrence
  • Remission Induction
  • Risk Factors
  • T-Lymphocytes, Cytotoxic / immunology
  • T-Lymphocytes, Cytotoxic / transplantation*
  • Texas
  • Time Factors
  • Transduction, Genetic
  • Transplantation, Autologous
  • Treatment Outcome
  • Viral Matrix Proteins / genetics
  • Viral Matrix Proteins / immunology*
  • Young Adult


  • EBV-associated membrane antigen, Epstein-Barr virus
  • Viral Matrix Proteins

Associated data