Epstein-Barr virus-specific cytotoxic T lymphocyte responses in the blood and tumor site of Hodgkin's disease patients: Implications for a T-cell-based therapy

Approximately 40% of Hodgkin's disease (HD) cases carry EBV in the malignan t Hodgkin-Reed Sternberg (H-RS) cells, with expression of viral latent memb rane proteins (LMPs) 1 and 2. These viral proteins are targets for CTLs in healthy EBV carriers, and their expression in EBV-associated HD raises the possibility of targeting them for a CTL-based immunotherapy. Here we charac terize the CTL response to EBV latent antigens in both the blood and tumor- infiltrating lymphocytes of HD patients using two approaches: (a) in vitro reactivation of CTLs by stimulation with the autologous EBV-transformed lym phoblastoid cell line; and (b) an enzyme-linked immunospot assay to quantif y frequencies of CTLs specific for known LMP1/2 epitopes. We detected EBV-s pecific CTLs in blood and biopsy samples from both EBV-negative and EBV-pos itive HD patients. However, as in healthy EBV carriers, LMP-specific CTL pr ecursors occurred only at low frequency in the blood of HD patients, and wi th the exception of one EBV-negative HD case, were undetectable in the tumo r. These data give rise to two considerations: (a) they may explain why EBV -positive tumor cells persist in the presence of an existing EBV-specific i mmune response; and (b) they provide a rationale for selectively boosting/e liciting LMP-specific CTL responses as a therapy for EBV-positive HD.