ADOPTIVE CELLULAR IMMUNOTHERAPY FOR EBV LYMPHOPROLIFERATIVE DISEASES

Reactivation of EBV (Epstein-Barr virus) after bone marrow transplanta tion can result in EBV-associated lymphoproliferative disease (EBV-LPD ). We have administered donor-derived EBV-specific cytotoxic T lymphoc ytes (CTL) to patients who are at high risk of this complication after receiving a T-cell-depleted allograft from a matched unrelated or mis matched related donor. The cells were marked with the neo gene before infusion so that we could evaluate their persistence and efficacy. CTL infusion produced a virus-specific immune response to EBV that persis ted for up to 2 years. None of the 36 patients who received prophylact ic CTLs have developed EBV-LPD, compared with a cumulative risk of 14% in patients who did not receive this treatment. Strong evidence of cl inically valuable immune activity comes from 6 of these 36 patients wh ose pre-CTL levels of EBV DNA were elevated to a degree strongly predi ctive of the onset of lymphoma. In each of these cases, the levels ret urned to baseline after CTL infusion. 2 patients who were treated for clinically evident EBV-LPD attained prolonged remission after CTL infu sion and in situ hybridization and semiquantitative PCR showed that th e gene-marked CTL had selectively accumulated at disease sites. The pr ophylactic CTL treatment lacked acute adverse effects, Whereas 1 patie nt who received CTLs for bulky established disease developed initial t umor swelling and respiratory obstruction. We conclude that EBV-specif ic CTLs are a safe and effective prophylaxis for EBV lymphoma and can also eradicate established disease. This approach is now being extende d to other viruses that produce post-transplant morbidity and to other EBV-associated malignancies.