Cellular immunotherapy of EBV-associated lymphomas

We have administered donor-derived EBVspecifîc CTL lines to patients at high risk of developing EBV lymphoma after a T cell depleted transplant from a matched unrelated donor or mismatched family member. CTL infusion produced a virus-specific immune response to EBV that persisted for up to three years. None of 50 patients who received prophylactic CTLs have developed EBV-LPD, compared with a cumulative risk of 11% in patients who did not receive this treatment. Two patients who were treated for clinically evident EBV-LPD attained prolonged remission after CTL infusion and in situ hybridization and semiquantitative PCR showed that the gene marked CTL had selectively accumulated at disease sites. We conclude that EBV-specific CTLs are safe and effective prophylaxis for EBV lymphoma and can also eradicate established disease. This approach is now being extended to other viruses that produce post-transplant morbidity and to other EBV-associated malignancies. In other EBV-associated primary malignancies, tumor cells may be less susceptible to immunotherapeutic approaches because they express a more restricted array of subdominant EBV-encoded antigens. We have treated five patients with relapsed EBV genome positive Hodgkin disease with polyclonal EBV specific CTLs and the infused cells have persisted in peripheral blood for up to 12 weeks and in one patient were detected in a malignant pleural effusion.