Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes for the prevention and treatment of EBV-associated post-transplant lymphomas

Abstract

The Epstein-Barr virus (EBV)-associated lymphoproliferative disorders (LPD) that occur in individuals immunosuppressed by solid organ transplant (SOT) or T cell-depleted stem cell transplantation (SCT) are unequivocally a result of T cell dysfunction. Reconstitution of "at-risk" patients with EBV-specific cytotoxic T lymphocyte (CTL) lines that have been reactivated and expanded in vitro, should prevent the development of post-transplant lymphoproliferative disease or treat pre-existing disease. We have provided over 125 infusions of donor-derived EBV-specific CTL to 60 recipients of T cell-depleted stem cells. As prophylaxis, infusions were safe and effective, as no patient developed EBV-LPD, in contrast to 11.5% of controls who did not receive CTL. The CTL-reconstituted cellular immune responses to EBV, persisted for up to 80 months following infusion and reduced the high virus load seen in about 12% of patients. CTL were also effective in two of three patients who received CTL as treatment for fulminant disease. SOT recipients are also good candidates for CTL therapy, but present problems not seen in bone marrow transplant recipients. First the CTL product must be autologous, since the majority of tumors are recipient-derived and allogeneic CTL are unlikely to survive in vivo. Second most patients continue to receive immunosuppressive drugs, which may compromise the function of infused CTL. Third, unlike SCT recipients SOT recipients do not have an empty niche for EBV-specific CTL. Finally, standard protocols are not effective in generating CTL from seronegative recipients of EBV-carrying organs, who are the patients most at risk for the development of EBV-LPD. For CTL to be an option for the management of EBV in these patients, a sensitive and specific assay for the prediction of high-risk patients is required as well as an effective method for the generation of EBV-specific CTL from seronegative recipients.