VACCINATION OF PATIENTS AT RISK FOR POST-TRANSPLANT LYMPHOPROLIFERATIVE DISORDER

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Epstein-Barr virus (EBV) specific T cells play a central role controlling the replication of EBV throughout life. This is evidenced by the greatly increased incidence of EBV-associated lymphoproliferative diseases in immunocompromised patients. In addition, restoration of EBV-specific T cell-mediated immunity via adoptive transfer of ex vivo expanded EBV-specific cytotoxic T cells in patients who have undergone allogeneic bone marrow transplantation has been shown to mediate regression of post-transplant lymphoproliferative disorder (PTLD) lesions. PTLD is a major cause of morbidity and mortality in patients who have received solid organ transplants. In this population of patients, the source of EBV-specific T cells for adoptive transfer is highly problematic. The natural history of PTLD in solid organ recipients suggests that elicitation of a memory T cell response against EBV or the augmentation of an existing response is likely to reduce the incidence of PTLD in this population. A robust multivalent response seems most likely to remain effective in the face of therapeutic immunosuppression. A safe and feasible approach to accomplish this goal is the use of a cellular vaccine consisting of autologous EBV-infected lymphoblastoid cell lines (LCLs). The natural history of EBV infection and the immunogenicity of LCL in vitro suggest that this cellular vaccine may be a potent stimulator of EBV-specific T cell responses in vivo. The proposed study will test the safety and efficacy of a vaccine preparation consisting of an autologous Epstein-Barr virus (EBV)-infected lymphoblastoid cell line (LCL) in patients who are being considered for solid organ transplant. The LCL and the EBV will be inactivated by photochemical treatment that consists of amotosalen HCl (S-59) and UVA light. Forty patients (20 EBV seropositive and 20 seronegative) will be vaccinated on two occasions, 1 month apart. The primary surrogate endpoint for efficacy will be cellular responses to EBV latency antigens by intracellular cytokine synthesis. Measurements of humoral responses to EBV antigens will be done in both EBV seronegative and seropositive patients. The durability of these during the time course of this study will be characterized. Primary infection among seronegative patients will be characterized. Adverse events associated with the proposed vaccination scheme will be described. SPECIFIC AIMS - To assess the efficacy of a vaccine consisting of photochemically treated autologous EBV-infected lymphoblastoid cells in generating EBV-specific T cell and antibody responses in EBV seronegative patients or boosting the response in seropositive patients being considered for solid organ transplant. - To identify adverse events associated with such a vaccine - To assess the ability of the vaccine to protect from EBV primary infection in EBV seronegative patients during the time course of the study.