Cellular adoptive immunotherapy for virus-associated malignant disease is an attractive strategy, since viral antigens provide targets for specific T lymphocytes. In Epstein-Barr virus (EBV)-positive Hodgkin disease (HD), a limited number of EBV-encoded antigens such as the latent membrane antigens (LMP) 1 and 2 are expressed on the malignant Reed-Sternberg cells. The authors aimed to generate cytotoxic T lymphocytes (CTLs) from patients with relapsed HD by specifically targeting LMP2A. Patients with relapsed HD have highly immunosuppressive tumors and have been heavily pretreated with cytotoxic agents. As a result, monocytes and lymphocytes are numerically reduced and functionally impaired. Approaches using dendritic cells (DCs) as the sole antigen-presenting cell to expand LMP2-specific CTL lines in vitro have proved impractical. The authors now show how small amounts of patient peripheral blood can be used to produce DCs expressing LMP2 after Ad5F35 transduction, and how an initial reactivation of LMP2-specific CTLs can be followed by stimulation with lymphoblastoid cell lines overexpressing LMP2 from the same vector. Large numbers of LMP2-specific cytotoxic lymphocytes are produced that contain both CD4+ and CD8+ T cells (favoring long-term persistence in vivo) and recognize multiple LMP2 epitopes (minimizing the risk of tumor antigen loss variants). This approach is being used in a current clinical trial.