Since its discovery as the first human tumor virus, Epstein-Barr virus (EBV) has been implicated in the development of a wide range of B-cell lymphoproliferative disorders, including Burkitt's lymphoma, classic Hodgkin's lymphoma, and lymphomas arising in immunocompromised individuals (post-transplant and HIV-associated lymphoproliferative disorders). T-cell lymphoproliferative disorders that have been reported to be EBV associated include a subset of peripheral T-cell lymphomas, angioimmunoblastic Tcell lymphoma, extranodal nasal type natural killer/ T-cell lymphoma, and other rare histotypes. EBV encodes a series of products interacting with or exhibiting homology to a wide variety of antiapoptotic molecules, cytokines, and signal transducers, hence promoting EBV infection, immortalization, and transformation. However, the exact mechanism by which EBV promotes oncogenesis is an area of active debate. The focus of this review is on the pathology, diagnosis, classification, and pathogenesis of EBVassociated lymphomas. Recent advances in EBV cellbased immunotherapy, which is beginning to show promise in the treatment of EBV-related disorders, are discussed. The Oncologist 2008;13:577-585

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Transgenic human CD40 ligand (hCD40L) activates B-Chronic Lymphocytic Leukemia (B-CLL) cells by CD40 stimulation and may thereby enhance their capacity to present tumor antigens. Pre-clinical models show that co-expression of IL-2 further potentiates the immunogenicity of CD40L-expressing tumor cells. To discover whether these promising pre-clinical data could usefully be applied to patients with B-CLL, we used adenovectors to prepare hIL2- and hCD40L-expressing autologous tumor vaccines. Within these vaccines, a mean of 92% B-CLL cells were CD40L positive (versus <1% pre-treatment), and costimulatory molecules were also upregulated on the tumor cells (CD80 from 6% to 74% and CD86 from 16% to 73% positive cells). The mean secretion of IL-2 (measured by ELISA at 72 hours after transduction) was 1,780 pg/ml/10E6 cells (range = 175–400). To date, 8 patients have received between 5 and 8 subcutaneous injections in a modified Phase I design, in which the dose of IL-2 secreting cells was fixed at 2x10E7 per injection, while the dose of CD40L-expressing leukemia cells was escalated from 2x10E5 (level 1) to 2x10E7 (level 3) per injection. 12 additional patients will receive this final dose combination. Of those treated, two patients were in Rai stage 4; 2 in stage 3; 2 in stage 2; and 2 in stage 1. There were no adverse events from any injection in the patients. Injection-site biopsies revealed a modest infiltration of CD3+ cells, and the vaccine also had systemic immunomodulatory effects. Total T-cell numbers were significantly increased in only 2 patients, but an anti-B-CLL immune response was detected in 5/6 individuals currently analyzed. Using ELISPOT assays with autologous B-CLL cells as stimulators, and allogeneic B-CLL cells as controls, we found a rise in IFN-gamma spot-forming T-cells (<1/100,000 pre to >1/1500 post vaccination) and of Granzyme-B expressing T-cells (<1/100,000 pre to >1/2500 post). This reactivity is mediated at least in part by CD8-positive T cells with specificity to survivin, a known B-CLL associated tumor antigen. Although these immunologic effects have as yet been accompanied by only transient disease responses, our continuing accrual of additional patients who will receive immunomodulatory doses of vaccine should indicate whether the approach could contribute to the management of early or advanced B-CLL.