Cohen JI, Bollard CM, Khanna R, et al. Current understanding of the role of Epstein-Barr virus in lymphomagenesis and therapeutic approaches to EBV-associated lymphomas.

Medical Virology Section, Laboratory of Clinical Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-1888, USA.
Leukemia & lymphoma (Impact Factor: 2.89). 01/2008; 49 Suppl 1(1):27-34. DOI: 10.1080/10428190802311417
Source: PubMed


A heterogeneous group of malignancies are associated with Epstein-Barr virus (EBV) infection. These malignancies arise in both immunosuppressed and immunocompetent individuals and can be divided into three patterns of latency depending on the viral genes that are expressed. In Type III latency malignancies, such as post-transplant lymphoproliferative disorder (PTLD), EBV has a direct role and the activated B-cell phenotype is characterised by high-level expression of all the immunodominant EBV latency proteins. Thus, EBV-infected B cells are good targets for EBV-specific cytotoxic T lymphocytes (CTLs). New immune-based treatments for PTLD include transfer of ex vivo generated autologous EBV-specific CTLs or, in the case of bone marrow transplant recipients, donor-derived EBV-specific T cells. This strategy could, perhaps, also work in Type II latency malignancies, where EBV acts like a cofactor rather than having a direct role. In initial studies, T cells specific for the weakly immunogenic latent membrane protein 2 have been expanded ex vivo and have promoted tumor regression in a subset of patients. Another potential therapeutic strategy could be to try to induce lytic EBV infection in the tumor cells. This could be done by targeting genes that switch the EBV-infected B cells from the latent to the lytic cycle.

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Available from: Catherine M Bollard, Jun 18, 2015
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    • "The clinical symptoms of PTLD include fever, sweats, lymphadenopathy, sepsis and mass lesions in lymph nodes, the spleen and the brain2324252627. It is important to mention that PTLD emerging soon after the transplant is invariably positive for EBV2829, while a large proportion of the PTLD cases which develops 2-5 years or more after transplantation are negative for EBV27. These EBV-negative PTLD are generally more aggressive and are highly resistant to standard treatments including immunotherapies. "
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    ABSTRACT: Stem cell and organ transplantation are considered as the major advances of modern medicine. Unfortunately the success of transplantation is limited by its toxicity and infectious complications as a result of profound immunosuppression. Viral infections are an extremely common and predictable problem in these patients. Antiviral drugs given either prophylactically or as early therapy for patients with detectable viral loads appear to be an effective strategy for reducing viral infections. However, long-term treatment with these drugs is associated with significant toxicity, expense and the appearance of drug resistant virus isolates ultimately resulting in treatment failure. Over the last few years, there is increasing evidence that cellular immune therapies can reverse the outgrowth of haematological malignancies and can also provide therapeutic benefit against lethal viral infections. While the expansion and adoptive transfer of virus-specific T-cells from the healthy donor can be an effective strategy to control viral replication, this is not possible when donors are seronegative or are subsequently inaccessible. Recent studies have demonstrated successful expansion of virus-specific T-cells from seropositive stem cell transplant recipients of a seronegative graft with active virus disease and the long term reconstitution of protective anti-viral immunity following their adoptive transfer back into the patients. Furthermore, this immunotherapeutic strategy has also been extended for multiple pathogens including cytomegalovirus, Epstein-Barr virus, adenovirus and BK polyoma-virus. This approach can be employed to rapidly expand multiple pathogens-specific T cells that can be used for adoptive immunotherapy. Finally, new assays to monitor T cell immunity have been developed which will allow to identify the high risk transplant patients who may develop virus-associated complications post-transplantation and can be given adoptive T cell therapy prophylactically.
    The Indian Journal of Medical Research 11/2013; 138(5):796-807. · 1.40 Impact Factor
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    • "Recently, the association between synchronous gastric adenocarcinoma and primary gastric lymphoma was found to be related to infection by H. pylori [12]. EBV is also related to some types of lymphoma, nasopharyngeal carcinoma, and certain forms of gastric carcinoma [13]. However, H. pylori was not detected and EBV was only found in HL but not in the gastric adenocarcinoma in our patient. "
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    ABSTRACT: We report the rare case of a 72-year-old man with double cancers (gastric adenocarcinoma and Hodgkin's lymphoma) with collision between gastric adenocarcinoma and Hodgkin's lymphoma. Abdominal computed tomography showed increased wall thickness in the fundus region of the stomach and multiple lymph node swellings in the lesser curvature, periceliac and left cardial regions. Upper gastrointestinal endoscopy showed an ulcer approximately 5 cm in diameter with a malignant appearance in the fundus region of the stomach. On histopathologic examination, two completely different tumors were recognized in the stomach. One tumor was a poorly differentiated adenocarcinoma characterized by poorly developed tubular structures associated with prominent lymphoid infiltration of the stroma. The other tumor was found to have proliferated in the wall of the stomach, with diffuse granulomatous lesions and bordering the adenocarcinoma. Large atypical lymphoid cells with prominent nucleoli and enlarged mononuclei or multinuclei were seen in the latter tumor. Hodgkin's lymphoma was also found in the swollen lesser curvature lymph nodes. As a result, gastric adenocarcinoma and metastasis of Hodgkin's lymphoma were collided in the stomach. In conclusion, this case might be helpful in exploring the occurrence mechanism of tumor collision between lymphoma and carcinoma.
    Case Reports in Gastroenterology 09/2012; 6(3):797-802. DOI:10.1159/000346465
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    • "EBV-associated lymphoid malignancies include a subset of Burkitt lymphoma (BL), acquired immune deficiency syndrome lymphoma, Hodgkin’s lymphoma, post-transplant lymphoma, age-associated B-cell lymphoma, and peripheral T- and natural killer-cell lymphomas (1–3). The EBV life cycle includes distinct latent and lytic genetic programs (4–6). Several therapeutic strategies requiring the activation of EBV lytic genes for tumor cell killing have been described (7,8). "
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    ABSTRACT: Burkitt lymphoma (BL) has been reported to be strongly associated with Epstein-Barr virus (EBV) infection. The fact that EBV is generally present in cancer cells but rarely found in healthy cells represents an opportunity for targeted cancer therapy. One approach is to activate the lytic replication cycle of the latent EBV. Nuclear factor (NF)-κB is thought to play an essential role in EBV lytic infection. Elevated NF-κB levels inhibit EBV lytic replication. Parthenolide (PN) is a sesquiterpene lactone found in medicinal plants, particularly in feverfew (Tanacetum parthenium). The aim of the present study was to analyze the effect of PN on the survival of Raji EBV-positive lymphoma cells. Raji cells were treated with 0, 4 or 6 µmol/l PN for 48 h. MTT assay and western blot analysis were performed to evaluate the findings. Results showd that PN suppressed the growth of the EBV-positive BL cell line, Raji, and activated the transcription of BZLF1 and BRLF1 by inhibiting NF-κB activity. Most notably, when PN was used in combination with ganciclovir (GCV), the cytotoxic effect of PN was amplified. These data suggest that the induction of lytic EBV infection with PN in combination with GCV may be a viral‑targeted therapy for EBV-associated BL.
    Molecular Medicine Reports 06/2012; 6(3):477-82. DOI:10.3892/mmr.2012.959 · 1.55 Impact Factor
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