Allogeneic cytotoxic T-cell therapy for EBV-positive posttransplantation lymphoproliferative disease: results of a phase 2 multicenter clinical trial

Iatrogenic immunosuppression is a unique setting for investigating immune-related mechanisms of carcinogenesis. Solid organ transplant recipients have a 3-fold excess risk of cancer relative to the age- and sex-matched general population. Population-based studies utilizing cancer registry records indicate that a wide range of cancers, mostly those with a viral etiology, occur at excess rates. To date, cancer risk has predominantly been examined in adult kidney transplant recipients in Western countries. It is yet to be established whether a similar incidence profile exists in the long-term for other solid organ, pediatric and non-Western transplant recipients. The cancer incidence profile before and after kidney transplantation strongly suggests a relatively minor contribution by both preexisting cancer risk factors and the conditions underlying end-stage kidney disease, and points to a causal role for immunosuppression. Within-cohort risk factor analyses have largely been performed on cohorts with voluntary cancer notification, and very few have incorporated biomarkers of the level of immunosuppression, the current receipt of immunosuppressive agents, or genetic risk factors. Because of their markedly high risk of certain cancers, findings from comprehensive studies in transplant recipients have the potential to raise new avenues for investigation into causal mechanisms and preventive measures against immune-related and infectious causes of cancer.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/ijc.24439

Cancer incidence and risk factors after solid organ transplantation

Epstein-Barr virus is a tumorigenic herpes virus that is ubiquitous in the adult population. The virus is generally spread to and between young children through salivary contact, and only causes clinical illness where primary infection is delayed until adolescence or beyond, when an intense immunopathological reaction leads to the symptoms of infectious mononucleosis in roughly 50% of cases. More than 90% of the world's population carry Epstein-Barr virus as a life-long, latent infection of B lymphocytes. Recent data show that by mimicking B-cell antigen-activation pathways the virus enters the long-lived memory B lymphocyte pool where it evades immune elimination by severely restricting its own gene expression. By influencing B-cell survival mechanisms Epstein-Barr virus may induce tumours such as B lymphoproliferative disease and Hodgkin's disease. Vaccines are being developed to prevent and/or treat these conditions, but an animal model is required to study pathogenesis before a rational vaccine strategy can be formulated.

https://www.thelancet.com/pdfs/journals/laninf/PIIS1473309903005437.pdf

Epstein-Barr virus—recent advances

The treatment of Epstein–Barr virus (EBV)-associated lymphoproliferative disease (PTLD) in EBV seronegative solid organ transplant recipients who acquire their EBV infection after engraftment poses a considerable challenge because of underlying immunosuppression that inhibits the virus-specific cytotoxic T cell (CTL) response in vivo. We have developed a protocol for activating autologous EBV-specific CTL lines from these patients and show their potential use for immunotherapy against PTLD in solid organ transplant patients. Peripheral blood mononuclear cells from a panel of solid organ transplant recipients with and without active PTLD were used to assess EBV-specific memory CTL responses. The activation protocol involved cocultivation of peripheral blood mononuclear cells with an autologous lymphoblastoid cell line under conditions that favored expansion of virus-specific CTL and hindered the proliferation of allospecific T cells. These CTL consistently showed (i) strong EBV-specificity, including reactivity through defined epitopes in spite of concurrent immunosuppressive therapy, and (ii) no alloreactivity toward donor alloantigens. More importantly, adoptive transfer of these autologous CTLs into a single patient with active PTLD was coincident with a very significant regression of the PTLD. These results demonstrate that a potent EBV-specific memory response can be expanded from solid organ recipients who have acquired their primary EBV infection under high levels of immunosuppressive therapy and that these T cells may have therapeutic potential against PTLD.

https://www.pnas.org/content/pnas/96/18/10391.full.pdf

Activation and adoptive transfer of Epstein–Barr virus-specific cytotoxic T cells in solid organ transplant patients with posttransplant lymphoproliferative disease

Frequent monitoring of Epstein-Barr virus DNA load in unfractionated whole blood is essential for early detection of posttransplant lymphoproliferative disease in high-risk patients

Epstein—Barr virus (EBV) is associated with post-transplant lymphoproliferative disease (PTLD). To determine whether the donor EBV isolate is transmitted to the recipient via the allograft and causes PTLD, EBV isolates from four cases of PTLD in cadaveric heart and/or lung transplant recipients were compared with the donor isolates by PCR and DNA sequence analysis. Two recipients who were EBV seronegative at transplantation acquired an EBV isolate indistinguishable from that of the donor and developed PTLD. In contrast, in two patients who were seropositive before transplantation, the donor isolate differed from that present in PTLD of the recipient. The results suggest that the acquisition of donor EBV is a risk factor for PTLD development in a previously seronegative transplant recipient.

Transmission of donor Epstein-Barr virus (EBV) in transplanted organs causes lymphoproliferative disease in EBV-seronegative recipients

BACKGROUND Organ transplantation is associated with a greatly increased risk of Epstein-Barr virus (EBV)-associated lymphoproliferative disease (LPD), which is often fatal. There has been little epidemiological analysis, however, of the risk factors for LPD in transplant patients and none on whether the risks of non-EBV-associated lymphoid neoplasms are also increased. METHODS The risk of lymphoid neoplasia was assessed in a cohort of 1563 patients who underwent cardiothoracic transplantation at Harefield Hospital, UK from 1980 to 1994 and were followed until December 1995. EBV antibody was assessed in the patients before transplantation, and lymphoid neoplasms were assessed for EBV RNA and latent EBV gene expression. RESULTS Thirty cases of LPD occurred during follow-up. One lymphoma of unknown EBV status occurred. There were also six cases of EBV-negative non-Hodgkin's lymphoma (EBV-negative NHL), a highly significant excess over expectations from the general population rates of NHL (standardized incidence ratio 10.2 [95% confidence interval, 4.6-22.8]). The risk of LPD was significantly 10-fold raised in individuals who were EBV seronegative before transplantation; independently of this, it decreased steeply with age at transplantation and was greatest in the first year after transplantation. The risk was significantly raised in young seronegative recipients if the donor was older than the recipient. EBV-negative NHL occurred entirely in men 45 years old and older who were EBV seropositive before transplantation, and risk was not related to duration since transplantation. CONCLUSIONS The risk factors found for LPD accord with EBV etiology and with greater hazard from primary infection than from reactivation. A second non-Hodgkin's lymphoid neoplasm, not related to EBV, seems also to be a consequence of transplantation and immunosuppression but is unlikely to be due to first infection by a ubiquitous agent. Its etiology and prevention need investigation separately from LPD.

Risk of lymphoid neoplasia after cardiothoracic transplantation. a cohort study of the relation to Epstein-Barr virus.

This report describes a case of Epstein-Barr [correction of Epstein Barr] Virus related post-transplantation B lymphoproliferative disease of unusual Burkitt lymphoma (BL) type in which combined cytotoxic agents (PACE BOM) successfully produced complete and long-term tumor remission.

Epstein-Barr virus associated Burkitt lymphoma in a heart transplant recipient

Background. A 2-year prospective study was set up with 30 cardiothoracic transplant recipients to study Epstein-Barr virus (EBV) infection and immunity and their correlation with clinical events. Methods. Regression assays were used to measure EBV-specific cytotoxic T lymphocyte (CTL) function. Tissue culture, immunoblotting, and polymerase chain reaction were used for EBV detection and isolate variation studies. Results. CTL activity was significantly lower in pretransplant seropositive patients than in healthy controls (P<0.001). CTL response was undetectable in all patients during the first 6 months after transplantation, but returned at levels significantly lower than pretransplant and control levels during the second posttransplant year (P<0.001). Return of CTL function was directly correlated with time of last treated rejection episode (P<0.003) and duration of high plasma levels of cyclosporine (over 400 ng/ml; P<0.003). Significantly higher levels of EBV were detected in peripheral blood during the first 6 months than in pretransplant or control samples (P<0.05). Excretion of EBV in throat washings was significantly lower during the first 3 months when all patients were receiving acyclovir than in pretransplant and control samples (P=0.02). An increase in virus shedding was noted 3-6 months after transplantation, which was significantly higher than in pretransplant patients and controls (P<0.05). Comparison of recipients' and donors' virus isolates in 11 cases showed that seropositive recipients retained their original EBV isolate and did not acquire the donor virus. Conclusions. Immunosuppression decreased EBV-specific host immune function, which in turn favored increased EBV load in peripheral blood and increased excretion in the oropharynx. The transfer of donor virus to the seropositive recipients was not observed.

A prospective study in heart and lung transplant recipients correlating persistent Epstein-Barr virus infection with clinical events.

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Transmission of donor Epstein-Barr virus (EBV) in transplanted organs causes lymphoproliferative disease in EBV-seronegative recipients

Risk of lymphoid neoplasia after cardiothoracic transplantation. a cohort study of the relation to Epstein-Barr virus.

Epstein-Barr virus associated Burkitt lymphoma in a heart transplant recipient

A prospective study in heart and lung transplant recipients correlating persistent Epstein-Barr virus infection with clinical events.