Infusion of autologous Epstein-Barr virus (EBV)–specific cytotoxic T cells for prevention of EBV-related lymphoproliferative disorder in solid organ transplant recipients with evidence of active virus replication

Abstract

Epstein-Barr virus (EBV)-associated posttransplantation lymphoproliferative disorders (PTLDs) are a well-recognized complication of immunosuppression in solid organ transplant recipients. The reported therapeutic approaches are frequently complicated by rejection, toxicity, and other infectious pathologies, and overall mortality in patients with unresponsive PTLD remains high. Thus, low-toxicity treatment options or, preferably, some form of prophylactic/preemptive intervention are warranted to improve PTLD outcome in this setting. We assessed whether transfer of EBV-specific cytotoxic T lymphocytes (CTLs) generated in vitro from the peripheral blood of allograft recipients receiving immunosuppression could increase EBV-specific killing in vivo without augmenting the probability of graft rejection. Autologous EBV-specific CTLs were generated for 23 patients who were identified as being at risk of developing PTLD through the finding of elevated EBV DNA load. Of the 23 patients, 7 received 1 to 5 infusions of EBV-specific CTLs. CTL transfer was well tolerated, and none of the patients showed any evidence of rejection. An increase of the EBV-specific cytotoxicity was observed after infusion, notwithstanding continuation of immunosuppressive therapy. EBV DNA levels had a 1.5-to 3-log decrease in 5 patients, whereas in the other 2 graft recipients CTL transfer had no apparent stable effect on EBV load. Our data suggest that the infusion of autologous EBVspecific CTLs obtained from peripheral blood mononuclear cells recovered at the time of viral reactivation is able to augment virus-specific immune response and to reduce viral load in organ transplant recipients. This approach may, therefore, be safely used as prophylaxis of EBV-related lymphoproliferative disorders in these patients, following a strategy of preemptive therapy guided by EBV DNA levels. (Blood. 2002;99: 2592-2598

Epstein‐Barr virus (EBV) latent membrane protein‐1‐specific cytotoxic T lymphocytes targeting EBV‐carrying natural killer cell malignancies

“…There is increasing interest in immunotherapy for EBV-associated malignancies and adoptive transfer of in vitro activated EBV-specific CTL has proven effective for prevention and treatment of EBV-associated lymphoproliferative diseases after stem cell and organ transplants [9][10][11][12][13]. Extension of a similar strategy to other EBV-associated malignancies, such as HD [14] and NPC [15], has been reported to be efficacious in some patients.…”

Secondary malignancies and quality of life after stem cell transplantation

“…Adoptive immunotherapy with cytotoxic T-cell therapy has been shown to be efficacious in controlling BCLD with a decrease in the EBV DNA concentrations and a remission of clinical signs and symptoms. 4,14,16,17 This treatment appears to be safer and more effective used as prophylaxis or as treatment in early stage of development.…”

Successful T-cell-depleted, related haploidentical peripheral blood stem cell transplantation in a patient with Fanconi anaemia using a fludarabine-based preparative regimen without radiation

“…Since an increment of values of EBV DNA is considered to be predictive for a high risk of developing symptomatic EBV infection, 13 the girl received two doses of 2 Â 10 7 EBV-specific CTL/m 2 generated according to a method previously described. 14 In detail, EBV-specific CTLs were prepared from fresh donor PBMCs, plated in X-VIVO 20 medium (BioWhittaker, Walkersville, MD, USA) with 2% autologous plasma at 2 Â 10 6 cells per well, and stimulated with irradiated autologous B lymphoblastoid cell lines (B-LCL) at a responder/stimulator (R:S) ratio of 40:1. After 10 days, cultures were restimulated with irradiated autologous B-LCL at an R:S ratio of 4:1.…”