Biology and adoptive cell therapy of Epstein‐Barr virus‐associated lymphoproliferative disorders in recipients of marrow allografts

Abstract

Epstein-Barr virus (EBV) is an ubiquitous herpesvirus which is carried as a latent infection of B lymphocytes and salivary gland epithelial cells in over 90% of normal adults. Latently infected EBV-transformed B cells circulate at low frequency in the blood for the life of the host. These transformed B cells stimulate a heterogeneous and complex host cell response, ultimately leading to the development and maintenance of high frequencies of HLA-restricted T cells specific for the EBV-encoded nuclear antigens EBNA2-EBNA6 and the latency membrane proteins LMP-1 and LMP-2. Responses to latent EBV-encoded proteins are hierarchical with responses to certain epitopes predominating, dependent upon the HLA genotype of the host. Profound suppression of T-cell immunity may permit the emergence of polyclonal, oligoclonal or monoclonal EBV antigen-expressing lymphoproliferative disorders or malignant B-cell lymphomas expressing these latent EBV antigens. Adoptive transfer of small numbers of peripheral blood mononuclear cells or HLA-partially matched T cells from in vitro expanded EBV-specific T-cell lines derived from a seropositive marrow donor has induced durable regressions of bulky, widely metastatic monoclonal EBV lymphomas in a high proportion of cases. This review describes the current state of knowledge and hypothesis regarding the biology and immunology of EBV infection in the normal host, the features of donor, host and virus which contribute to the development of EBV-associated lymphoproliferative diseases and the mechanisms whereby they are controlled by adoptive transfer of immune T cells.

Characterization of antigen‐specific repertoire diversity following in vitro restimulation by a recombinant adenovirus expressing human cytomegalovirus pp65

“…Adoptive immunotherapy by infusion of virus-specific CTL has become a powerful tool for the treatment of lifethreatening viral infections in immunocompromised hosts [1,2]. Protective immunity has been restored in patients after hematopoietic stem cell transplantation (HSCT) using intravenous injections of allogeneic CTL specific for human cytomegalovirus (HCMV) [1][2][3] and Epstein-Barr virus (EBV) [4,5].…”

“…Protective immunity has been restored in patients after hematopoietic stem cell transplantation (HSCT) using intravenous injections of allogeneic CTL specific for human cytomegalovirus (HCMV) [1][2][3] and Epstein-Barr virus (EBV) [4,5]. Also, a recent report has investigated the adoptive transfer to patients with metastatic melanoma of highly selected tumor-reactive T cells directed against overexpressed self-derived differentiation antigens after a nonmyeloablative conditioning regimen.…”

A prospective study of Epstein–Barr virus load in 85 hematopoietic stem cell transplants

“…[6][7][8][9][10][11] Because clinical signs occur late, are non-specific and treatment is generally unsuccessful in patients with aggressive disease, the identification of patients at high-risk of developing EBV-LPD could possibly allow prophylactic or early therapeutic intervention by B cell-specific monoclonal antibodies or adoptive transfer of EBV-specific cytotoxic T lymphocytes. [12][13][14][15][16][17][18][19][20][21][22] Using quantitative PCR, previous studies in both solid organ and hematopoietic stem cell transplantation have shown that the median number of EBV copies in peripheral blood mononuclear cells (PBMC) is higher in patients who have received a SCT than in healthy individuals and the onset of EBV-LPD is usually preceded by a further increase in EBV viral load (EBV-VL). [23][24][25][26][27] Nevertheless, the kinetics of EBV-VL after hematopoietic SCT has yet to be analyzed in large studies.…”

Successful treatment of Epstein–Barr virus-induced transverse myelitis with ganciclovir and cytomegalovirus hyperimmune globulin following unrelated bone marrow transplantation

“…The late onset of the acute EBV-induced disease 19 months after BMT, the absence of fever and lymphadenopathy, and the disease course suggested a transverse myelitis rather than a lymphoproliferative disorder. 5 In vitro studies have demonstrated that ganciclovir has more inhibitory effects on EBV replication than do other antiviral drugs. 6 Ishida et al 7 reported a patient with chronic active EBV infection who became resistant to acyclovir but responded to ganciclovir.…”