Epstein-Barr virus–specific T cell therapy for progressive multiple sclerosis

Abstract

Role of the funding source:The funders of the study had no role in the study design, data collection, data analysis, data interpretation, or the writing of the manuscript. The corresponding authors had full access to all the data in the study and had final responsibility for the decision to submit for publication. Conflict of interest: MPP has received consulting fees and research funding from Atara Biotherapeutics and is a member of the Neurology Clinical Advisory Panel of Atara Biotherapeutics. CS has received consulting fees from Atara Biotherapeutics. SB is a member of the advisory boards of Roche, Sanofi Genzyme, Merck, and Teva. KAG has received personal fees from Roche and travel support from Sanofi Aventis. AS has received educational and travel support from Merck Serono Australia. KDH is a member of the advisory boards of Merck Serono Australia, Biogen Australia, and Roche Australia. BTA is an employee of, and owns equity shares in, Atara Biotherapeutics. SRB has received a license fee payment from Atara Biotherapeutics. AC has received a consulting fee from Sanofi Genzyme. RK is a consultant and member of the scientific advisory board of Atara Biotherapeutics and has received a license fee payment and research funding from Atara Biotherapeutics.

Epstein–Barr Virus in Multiple Sclerosis: Theory and Emerging Immunotherapies

“…This was accompanied by an increase in the percent of circulating LMP and B-lymphoblastic cell line (LCL)-reactive effector CD8 + memory cell populations. Success observed in this study led to a Phase I clinical trial of autologous EBV-specific T cell therapy in progressive MS [86]. The authors noted no serious adverse effects, including no disease exacerbation.…”

“…In the 1980s, largely driven by the increasing use of experimental autoimmune encephalomyelitis (EAE) as an animal model of MS, there was a more T cell-centric view of MS pathophysiology. Currently MS disease pathology is thought to invoke key interactions between T and B cells, particularly between their memory subsets, all supported by convergence of clinical trial results and laboratory-based studies [6][7][8][9][10]18,25,52,86]. The high tropism that EBV has for B cells, and its mechanisms of immune avoidance, serve to promote long-term survival and persistence (of both the virus and memory B cells), which fundamentally alter B cell biology, resulting in persistence and accumulation of disease-relevant EBV-infected autoreactive B cells.…”

“…The recent application of an autologous or allogeneic T cell therapy targeting EBV-infected B cells using an EBV-specific cytotoxic CD8 + T cell therapy [18,86] provides an alternative cell-based approach. An example has been demonstrated in a patient with secondary progressive MS (SPMS), where infusion of EBV-specific CD8 + cytotoxic T cells had no adverse effects and the individual showed clinical improvement with reduced disease activity on magnetic resonance imaging (MRI) and decreased intrathecal immunoglobulin production, highlighting the likelihood of treatment effects occurring in the CNS [87].…”

Significant enrichment of Herpesvirus interactors in GWAS data suggests causal inferences for the association between Epstein Barr virus and multiple sclerosis

“…Our study indicates that the interaction between host genotype and Herpesviruses (including EBV) is relevant for multiple sclerosis etiology, reinforcing the rationale for experimental medicine approaches aimed at advancing therapies while proving the causality of viral agents in MS. The results of a recent study on EBV-specific adoptive T cell therapy in patients with progressive MS support this perspective (Pender et al 2018).…”

Latency and lytic replication in Epstein–Barr virus-associated oncogenesis

“…The symptoms of these diseases might be caused by the efficient stimulation of T cell mediated cytokine production by latently EBV infected B cells, in the absence of efficient cytotoxic elimination of infected cells. In multiple sclerosis, adoptive transfer of EBV specific T cells has been tried to eliminate this T cell stimulating EBV reservoir, with promising initial results 139 . In addition, vaccination against EBV will probably be further explored in EBV seronegative adolescents to prevent infectious mononucleosis 140 .…”