EBV meets its match

EBV-driven lymphoproliferative disease remains a significant clinical problem following HSCT. In this issue of Blood, Heslop and colleagues report their 15-year experience using EBV-specific T cells to prevent or treat this disease.¹ 

Posttransplantation lymphoproliferative disease (PTLD) in this setting usually arises through Epstein-Barr virus (EBV)–transformed B lymphocytes expanding opportunistically in the T cell–compromised host. Disease risk increases with the degree of T-cell impairment; thus, T-cell depletion of the graft or using incompletely human leukocyte antigen (HLA)–matched grafts that require greater immunosuppressive therapy will increase PTLD incidence, especially during the first 2 years after transplantation.²  In most such cases of PTLD, the proliferating cells express the full spectrum of EBV-latent proteins. Collectively, these proteins not only drive cell growth but also constitute the target antigens through which, in healthy EBV carriers, virus-transformed cells are recognized and destroyed by virus-specific T-cell surveillance. Accordingly, PTLD provides an ideal opportunity for the application of adoptive cell therapy using EBV-specific T cells.

Early attempts to treat PTLD using total peripheral blood mononuclear cells from the original, EBV-immune stem cell donor were marred by collateral graft-versus-host disease (GVHD).³  Showing real forethought, Heslop, Rooney, and colleagues took existing laboratory protocols for the in vitro generation of EBV-specific cytotoxic T-cell (EBV-CTL) preparations, adapted them for the clinic, and, by 1995 (a year before others showed proof of principle in a SCID mouse model⁴ ) had completed their first small trial demonstrating effectiveness against PTLD.⁵  The present report summarizes the wealth of clinical data that have been amassed in 3 clinical centers since that time.

With a median follow-up of 10 years, the authors report a total of 114 patients (mean age of 8 years; range, 0.5-38 years) who have received EBV-CTLs following hematopoietic stem cell transplantation (HSCT). Of these, 101 patients deemed to be at high risk for PTLD (through having a T cell–depleted graft, greater donor/recipient HLA disparity, or a history of immune deficiency) received T cells prophylactically. Such treatment led to a fall in EBV genome load in the circulating B-cell pool; more importantly, none of these patients developed PTLD, compared with an observed incidence of 11% in a control cohort receiving similarly T cell–depleted allografts. The remaining 13 patients received EBV-CTLs therapeutically for either biopsy-proven EBV-positive PTLD or probable disease diagnosed on radiologic and clinical grounds. Complete responses were confirmed in 11 of 13 patients, some with extensive extranodal disease including 1 patient with biopsy-proven monoclonal lesions in the central nervous system. Dramatic inflammatory reactions at the site of disease (shown to be mediated by infiltrating EBV-CTLs) occurred in 2 patients, both of whom fully recovered, but no other toxicity or GVHD attributable to EBV-CTLs was observed.

Interestingly, 26 patients received EBV-CTLs genetically marked with a retroviral vector encoding the neomycin resistance gene, enabling in vivo tracking of the number, durability, and safety of the infused cells. The authors now show that these gene-marked cells can persist in the circulating memory pool for as long as 105 months after CTL infusion and can still expand in vitro in response to EBV antigen challenge. Importantly from a safety perspective, extensive PCR analysis of retroviral integration sites did not reveal any evidence for the emergence of dominant T-cell clones within these gene-marked populations.

Overall, this study clearly demonstrates the long-term safety and efficacy of EBV-CTL infusion in a post-HSCT setting. Nevertheless, questions as to its optimal role still remain, particularly since the advent of an effective alternative in the form of anti-CD20 monoclonal antibody treatment for PTLD.⁶  Clearly EBV-CTLs can still fill an important niche, for example, in patients who do not respond to or relapse after antibody treatment. Methodological improvements have now shortened the time required to manufacture a CTL product from a specific donor, and the attractive concept of an “off-the-shelf” CTL product, from third-party HLA-compatible donors, has also been developed into an effective reality in the context of solid-organ transplantation.⁷  Furthermore, the engineering of EBV-CTLs resistant to calcineurin inhibitors is an advance for those patients who require ongoing immunosuppressive therapy.⁸ 

However, the greater importance of this work currently lies in its heuristic value for the field of adoptive T-cell therapy, whether one is seeking to target other viral infections of the immunocompromised or other virus-associated malignancies. In this latter context, EBV-positive lymphomas such as Hodgkin and T/NK-cell lymphomas, where viral target antigen expression is much more limited, constitute the next battleground.⁹  Looking further ahead, might T-cell preparations against such a common human virus be exploited for even greater therapeutic benefit? That is as recipients of additional reactivities, conferred by T cell–receptor transfer in vitro, where the second specificity is directed against a target antigen of choice while the native EBV specificity guarantees retention of the cells in the virus-carrying host.