Epstein-Barr virus (EBV) infection is associated with a number of lymphoma subtypes including post-transplant lymphoproliferative disorder (PTLD), NK/T cell lymphoma, EBV-positive diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma, and classical Hodgkin lymphoma (HL). The application of immunotherapy in the form of cytotoxic T cells (CTLs) directed against EBV has been largely limited to use in immunocompromised patients who lack the capacity to generate an effective immune response. A recent study reported by Catherine Bollard and colleagues, however, describes a novel approach to the generation of CTLs, targeting a broader array of EBV antigens that holds promise for treatment of EBV-associated lymphomas affecting both immunocompetent and immunocompromised hosts.
EBV-associated lymphomas are characterized by expression of a limited number of viral proteins, the pattern of which is determined by the particular latency program that is active (there are three latency programs: type I, type II, and type III). Lymphomas that arise in immunocompromised hosts (e.g., PTLD) express the latency III program that is defined by expression of EBV nuclear antigens (EBNAs) 1, 2, 3A, 3B, 3C, 6/LP, and latent membrane proteins (LMPs) 1 and 2. Immunosuppressed patients are at risk for developing EBV-driven PTLD after donor stem cell or solid organ transplantation because immunosuppressive therapy renders them unable to mount an adequate T-cell response against the latency III panel of EBV proteins that is otherwise highly immunogenic. Patients with PTLDs that develop after stem cell transplantation have been successfully treated with ex vivo-generated, donor-derived CTLs that recognize latency IIIexpressing, EBV-infected B cells. On the other hand, lymphomas such as EBV-associated classical HL, DLBCL, and NK/T-cell lymphoma express the less immunogenic latency II program that consists only of EBNA1, LMP1, and LMP2. Consequently, treatment of patients with latency II-type lymphomas has been marginally effective.
To generate CTLs that are effective against latency II-expressing lymphomas, the investigators constructed an adenoviral vectorencoding LMP2 and later an LMP2 combined with a truncated version of LMP1. The vector was used to transduce both dendritic cells and EBV-transformed B-lymphoblastoid cell lines that were then used to stimulate antigen-specific CTLs from patient-derived peripheral blood mononuclear cells.
In the clinical arm of the study, 50 patients with latency II- or latency III-expressing EBV-positive lymphomas were treated, including 25 patients with HL, 11 with NK/T cell lymphoma, seven with DLBCL, two with PTLD, and one with peripheral T-cell lymphoma. Twelve patients had high-risk disease in first remission. Seventeen patients had relapsed disease in remission after salvage therapy. Of these 29 patients with high risk of disease recurrence, none relapsed, and the event-free survival (EFS) was 82 percent at two years. Nine patients died of complications related to prior therapy. Twenty-one patients on the study had active disease after standard therapy. Of these 21, 13 responded (11 complete responses and two partial responses). The EFS was 50 percent. The therapy was well tolerated without significant infusion-related toxicity.
In Brief
The technique developed by Bollard and colleagues to generate EBV antigen-specific CTLs that can be used to treat both latency II- and latency III-expressing lymphomas represents a major advance in the field of immunotherapy. Based on an understanding of the characteristics of EBV-driven lymphoproliferative disorders, the investigators developed highly specific T cells capable of eradicating a broad array of lymphomas, even in the refractory-disease setting. In the future, their approach may have broader application to include treatment of other virally induced cancers.
Competing Interests
Dr. LaCasce indicated no relevant conflicts of interest.
