Adoptive T-Cell Immunotherapy

Abstract

Epstein-Barr virus (EBV) is associated with a range of malignancies involving B cells, T cells, natural killer (NK) cells, epithelial cells, and smooth muscle. All of these are associated with the latent life cycles of EBV, but the pattern of latency-associated viral antigens expressed in tumor cells depends on the type of tumor. EBV-specific T cells (EBVSTs) have been explored as prophylaxis and therapy for EBV-associated malignancies for more than two decades. EBVSTs have been most successful as prophylaxis and therapy for post-transplant lymphoproliferative disease (PTLD) , which expresses the full array of latent EBV antigens (type 3 latency), in hematopoietic stem-cell transplant (HSCT) recipients. While less effective, clinical studies have also demonstrated their therapeutic potential for PTLD post-solid organ transplant and for EBV-associated malignancies such as Hodgkin's lymphoma, non-Hodgkin's lymphoma, and nasopharyngeal carcinoma (NPC) that express a limited array of latent EBV antigens (type 2 latency). Several approaches are actively being pursued to improve the antitumor activity of EBVSTs including activation and expansion of T cells specific for the EBV antigens expressed in type 2 latency, genetic approaches to render EBVSTs resistant to the immunosuppressive tumor environment, and combination approaches with other immune-modulating modalities. Given the recent advances and renewed interest in cell therapy, we hope that EBVSTs will become an integral part of our treatment armamentarium against EBV-positive malignancies in the near-future.

Keywords: Cancer; EBV; Gene transfer; Immunotherapy; T‐Cell therapy.

Figure 1. Immunogenicity of EBV-positive tumors according to latency

For details see text. EBNAs: EBNAs −2, −3a, −3b, and −3c; LMPs: LMP1 and LMP2.

Figure 2. T-cell products for EBV-positive malignancies

For details see text. DLI: Donor lymphocyte infusion.

Figure 3. Ex vivo generation of EBVSTs for clinical studies

(A) For most clinical studies EBVSTs have been generated using LCLs as antigen presenting cells (APCs). (B) In an effort to increase the frequency of T cells for type 2 latency antigens, DCs and LCLs have been used as APCs that are modified with recombinant adenoviruses expressing LMP2 or LMP1 and LMP2. (C) EBVST generation not requiring LCLs or recombinant adenoviruses. For additional details see text.