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Review
. 2021 Feb 10;39(5):514-524.
doi: 10.1200/JCO.20.01709. Epub 2021 Jan 12.

Adoptive T-Cell Therapy for Epstein-Barr Virus-Related Lymphomas

Helen E Heslop  1 , Sandhya Sharma  1 , Cliona M Rooney  1
Affiliations
Review

Adoptive T-Cell Therapy for Epstein-Barr Virus-Related Lymphomas

Helen E Heslop et al. J Clin Oncol. .
No abstract available

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Figures

FIG 1.
FIG 1.
Epstein-Barr virus (EBV) latency states in different types of lymphoma. Type 3 latency is the most immunogenic, with expression of all of the latency-associated proteins that induce B-cell transformation, and is seen in lymphomas that arise in individuals with profound immunosuppression, such as occurs after stem cell transplantation. Type 2 latency tumors that include some cases of Hodgkin lymphoma and some non-Hodgkin lymphomas (NHLs) express EBV nuclear antigen 1 (EBNA1), latent membrane protein 1 (LMP1), and LMP2 and have intermediate immunogenicity. Burkitt’s lymphoma (BL) expresses type 1 latency with only EBNA1 expressed and is poorly susceptible to EBV-specific T cells. Below each type are listed the lymphomas associated with it and the percentage of these that are EBV+. There can be some transition between latency states with upregulation of latency and lytic genes. ALCL, anaplastic large cell lymphoma; CAEBV, chronic active ebstein barr virus; DLBCL, diffude large B cell lymphoma; HSCT, hematopoietic stem-cell transplant; NK, natural killer; PTLD, post-transplant lymphoproliferative disease; SOT, solid organ transplant.
FIG 2.
FIG 2.
Development of Epstein-Barr virus (EBV)–specific T-cell manufacturing strategies. (A) Strategies used with normal donor allogenic cells (APCs). Early clinical studies used EBV-transformed B lymphoblastoid cell lines (LCLs) as antigen-presenting cells (1). To add additional antigens, we next used an adenovirus vector expressing cytomegalovirus (CMV) antigens to transduce dendritic cells (DCs) for the first stimulation and adenovirus latent membrane protein (Ad-LMP)–transduced LCLs for subsequent stimulations (2). Both these methods required at least 6 weeks to generate the LCLs and 4 weeks to expand EBV-specific T cells (EBVSTs), prolonging the manufacturing time (1 and 2). We then moved to using DNA plasmids so EBV antigens could be transferred to DCs by electroporation, which reduced the manufacturing time to 17 days (3). When overlapping peptide libraries became available, we were able to further reduce manufacturing time to 10 days by pulsing peripheral blood mononuclear cells (PBMCs) with overlapping peptide libraries spanning viral antigens and using optimized cytokines to expand VSTs (4). (B) Strategies used with autologous cells from patients with lymphoma. To focus the specificity on EBV type 2 latency antigens, we used an adenovirus vector expressing LMP1 and LMP2 to transduced DCs for the first stimulation and Ad-LMP–transduced LCLs for subsequent stimulations (5). We also moved to using peptide libraries, but for patients with lymphoma a second stimulation was required to produce sufficient T-cell expansion and to produce larger cell numbers for a cell bank; we provided a second stimulation with autologous activated T cells (AATCs) combined with a human leukocyte antigen (HLA)–negative costimulatory cell line (6).
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References

    1. Taylor GS, Long HM, Brooks JM, et al. The immunology of Epstein-Barr virus-induced disease Annu Rev Immunol 33787–8212015 - PubMed
    1. Kanakry JA, Ambinder RF.EBV-related lymphomas: New approaches to treatment Curr Treat Options Oncol 14224–2362013 - PMC - PubMed
    1. Sharma S, Leung WK, Heslop HE, et al. Cells for the treatment of malignancies—Then, now, and the future Curr Stem Cell Rep 617–292020 - PMC - PubMed
    1. Kelly GL, Stylianou J, Rasaiyaah J, et al. Different patterns of Epstein-Barr virus latency in endemic Burkitt lymphoma (BL) lead to distinct variants within the BL-associated gene expression signature J Virol 872882–28942013 - PMC - PubMed
    1. Li L, Su X, Choi GC, et al. Methylation profiling of Epstein-Barr virus immediate-early gene promoters, BZLF1 and BRLF1 in tumors of epithelial, NK- and B-cell origins. BMC Cancer. 2012;12:125. - PMC - PubMed

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