Standard intensive chemotherapy and hematopoietic stem cell transplant usually benefit patients with Hodgkin (HL) and Non-Hodgkin Lymphoma (NHL), but for those with T or NK-T NHL or who relapse, the prognosis is less favorable. Furthermore, substantially increased morbidity and mortality from the complications of aggressive chemotherapies is evident for many years, even in patients who are cured of their original disease. About 30% of all lymphomas carry the Epstein-Barr virus (EBV) genome and express 4 viral proteins (EBNA1, LMP1, LMP2 ± BARF1), a pattern termed Type 2 latency. T-cells specific for these antigens circulate with low frequency in healthy donors, but are rendered anergic in patients by their immunosuppressive tumors. We have previously shown that potent in vitro T-cell stimulation can reverse anergy. Virus-specific T-cells specific for the EBV antigens (EBVSTs) have produced complete remissions in 60% of patients with multiply relapsed EBV+ HL and NHL. Though successful, our earlier method was labor intensive and prolonged, and the requirement for live EBV and adenoviral (Ad) vectors increased costs and regulatory complexity. We have overcome these problems by replacing Ad vectors with peptide mixtures (pepmixes) and the EBV lymphoblastoid cell lines (LCL) with professional antigen presenting cells to provide costimulation. We therefore seek to produce a safe and effective immunotherapy for relapsed, refractory EBV+ lymphoma that can be implemented rapidly by creating and characterizing a bank of T-cells targeted to the four EBV antigens expressed in EBV+ HL and NHL. Thus far, we have successfully screened 30 eligible blood donors and manufactured several EBVST lines with specificity for the four Type 2 EBV latency proteins using the rapid pep-mix method. This strategy robustly and rapidly produces higher frequencies of EBV-specific T cells that kill LCLs that naturally express viral antigens, showing that the pepmixes are not recruiting low-avidity T-cells. T-cell lines will be selected and infused based on their ability to recognize EBV antigens through HLA alleles shared with the recipient. The in vivo expansion and persistence of the infused EBVSTs will be evaluated together with their ability to reactivate endogenous T-cells specific for non-viral tumor antigens. We hypothesize that allogeneic, partially HLA-matched T-cells can produce benefit in patients with lymphoma both by direct tumor cell killing and by creating a proinflammatory tumor microenvironment that reactivates and restores effective endogenous tumor-specific T-cells.
Citation Format: Rayne H. Rouce, Serena K. Perna, Gayatri Vyas, Sandhya Sharma, Natalia Lapteva, Ann Leen, Cliona M. Rooney, Helen E. Heslop. Banked Epstein-Barr virus specific T-cells for treatment of EBV+ lymphoma. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B17.