An antigen presenting complex for the generation of broad-specificity effector T lymphocytes for the treatment of EBV-associated malignancies

      Broad-repertoire antigen-specific T cells are safe and effective for the treatment of multiply-relapsed or refractory Epstein-Barr virus (EBV)-associated malignancies and have produced complete remissions of melanoma when combined with lymphodepleting chemotherapy. However, difficulties with the maintenance of the T cell repertoire during large scale ex vivo expansion have limited the broader application of this therapy. Although EBV-transformed B lymphoblastoid cell lines (LCLs) transduced with adenoviral (Ad) vectors expressing the viral tumor antigens, LMP1 and LMP2 expanded broad repertoire CD4+ and CD8+ T cells, which produced complete tumor responses in about half of patients with lymphoma or nasopharyngeal carcinoma in our current clinical trials, LCLs contain live EBV and cannot be established from many lymphoma patients. We therefore evaluated a novel antigen-presenting complex comprising of autologous activated T cells pulsed with overlapping peptide libraries (pepmixes) spanning LMP1, LMP2 and EBNA1 together with an HLA-negative cell line (K562) expressing transgenic costimulatory molecules (K562cs) for costimulation in trans. This complex produced exponential growth (about 4 logs in 30 days) of antigen-specific T cells that killed target cells naturally expressing the tumor antigens and with phenotype and function similar to those of T cells used in our current clinical trials. This antigen-presenting complex reduced the time for CTL generation from over 3 months to less than one month, is GMP compliant and can be applied to T cells with recall antigen specificity.
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