This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We have previously used adoptively transferred Epstein-Barr virus (EBV)-specific cytotoxic T cells (CTL) to prevent and treat EBV-lymphoproliferative disease after hematopoietic stem cell transplant (HSCT). Recently we have investigated whether the same approach could be of value to treatment for EBV-positive Nasopharyngeal cancer (NPC. Adoptive transfer of EBV-specific CTLs has proven safe in all 10 NPC patients treated. Of six patients treated with recurrent disease, 2 patients are in biopsy proven complete remission (CR) post CTL, 1 had a partial response, 1 had stable disease for 14 months and 2 patients had progressive disease. Four patients who were treated in remission have remained disease free for >16 to 24 months. The above results are promising and indicate the potential anti-tumor activity of EBV-specific CTLs in this patient group. However, not all patients with bulky disease responded completely. We believe this failure was due in part to the failure of infused T lymphocytes to undergo adequate expansion in vivo. If a host is made lymphopenic, mature T cells will proliferate to restore the steady state. Hence, in the recipients of T cell depleted stem cell transplants, we have found that infused EBV specific T cells expand by 4 logs or more. In contrast, when EBV specific T cells are given to NPC patients, in whom the T cell compartment is already replete, expansion of adoptively transferred T lymphocytes is lower, by 2 orders of magnitude or more. Published data suggest that in vivo depletion of T cells with cytotoxic drugs, as in stem cell transplantation, can permit massive expansion of subsequently infused T cells with anti-cancer activity, since under those circumstances homeostatic mechanisms work to restore lymphoid compartments7. We now propose to take advantage of these homeostatic mechanisms in patients with advanced or refractory NPC. We will deplete their lymphoid compartment using short-lived CD45 monoclonal antibodies (MAbs), which we have shown can profoundly deplete lymphocytes in peripheral blood and lymphoid organs, whilst sparing hematopoietic progenitor cells. Subsequent adoptive transfer of EBV-specific CTL post MAb induced T cell depletion should result in expansion of the infused cells to restore the T cell compartment. Moreover, the expanded cells should enter and function unimpeded in tumor sites depleted of regulatory T cells.
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