Establishment of a bank of blood donor derived epstein barr virus specific cytotoxic T cell lines for treatment of post-transplant lymphoproliferative disease

Abstract

Epstein-Barr virus (EBV) driven lymphomas associated with immunosuppression are a significant problem, particularly after transplantation. Conventional treatment (withdrawal of immunosuppression, administration of rituximab/chemotherapy) is often effective but risks organ rejection and causes significant side effects. EBV specific cytotoxic T cells (CTL) generated in vitro from autologous lymphocytes can be effective with few side effects, but take months to prepare so are difficult to use in clinical practice. We have established a bank of EBV CTLs derived from platelet / plasma donors for issuing ‘off the shelf product’ to partially human leucocyte antigen (HLA) matched patients on a named patient basis. Donors from the New Zealand platelet / plasma panel were sourced to reduce the risk of Creutzfeldt-Jakob disease (CJD). The current panel of donors selected was EBV positive, Blood Group O, and met all current requirements for mandatory virology markers. The panel was also chosen to maximize the probability of HLA class I and II matches and minimize the number of mismatches. We estimated that this initial panel of 25 donors should provide a partial match for at least three (HLA-A, -B, -DRB1) loci for ∼80% of Caucasian patients. So far, lymphoblastoid cell lines have been made from 25 donors ready for use in stimulating CTLs and 18 CTLs have been manufactured and cryopreserved for clinical use. Since the bank was granted a ‘Specials’ license by the MHRA for this Advanced Therapy Medicinal Product in January 2012, there have been enquiries about 14 patients: 4 improved on conventional therapy without requiring CTLs, 3 died before any cells could be issued and 6 cell lines have been released. The indications for issue have been: 3 cases of post-transplant lymphoproliferative disorder (1 CD20- rituximab resistant 1 with concomitant graft versus host disease precluding reduction of immunosuppression 1 unfit for chemotherapy) 2 cases with congenital immunosuppression as a bridge to allogeneic haematopoietic stem cell transplant and 1 case of EBV-associated leiomyosarcoma post-cardiac transplant (related donor). Clinical improvement has been seen in 4 out of 6 assessable patients. A 3rd party donor-derived anti-EBV CTL cell bank can be operated under current legislation and is a valuable addition to existing therapies for selected patients.