Allogeneic T-Cell Therapy for Epstein-Barr Virus-Positive Posttransplant Lymphoproliferative Disease: Long-Term Follow-Up

Abstract

Epstein-Barr virus (EBV)-associated posttransplant lymphoproliferative disease (PTLD) is an important cause of morbidity and mortality in transplant patients. EBV-specific cytotoxic T-cell line (CTL) that are in vitro grown and donor derived have been used to prevent and treat EBV-positive PTLD in hematopoietic stem-cell transplant recipients (1). However, donor-derived T cells are neither generally available nor appropriate for PTLD arising after solid organ transplantation. Furthermore, although monitoring EBV load in blood may indicate a risk of PTLD after hematopoietic stem-cell transplant, allowing time for CTL preparation, this monitoring gives less convincing results after solid organ transplantation. Additionally, the alternative strategy of generating autologous CTL after PTLD diagnosis often produces unacceptable delays in treatment. To counter these problems, we generated a bank of 100 EBV-specific CTL from healthy blood donors covering more than 95% of common UK human leukocyte antigen (HLA) haplotypes and treated a patient with PTLD with a partially HLA-matched CTL line that resulted in complete tumor regression (2, 3). Subsequently, we used these cell lines in a phase 2 multicenter clinical trial to treat PTLD in a best HLA match basis (4). All 33 trial participants had progressive disease, despite conventional treatments. Our trial recorded a response rate of 52% at 6 months, with 14 patients achieving complete remission (CR), three patients with partial remission (PR), and 16 patients showed no response (NR); five of whom died during the CTL treatment. Significantly better response rates were seen in patients with closer HLA matches and higher numbers of CD4+ T cells in the infused CTL. We now report the long-term outcome of trial participants. We obtained follow-up data from 32 of the 33 trial participants, 4 to 9 years after their last CTL infusion. At 6 months, 15 of the 32 patients showed NR and 17 patients were responders (three PR and 14 CR). All those in the PR and NR groups, but none of the CR group, received further PTLD treatment after CTL therapy. Nineteen (59%) of the 32 patients are alive to date and 13 (41%) have died. Of the 14 patients who achieved CR at 6 months, 12 patients (86%) survived and are still in CR after 4 to 9 years. Two patients (14%) from the CR group had died; one at 10 months post-CTL therapy from relapsed PTLD and the other at 5 years from a chest infection while PTLD was in CR. Of the 19 surviving trial participants, 13 participants (68%) were responders (one PR and 12 CR) and six participants (32%) were NR at 6 months. In contrast, of the 13 patients who have died, nine patients (69%) were NR and four patients (31%) were responders (two PR and two CR) at 6 months. There was a significantly increased survival rate among the PR and CR group compared with the NR group (P=0.018; Fig. 1).FIGURE 1.: The Kaplan-Meier overall survival rate. There was a significantly increased survival rate in patients who achieved complete response (CR) and partial response (PR) compared with those who showed no response (NR) to cytotoxic T-cell (CTL) therapy (Log-rank test; P=0.018).Our clinical trial showed allogeneic T-cell therapy for PTLD to be safe and effective in the short term, and this 4- to 9-year follow-up data are important in showing that, although of indeterminate life-span in vivo, CTL induces long-term remission of PTLD in patients with refractory disease. Therefore, it seems appropriate to use this therapy early in PTLD and for prophylaxis in high-risk cases. We are generating a new bank of clinical-grade EBV-specific CTL under good manufacturing practice conditions to provide partially matched CTL internationally on a not-for-profit basis, funded by The Wellcome Trust, UK. Tanzina Haque1 Karen A. McAulay2 Deirdre Kelly3 Dorothy H. Crawford2 1 Department of Virology Royal Free Hospital UCL Medical School London, United Kingdom 2 Clinical and Molecular Virology Laboratory University of Edinburgh Edinburgh, United Kingdom 3 Liver Unit Birmingham Children's Hospital Birmingham, United Kingdom