Administration of LMP-specific cytotoxic T-lymphocytes to patients with relapsed EBV-positive lymphoma post allogeneic stem cell transplant

Abstract

EBV associated tumors in the immunocompetent host express the type II latency antigens LMP1 and LMP2 which can serve as potential targets for immunotherapy. For many patients with Chronic Active Epstein Barr Virus (CAEBV) infection and relapsed Hodgkin’s Lymphoma (HL), the only potential curative option is allogeneic HSCT. However, relapse rates remain high (>50%). We hypothesized that the administration of donor-derived LMP-CTL would rapidly restore LMP-specific T-cell immunity and prevent relapse in these high-risk patients. LMP-CTL lines were expanded using donor-derived monocytes and EBV transformed lymphoblastoid cell lines, transduced with an adenoviral vector expressing either LMP2 (n=4) or ΔLMP1 and LMP2 (n=15). Characterization of CTL lines at cryopreservation revealed CD4+ and CD8+ cells which were predominantly effector and effector memory phenotype. CTL lines had LMP2 (+/-LMP1) specific activity as determined by ELISPOT and cytotoxicity assays. Sixteen patients (n=6 HL, n=4 B-cell CAEBV/NHL, n=6 T-cell CAEBV/NHL) received CTL (dose range: 0.4-3x10e8/m2) approximately 100 days post HSCT. No toxicities related to CTL were observed. Fourteen patients were in remission at the time of CTL infusion and 13/14 of these patients remained in remission for a median of 30 months post CTL (range 3-90 months). One patient relapsed 6 months post CTL and died of progressive disease. Two patients received CTL for relapsed disease after HSCT and both died of disease progression. In general, donor-derived LMP-CTL seem to be well tolerated in high-risk patients with EBV+ lymphoma or CAEBV post HSCT. In addition, the use of donor-derived tumor-directed T-cells as adjuvant therapy post HSCT may restore LMP-specific T-cell immunity and prevent relapse in this high-risk patient population. Moreover, we are able to use these normal donor–derived LMP-CTL to develop a bank of LMP-specific CTL for third party use as an “off the shelf” therapeutic for EBV associated malignancies.