Successful Post-Remission Therapy Using LMP1/LMP2a-Specific Cytotoxic T Lymphocytes (CTLs) in Extranodal NK/T Cell Lymphoma

Extranodal NK/T-cell lymphoma (ENKTCL) is highly associated with latent Epstein-Barr virus (EBV) infection and frequent relapse even after complete response (CR) to intensive chemotherapy and radiotherapy. The role of the EBV in pathogenesis of this disease and EBV proteins expressed in this lymphoma provide targets for the adoptive immunotherapy with antigen-specific cytotoxic T lymphocyte (CTL) and raise the possibility of EBV-specific CTL as therapeutic strategies. This prospective pilot study is aimed to evaluate the effectiveness and safety of EBV-specific CTL as a maintenance therapy in patients with chemo-sensitive EBV positive ENKTCL.

A total of thirteen adult patients with EBV positive ENKTCL were enrolled but two patients died due to disease progression during the generation of EBV-CTLs. Ultimately, eleven patients who were responded to chemotherapy were received EBV-CTLs. For generation of EBV-CTLs in vitro, mature dendritic cells(DC) derived from monocytes were pulsed with RNAs of EBV LMP1 and LMP2a antigens, and then T cells were stimulated with DCs three times for 3 weeks in Catholic GMP cell processing center. EBV-CTLs were cryopreserved for later usage and some remaining cells were analyzed. Patients completed the induction treatments including chemotherapy, radiotherapy, and/or high-dose therapy followed by autologous peripheral blood stem cell transplantation (HDT/SCT) before the infusion of EBV-CTLs and received 8 doses of 2 ×10E7 CTLs/m².

Nine newly diagnosed and two chemo-sensitive relapsed patients (six male and five female) received maintenance therapy with EBV-CTLs. Median age was 47 years (range, 20–71 years). Ten patients achieved CR and one patient achieved partial response (PR) after induction therapy, and five patients including one patient in PR underwent HDT/SCT. During the maintenance therapy with EBV-CTLs, one patient dropped out of infection after 5 doses of EBV-CTLs therapy and the others completed 8 doses of EBV-CTLs. Among eleven patients, one patient relapsed 17.3 months since induction therapy. In overall, the 3-year overall survival (OS), progression-free survival (PFS) since induction therapy were 85.7±13.2%, 88.9±10.5%, respectively with a median follow-up of 25.2 months. For five patients who had HDT/SCT, DFS from SCT was 80.0±17.9% with a median follow-up of 21.0 months.

This pilot study indicated that both LMP1 and LMP2a-specific CTLs can be effectively manufactured by stimulation with DCs in vitro from blood of patients with ENKTCL in current trial. This approach could be applied to patients with ENKTCL with safety and effectiveness. The larger prospective randomized study is needed to define the role of EBV-CTLs therapy to prevent unpredictable relapse in EBV-positive ENKTCL.

No relevant conflicts of interest to declare.