Efficacy of Donor and ‘Third Party’ (Tabelecleucel) EBV-Specific T Cells for Treatment of Central Nervous System (CNS) EBV-PTLD

Abstract

Background EBV+PTLD is a life-threatening complication after hematopoietic cell transplantation (HCT) and solid organ transplantation (SOT). Introduction of EBV-specific T-cells (EBV+CTLs) as second line treatment after rituximab has reduced overall EBV+PTLD related mortality. Due to limited efficacy of rituximab for EBV+PTLD disease involving the CNS there remains a clear clinical need. We studied the ability of EBV+CTLs to mediate responses in CNS EBV+PTLD. Methods Patients with CNS EBV+PTLD, with or without systemic disease, after HCT or SOT were eligible to receive either donor-derived or ‘third party' Tabelecleucel between 1996 and 2016 on two IRB approved MSKCC protocols (95-024: NC2663 and 11-130: NCT01498484). Donor EBV+CTLs were generated from EBV seropositive HCT-donors, while Tabelecleucel were selected from a bank of 330 lines from volunteer HCT donors. Selection of Tabelecleucel lines was based on matching for > 2/10 recipient alleles and HLA restriction by at least one HLA allele shared by the patient's tumor. Patients received 3 weekly infusions of ∼1-2 × 106 T cells/kg. Responses were assessed 21-35 days after the start of each cycle of EBV+CTLs based on Lugano criteria with CNS disease being assessed by MRI, CSF (EBV-PCR) or thalium scan. Patients not achieving a complete response (CR) to an initial cycle of EBV+CTLs were eligible to receive a subsequent cycle. Main outcome of interest was response to EBV+CTLs. Other outcomes of interest were 1-year overall survival (OS) and infusion-related toxicities. Results Nineteen patients were treated: 12 after HCT (T-cell depletion 6, cord blood 3, T-replete 3) and 7 after SOT (renal 4, heart 1, liver 1, heart/liver 1). 7 patients received EBV+CTLs from their primary donor, 11 from a third-party donor and 1 from both donor types. Ten were treated for had isolated-CNS disease while 9 had CNS and systemic disease. All of these patients had received prior therapy including rituximab (N = 17), radiation therapy (N = 6), and/or systemic chemotherapy (N = 9). The overall response rate was 63% and the one-year OS was 60% (70% for isolated-CNS, 56% for combined). Two patients with combined disease had simultaneous radiation therapy and achieved response, and thus, the CNS specific response could not be attributed to cell therapy alone. Toxicities associated with infusions were limited; 8 patients experienced ≥ grade 3 events with one patient experiencing a possibly related grade 3 event. Interpretation This study demonstrates clear responses and promising survival among patients with otherwise refractory and lethal CNS EBV+PTLD. Adoptive therapy with EBV directed cellular therapy (either primary donor or third party derived Tabelecleucel is a promising treatment modality for CNS EBV+PTLD.