Adoptive Therapy with EBV-Specific T Cells for Treatment of CNS EBV Post-Transplant Lymphoproliferative Disease Arising after Hematopoietic Stem Cell Transplant or Solid Organ Transplant
Authors: Prockop Susan , Suser Stephanie , Doubrovina Ekaterina , Castro-Malaspina Hugo R. , Papadopoulos Esperanza B. , Sauter Craig S. , Young James W. , Szenes Victoria , Slocum Alison , Baroudy Karim , O'Reilly Richard J. 
Published: October 2019

Abstract
Adoptive immunotherapy with EBV-specific T-cells (EBV-CTLs) derived from primary hematopoietic transplant donors is effective in the treatment of EBV disease complicating allogeneic hematopoietic stem cell transplant (HCT). In addition, third party donor-derived EBV-CTLs (tabelecleucel) have demonstrated efficacy in the treatment of EBV post-transplant lymphoproliferative in the setting of both HCT and solid organ transplant (SOT). While the introduction of first line therapy with rituximab has reduced the mortality associated with EBV-PTLD, EBV PTLD involving the central nervous system (CNS) remains a particularly ominous event as the efficacy of rituximab for CNS disease is limited by poor CNS bioavailability.
Between 1996 and 2016 we treated nineteen patients for EBV-PTLD involving the CNS arising after HCT (12) or SOT (7). These patients received EBV-CTLs from their primary transplant donor (7), tabelecleucel from a third-party donor (11) or from both types of donor (1). Patients were treated for either isolated CNS disease (10) or CNS and systemic disease (9). Patients developing EBV-PTLD after HCT were recipients of T Cell Depleted (N=6), cord blood (N=3) and conventional (N=3) transplant. Those developing EBV-PTLD after SOT had undergone renal (N=4) heart (1) liver (1) and heart/liver (1) transplants.
All of these patients had received prior therapy including rituximab (N=17), radiation therapy (N=6), and chemotherapy (N=9).
Primary donor EBV-CTLs were generated from EBV seropositive hematopoietic transplant donors at the time of or after the patient underwent transplant. Third party tabelecleucel were selected from a bank of 330 lines generated under GMP conditions from normal HCT donors who specifically consented to use of their T cells in patients other than their designated transplant recipient. Selection of third party tabelecleucel lines was made on the basis of HLA restriction by at least one HLA allele shared by the patient's tumor and the HCT donor, and matching for ≥ 2/10 recipient alleles. Patients received 3 weekly infusions of approximately 1-2x106 T cells/kg/infusion. Patients were sequentially evaluated for clinical and radiographic response, and quantifications of EBV DNA by PCR. Patients not achieving a complete response to an initial cycle of EBV directed cellular therapy were eligible to receive subsequent cycles of cells from either the same or a different donor. Responses were assessed 21-35 days after the first of each cycle of EBV-CTLs. Responses were evaluated based on Lugano criteria with CNS disease being assessed by MRI, CSF or thalium scan. Two patients treated for CNS and systemic disease had simultaneous therapy of their CNS disease and achieved responses of both CNS and systemic disease but the CNS specific response could not be attributed to cell therapy alone.
Of the 19 patients, 7 achieved complete responses and 5 durable partial responses for an overall response rate of 63%. The one-year overall survival (OS) for this cohort of 19 patients was 60% with responding patients experiencing one year OS of 91.7% and non-responding patients one year OS of just 14.3%. Eight of the 10 patients treated for isolated CNS disease responded to adoptive EBV directed T cell therapy. One-year overall survival for patients treated for isolated CNS disease is 70% and with CNS and systemic disease is 55.6%. Toxicities associated with infusions in this cohort are limited with 8 patients experiencing adverse events of ≥ grade 3 severity with one patient experiencing a possibly related grade 3 event
This study demonstrates a high response rate among patients with otherwise refractory EBV PTLD affecting the CNS. Adoptive therapy with EBV directed cellular therapy (primary donor or third party derived) can effectively treat this otherwise frequently lethal complication. The availability of 3rd party tabelecleucel enables treatment early in the course of disease and may thereby improve response rates while minimizing toxicity from chemotherapy.
Atara Biotherapeutics holds the IND and has a license to develop and commercialize the EBV and CMV cell therapy programs at Memorial Sloan Kettering. MSKCC and several MSK investigators hold a financial interest in Atara Biotherapeutics.
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Disclosures
Prockop: Atara Biotherapeutics: Research Funding; Mesoblast: Research Funding. Doubrovina:Atara Biotherapeutics: Consultancy, Patents & Royalties, Research Funding. Sauter:Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Precision Biosciences: Consultancy; Kite: Consultancy. O'Reilly:Atara Biotherapeutics: Consultancy, Patents & Royalties, Research Funding.