Third Party Donor Derived EBV Specific T Cells for the Treatment of Refractory EBV-Related Post-Transplant Lymphomas

Adoptive immunotherapy is an effective strategy for the treatment of EBV⁺ lymphoproliferative diseases (EBV-LPD) arising after allogeneic hematopoietic stem cell (HSCT) or solid organ transplant (SOT). This approach is often limited by an inability to generate donor derived in vitro expanded EBV-specific cytotoxic T-lymphocyte (EBV-CTL) lines in a timely manner and/or donor derived EBV CTLs being restricted by non-shared HLA alleles in the patient.

We have treated 28 consecutive patients for EBV LPD with in vitro expanded EBV-CTLs derived from a donor other than the patient or their transplant (HSCT or SOT) donor.  EBV CTLs were selected from a bank of 345 lines generated under GMP conditions from normal donors.  Patients were recipients of unmodified (n=7), T cell depleted (n=7) or unrelated cord blood (n=7) HSCT or one (n=5) or two (n=2) SOTs. Patients received infusions of 3rd party EBV-CTLs after failing a median of 2 prior therapies including rituximab in all but one case. Three patients failed prior infusions with EBV-CTLs which were autologous (n=1) or derived from their original HSCT donor (n=2).  In these two patients it was demonstrated that the donor derived EBV CTLs were restricted by a non-shared HLA allele. 

Third party EBV-CTLs were selected on the basis of HLA matching at a minimum of 2/8 recipient alleles.  When known, EBV-CTLs restricted through HLA alleles present on the EBV+ tumor were selected.   A total of 25 lines were infused.  We evaluated HLA restriction in 20 of these lines and inferred it in five. CTLs were restricted by a single HLA allele (n=12), by two alleles (n=6) and less frequently by > than two alleles (n=2). 

Patients received a median of 6 infusions most at 1x10⁶ EBV-CTL/kg.  Five patients received EBV-CTLs from >1 3rd party donor.  Infusions were associated with minimal toxicity.  Sixteen patients achieved CR, two patients PR and two SD.  Eight patients died of progressive disease, five shortly after the first infusion (17- 29 days). Response to EBV CTL therapy correlated with HLA restriction but not the degree of HLA matching.  Radiographic and clinical responses correlated with detectable increases in the frequency of CTL precursors in the blood.  However durable EBV CTL engraftment was not seen. 

This study demonstrates a high response rate among patients with otherwise refractory EBV malignancy treated with EBV specific 3rd party CTLs.  EBV CTLs can be effective when selected based on restriction to shared alleles despite significant HLA disparity.  The bank of EBV specific T cells can provide an immediate source of HLA partially matched appropriately restricted T cells for adoptive immunotherapy to treat EBV associated malignancy.  This enables treatment early in the course of disease and is anticipated to maximize the response rate.