Epstein-Barr virus induced lymphoproliferative disease and EBV+ lymphomas are a significant cause of morbidity and mortality in recipients of allogenic hematopoietic cell (HSCT) and organ transplants (SOT) as well as patients with severe genetic and acquired immunodeficiencies. EBV+ Hodgkin's disease (HD), EBV+ hemophagocytic lymphohistiocytosis, EBV+ nasopharyngeal carcinoma and EBV+ leiomyosarcomas also constitute a group of malignancies for which current chemotherapy is often ineffective. Adoptive therapy with donor-derived EBV-specific T-cells generated in vitro has been effective in the treatment and prevention of EBV lymphomas complicating allogeneic HSCT. However, application has been limited by the lack of specialized facilities required for T-cell production and the time required (approximately 65 days) to generate EBV-specific T-cells that are adequate in number, EBV-specificity and lack of alloreactivity. Effective treatment with EBV-specific T-cells may also be hampered or prevented by limited availability of donor cells for T-cell propagation, lack of prior sensitization of the donor to the virus in vivo, or failure of the donor's T-cells to recognize EBV in the context of an HLA allele expressed by the tumor. Based on our preliminary studies, we hypothesize that EBV-specific T-cells derived from appropriately selected third party donors from a pre established bank of T-cell lines can address these limitations. Accordingly, in Aim 1 we will: conduct a Phase II trial of EBV-specific T-cells derived from third party donors selected on the basis of matching for 2 HLA alleles and appropriate HLA restriction, in the treatment of patients with EBV lymphomas complicating allogeneic HSCT or organ transplants or other EBV-associated malignancies associated with immune deficiencies. In this trial, we will correlate clinical responses and alterations in circulating levels of EBV DNA observed with quantitative evaluations of the in vivo growth, expansion and survival of the EBV-specific T-cells in vivo following adoptive transfer.
In Aim 2, we will establish of a large, genetically diverse bank of EBV-specific T-cell lines specifically consented for third party use. Each of the 300 T-cell lines that has been previously generated from consenting donors, and is a candidate line for this bank has been manufactured under GMP conditions and characterized as to its HLA genotype, EBV specificity, lack of alloreactivity and requisite microbial sterility. We plan to identify the HLA restriction of the EBV-specific T-cells in each line, so as to permit selection of EBV T-cells for a given patient that are restricted by an HLA allele shared by the patient's tumor. We will also identify lines containing T-cells specific for LMP-1 and/or LMP-2, which could be used to treat EBV+ malignancies that selectively express these antigens. We expect this phase II trial will provide the data needed to initiate a phase III study comparing this therapy with chemotherapy and/or Rituxan. The bank of well characterized EBV-specific T-cells should also provide a broadly applicable and accessible resource for such trials.
EBV-associated PTLDs and lymphomas are a major and life-threatening complication for patients receiving hematopoietic cell and solid organ transplants and patients with severe genetic and acquired immunodeficiencies. Current treatment with chemotherapy and/or Rituxan is durably effective in no more than 50% of cases and may induce significant toxicity. Adoptive transfer of donor-derived EBV specific T-cells has been found to be effective for prevention and treatment of these disorders. Studies in the United Kingdom and at our center may also be effective. This grant proposes a Phase II trial of third-party derived EBV-specific T-cells selected on the basis of partial HLA matching and tumor-directed HLA restriction to assess this approach. It also proposes the establishment of a fully characterized specifically consented bank of GMP-grade EBV-specific T-cells so as to provide a broadly applicable and immediately accessible resource for adoptive therapy of these diseases.
