Therapeutic Effects of Epstein-Barr Virus Immune T-Lymphocytes Derived From a Normal HLA-Compatible Or Partially-Matched Third-Party Donor in the Treatment of EBV Lymphoproliferative Disorders and EBV-Associated Malignancies

Inclusion criteria

• Pathologically documented EBV antigen positive lymphoproliferative disease, lymphoma or other EBV-associated malignancy.

OR

• Evaluable disease as demonstrated by clinical and/or radiologic studies with current or prior elevated blood levels of EBV DNA exceeding 500 copies/ml by quantitative real time polymerase chain reaction (PCR).

OR

• Persistent or recurrent elevations in levels of EBV DNA exceeding 500 copies/ml in patients previously treated for EBV-LPD with chemotherapy and/or rituximab who do not yet have clinically or radiologically evaluable disease but are at high risk of disease recurrence.
• EBV-specific T cells are available for adoptive immune cell therapy from a consenting third party donor. The third party EBV-CTLs to be administered will be selected on the basis of two criteria: 1) that they are matched for at least 2 HLA antigens and 2) that they are restricted by an allele shared with the EBV+ malignancy (if known), or with the donor in HSCT recipients, or patient in organ transplant or immunodeficient patients
• KPS or Lansky score ≥ 20.
• A life expectancy of at least 6 weeks.
• Adequate bone marrow, heart, lung, liver and kidney function at the time of treatment with EBV-specificT cells is initiated, including:

• Absolute neutrophil count (ANC) ≥ 1,000/µL, with or without GCSF support
• Platelets ≥ 20,000/µL
• Creatinine ≤ 2.0mg/dl
• Alanine aminotransferase (ALT), aspartate aminotransferase (AST) < 3.0x and total bilirubin < 2.5x the institutional upper limit of normal (ULN)
• Stable blood pressure and circulation not requiring pressor support
• Adequate cardiac function as demonstrated by EKG and/or echocardiographic evidence (may be performed within 30 days prior to treatment)
• However, abnormalities of specific organs will not be considered grounds for exclusion if they are the result of the EBV+ malignancy or its treatment (e.g. a renal allograft recipient with an EBV LPD may be on dialysis because the allograft was rejected when the immune suppression was stopped as a first approach to treatment of the EBV LPD). At the discretion of the investigator, patients with elevated but stable creatinine will not be precluded from treatment on study.
• There is no age restriction to eligibility for this protocol.

It is expected that five types of patients afflicted with EBV-associated lymphomas, lymphoproliferative diseases or malignancies will be referred and will consent to participate in this trial. These are:

• Patients developing EBV lymphomas or lymphoproliferative disorders following an allogeneic hematopoietic progenitor stem cell transplant (HSCT) (ie, marrow, PBSC, or umbilical cord blood).
• Patients developing EBV lymphomas or lymphoproliferative disorders following an allogeneic organ transplant.
• Patients with AIDS developing EBV lymphomas or lymphoproliferative diseases as a consequence of the profound acquired immunodeficiency induced by HIV.
• Patients who develop EBV lymphomas or lymphoproliferative diseases or other EBV-associated malignancy as a consequence of profound immunodeficiencies associated with a congenital immune deficit or acquired as a sequela of anti-neoplastic or immunosuppressive therapy.
• Patients who develop other EBV-associated malignancies without pre-existing immune deficiency, including: EBV+ Hodgkin's and Non-Hodgkin's disease, EBV+ nasopharyngeal carcinoma, EBV+ hemophagocytic lymphohistiocytosis, or EBV+ leiomyosarcoma.

Exclusion criteria

The following patients will be excluded from this study:

• Patients with active (grade 2-4) acute graft vs. host disease (GVHD), chronic GVHD or an overt autoimmune disease (e.g. hemolytic anemia) requiring high doses of glucocorticosteroid (>0.5 mg/kg/day prednisone or its equivalent) as treatment
• Patients who are pregnant
• Patients with severe comorbidities, not related to their EBV-associated malignancy, that would be expected to preclude their survival for the 6 weeks required to assess response of T cell therapy
• Patients eligible for MSK protocol #16-803 (EBV-CTL-201)