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
Condition: EBV-induced Lymphomas; EBV-associated Malignancies; Transplant Patients With EBV Viremia at High Risk for Developing a Recurrent EBV Lymphoma
MeSH terms: Epstein-Barr Virus Infections; Viremia; Lymphoma; Neoplasms; Lymphoproliferative Disorders
Intervention: EBV-specific T cells (EBV-CTLs)
Intervention description: EBV-CTLs are cytotoxic T lymphocytes that specifically kill cells presenting EBV protein antigens including EBV-transformed B lymphocytes responsible for EBV-associated lymphomas and lymphoproliferative disorders.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 87.0
Sex: All
Healthy volunteers: Accepts Healthy Volunteers
Keywords: EBV-specific T-cell lines; 11-130

Summary:

      This is a Phase II trial to evaluate the efficacy and safety of human leukocyte antigen (HLA)
      partially-matched third-party allogeneic Epstein-Barr virus cytotoxic T lymphocytes
      (EBV-CTLs) for the treatment of EBV-induced lymphomas and EBV-associated malignancies.
    

Eligibility criteria:

        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:

               1. Absolute neutrophil count (ANC) ≥ 1,000/µL, with or without GCSF support

               2. Platelets ≥ 20,000/µL

               3. Creatinine ≤ 2.0mg/dl

               4. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) < 3.0x and total
                  bilirubin < 2.5x the institutional upper limit of normal (ULN)

               5. Stable blood pressure and circulation not requiring pressor support

               6. 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:

          1. Patients developing EBV lymphomas or lymphoproliferative disorders following an
             allogeneic hematopoietic progenitor stem cell transplant (HSCT) (ie, marrow, PBSC, or
             umbilical cord blood).

          2. Patients developing EBV lymphomas or lymphoproliferative disorders following an
             allogeneic organ transplant.

          3. Patients with AIDS developing EBV lymphomas or lymphoproliferative diseases as a
             consequence of the profound acquired immunodeficiency induced by HIV.

          4. 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.

          5. 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)