Administration of Rapidly Generated Multivirus-specific Cytotoxic T-Lymphocytes (VIRAGE)

INCLUSION CRITERIA:

Patients will be eligible following any type of allogeneic transplant to receive CTLs as prophylaxis or for early reactivations as defined below.

1. Prior myeloablative or non-myeloablative allogeneic hematopoietic stem cell transplant using either bone marrow or peripheral blood stem cells.
2. Prophylaxis for patients at risk of CMV, adenovirus or EBV infection (for Phase 2 portion only). In the phase 1 portion patients must meet criteria in 3 below.
3. Early treatment of reactivation or infection which is defined for each virus as below:

   1. CMV: CMV antigenemia is monitored at least weekly post transplant. Early reactivation is defined at CMV antigenemia with less than 10 leucocytes positive. If any patient develops CMV antigenemia (with greater than 10 leukocytes positive) or clinical evidence of CMV infection (defined as the demonstration of CMV by biopsy specimen from visceral sites (by culture or histology) either pre or after CTL infusions, standard treatment with Ganciclovir, and/or Foscarnet and Immunoglobulins will be initiated. Patients may receive CTLs for antigenemia or elevated PCR without visceral infection.
   2. Adenovirus: Adenovirus infection will be defined as the presence of adenoviral positivity as detected by PCR or culture from ONE site such as stool or blood or urine or nasopharynx. Adenovirus disease will be defined as the presence of adenoviral positivity as detected by culture from more than two sites such as stool or blood or urine or nasopharynx. In patients who meet the criteria for disease Cidofovir may be added unless the subject could not tolerate this agent due to nephrotoxicity. Patients may receive CTLs for elevated PCR in blood or stool.
   3. EBV EBV-LPD is defined according to recent guidelines as proven EBV-LPD defined by biopsy or probable EBV-LPD defined as an elevated EBV DNA level associated with clinical symptoms (adenopathy or fever or masses on imaging) but without biopsy confirmation. Patients with EBV DNA reactivation only defined as EBV DNA levels \> 1000 copies/ug may also receive CTLs on study. Patients with proven or probable EBV-LPD should also receive Rituxan
4. Early treatment may be given to eligible patients with a single or multiple infections. Patients with multiple infections with one reactivation and one controlled infection are eligible to enroll.
5. Patient with a CMV seronegative donor may only receive CTLs for a CMV reactivation in the dose escalation phase if the line has activity against CMV.
6. Clinical status at enrollment to allow tapering of steroids to less than 0.5 mg/kg/day prednisone.
7. Karnofsky/Lansky score of 50 or greater
8. ANC greater than 500/µL.
9. Bilirubin 2x upper limit normal or less
10. AST 3 x normal or less
11. Serum creatinine 2 x upper limit normal or less
12. HgB \>8.0
13. Pulse oximetry of \> 90% on room air
14. Available multi-virus-specific cytotoxic T lymphocytes
15. Negative pregnancy test in female patients if applicable (childbearing potential who have received a reduced intensity conditioning regimen).
16. Written informed consent and/or signed assent line from patient, parent or guardian.

DONOR ELIGIBILITY: The donor for the CTL product will be the same donor who donated the allogeneic product for the patient's transplant. These donors for allogeneic (i.e. HLA matched or mismatched related or unrelated) stem cell transplants will have fulfilled eligibility for and consented to stem cell donation as per the stem cell transplant program's standard operating procedures.

EXCLUSION CRITERIA:

Exclusion Criteria for initial CTL and for subsequent infusions:

1. Patients receiving ATG, or Campath or other immunosuppressive T cell monoclonal antibodies within 28 days of screening for enrollment.
2. Patients with other uncontrolled infections. For bacterial infections, patients must be receiving definitive therapy and have no signs of progressing infection for 72 hours prior to enrollment. For fungal infections patients must be receiving definitive systemic anti-fungal therapy and have no signs of progressing infection for 1 week prior to enrollment.

   Progressing infection is defined as hemodynamic instability attributable to sepsis or new symptoms, worsening physical signs or radiographic findings attributable to infection. Persisting fever without other signs or symptoms will not be interpreted as progressing infection.
3. Patients who have received donor lymphocyte infusion (DLI) within 28 days.
4. Patients with active acute GVHD grades II-IV.
5. Active and uncontrolled relapse of malignancy.