Multivirus-specific T Cells for the Treatment of Virus Infections After Stem Cell Transplant

Inclusion Criteria: For Initial VSTs and subsequent infusions: patients will be eligible following any type of allogeneic transplant if they have CMV, adenovirus, EBV, BK virus and/or HHV6 infection/disease persistent or recurrent despite 14 days of standard therapy OR after failure of treatment after 7 days of standard therapy OR if unable to tolerate standard therapy. Patients with persistent JC virus infection will be eligible as well. 1. Prior myeloablative or non-myeloablative allogeneic hematopoietic stem cell transplant using either bone marrow or peripheral blood stem cells or single or double cord blood. 2. Treatment of the following persistent or relapsed infections despite standard therapy; 1. CMV: Treatment of persistent or relapsed CMV disease or infection after standard therapy. For CMV infection, standard therapy is defined as antiviral therapy with ganciclovir, foscarnet or cidofovir. * CMV disease: defined as the demonstration of CMV by biopsy specimen from visceral sites (by culture or histology) or the detection of CMV by culture or direct fluorescent antibody stain in bronchoalveolar lavage fluid in the presence of new or changing pulmonary infiltrates or changes consistent with CMV retinitis on ophthalmologic examination. * CMV infection: defined as the presence of CMV positivity as detected by PCR or pp65 antigenemia or culture from ONE site such as stool or blood or urine or nasopharynx. * Failure of antiviral therapy: defined as a rise or a fall of less than 50% in viral load in peripheral blood or any site of disease as measured by PCR or pp65 antigenemia after 7 days of antiviral therapy. 2. Adenovirus: Treatment of persistent adenovirus infection or disease despite standard therapy. Standard therapy is defined as antiviral therapy with cidofovir or an alternative antiviral agent if patient will not tolerate cidofovir therapy because of poor renal function. * Adenovirus infection: 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: defined as the presence of adenoviral positivity as detected by PCR, DFA or culture from two or more sites such as stool or blood or urine or nasopharynx. * Failure of therapy: defined as a rise or a fall of less than 50% in viral load in peripheral blood or any site of disease as measured by PCR or any other quantitative assay) after 7 days of antiviral therapy. 3. EBV: For treatment of persistent EBV infection despite standard therapy. For EBV infection, standard therapy is defined as rituximab given at 375mg/m2 in patients for 1-4 doses with a CD20+ve tumor. * EBV infection: defined as Biopsy proven lymphoma with EBV genomes detected in tumor cells by immunocytochemistry or in situ PCR,Or clinical or imaging findings consistent with EBV lymphoma and/or elevated EBV viral load in peripheral blood. * Failure of therapy is defined as: Increase or less than 50% response at sites of disease for EBV lymphoma OR, Increase or a fall of less than 50% in EBV viral load in peripheral blood or any site of disease after 1st dose of rituximab. 4. BK virus: Treatment of persistent BK virus infection or BK virus disease despite antiviral treatment with cidofovir or leflunomide. No clear standard treatment is defined. Cidofovir has been administered in low doses as well as high doses to HSCT patients with BK infections but no randomized trials are available proving its clinical efficacy. In small trials leflunomide had activity against BK virus, therefore we will consider this agent an acceptable alternative to cidofovir, given the absence of a clear first line option. * BK virus infection is defined as the presence of BK virus positivity as detected by PCR or culture in one site such as blood or urine. * BK virus disease is defined as the presence of BK virus detectable by culture or PCR in blood or urine or other body fluids and symptoms of disease including, but not limited to persistent microscopic or macroscopic hematuria or detectable BK virus in more than one site. * Failure of therapy is defined as a rise or a fall of less than 50% in viral load in peripheral blood or any site of disease as measured by PCR or any other quantitative assay) or worsening hematuria after 7 days of antiviral therapy. 5. HHV6: Treatment of persistent HHV6 infection or disease despite antiviral treatment with ganciclovir, cidofovir and foscarnet. No clear standard treatment is defined. Ganciclovir, cidofovir and foscarnet all have variable in vitro activity against HHV-6, and may have a role in treating HHV-6-associated disease - therefore antiviral treatment with one or more of these agents will we acceptable initial therapy. * HHV6 virus infection is defined as the presence of elevated HHV-6 levels as detected by PCR or positive culture in one site such as CSF or blood. * HHV6 disease is defined as defined as the presence of HHV6 detectable by culture or PCR in one or more sites such as blood or CSF and symptoms of disease including symptoms of HHV6 encephalitis OR detectable HHV6 by PCR or culture in more than one site. * Failure of therapy is defined as a rise or a fall of less than 50% in viral load in peripheral blood or any site of disease (as measured by PCR or any other quantitative assay) after 7 days of antiviral therapy. 6. JC virus: Treatment of progressive or persistent JC virus infection or disease without suitable alternative treatment option. Pepmixes specific for antigens on adenovirus, EBV, CMV, HHV6 and BK virus are used to generate our multivirus-specific VSTs. No pepmix specific for the rare JC virus is used for generation of these CTLs, however given the high homology (\>90%) between JC and BK and the fact that BK virus-specific T cells targeting VP1 and Large T (as targeted in our multivirus VSTs) have been administered to treat JCV-PML, resulting in viral clearance from the cerebrospinal fluid it is likely that our VSTs are efficacious against JC virus. Given the current lack of treatment options for JC virus infection or reactivation after HSCT and the risk of progression to JML, which is almost uniformly fatal, and the apparent activity of BK virus-directed T cells against JC virus infected cells, we propose including patients with progressive or persistent JC virus on this study, unless a suitable alternative therapy is available. * JC virus infection is defined as the presence of elevated JC virus levels as detected by PCR or positive culture in one site such as CSF or blood. * JC virus disease is defined as defined as the presence of JC virus detectable by culture or PCR in one or more sites such as blood or CSF and symptoms of disease including symptoms of PML OR detectable JC virus by PCR or culture in more than one site. 3. Patients with multiple CMV, EBV, Adenovirus, HHV6 and BK virus infections are eligible given that each infection is persistent despite standard therapy as defined above. Patients with multiple infections with one or more reactivation and one or more controlled infection are eligible to enroll. 4. Clinical status at enrollment to allow tapering of steroids to equal or less than 0.5 mg/kg/day prednisone (or equivalent). 5. HgB\>8.0 6. Pulse oximetry of \> 90% on room air 7. Available multivirus-specific VSTs 8. Negative pregnancy test in female patients if applicable (childbearing potential who have received a reduced intensity conditioning regimen). 9. Written informed consent and/or signed assent line from patient, parent or guardian. Exclusion Criteria: 1. Patients receiving ATG, 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 are less than 28 days removed from their allogeneic hematopoietic stem cell transplant or who have received donor lymphocyte infusions (DLI) within 28 days. 4. Patients with active acute GVHD grades II-IV. 5. Active and uncontrolled relapse of malignancy