Allogeneic Virus-Specific T-lymphocyte Infusion for the Treatment of Patients with Epstein-Barr Virus, Cytomegalovirus, Adenovirus, or BK Virus Infection

Inclusion Criteria

• Men and women ages 18 years or older of all ethnic groups will be eligible for the treatment
• Patients with history of hematopoietic stem cell transplant (HCT) or solid organ transplant (SOT) who demonstrate evidence of viral reactivation and/or infection manifesting as end-organ or systemic disease due to one or more of the following viruses: EBV, CMV, adenovirus (ADV) or BK virus and suboptimal response to the standard of care therapy as defined below:
• CMV: * Reactivation is defined as elevated polymerase chain reaction (PCR) (above 96 IU/ml) or clinical evidence of active disease (e.g., organ biopsy or culture suggestive of CMV-mediated process, evidence of CMV retinitis on ophthalmologic examination). Patients with detectable (positive or low positive) CMV viremia and documented or suspected resistance will be eligible * Adequate standard of care pharmacological therapy (as per infectious disease [ID] and bone marrow transplant [BMT] supportive care standard operating procedure [SOP]) for 14 days unless patient could not tolerate the standard of care therapy e.g., nephrotoxicity (defined as increase in creatinine by 50% or 25% drop in glomerular filtration rate [GFR]) or bone marrow myelosuppression * Failure is defined as a reduction of less than 1 log in viral load in blood or other tissue since baseline after 14 days on the initial medication or minimum of 7 day on the second line of therapy or a clear progression of end organ disease by clinical manifestations or inability to tolerate the pharmacological treatment due to toxicities, or there is a documented evidence of resistance
• ADV: * Adenovirus infection will be defined as the presence of adenoviral positivity as detected by PCR or culture from ONE of the following sites: ** Stool ** Blood ** Urine ** Nasopharynx * Adenovirus disease will be defined as the presence of adenoviral positivity as detected by culture or PCR or histological findings from more than TWO sites of the following sites: ** Stool ** Blood ** Urine * Nasopharynx * Due to toxicities associated with standard of care cidofovir therapy for ADV infection, subjects displaying any degree of ADV viremia or ADV-associated end-organ or systemic disease will be eligible for this study
• BK virus: * Infection is defined as reactivation in peripheral blood (defined as PCR positivity) or evidence of active end organ involvement (i.e., hemorrhagic cystitis or evidence of polyomavirus-associated nephropathy [PVAN]) * No standard of care therapy exists for BK reactivation or disease, thus refractory disease will be defined as persistence of clinical symptoms or reduction in PCR viremia of less than 1 log from baseline at 7 days despite standard supportive care measures (e.g., including reduction in immunosuppression) or any other intervention. Any subject receiving cidofovir for BK-associated disease will be eligible for this study
• EBV: * Patients with active proven or probable EBV-LPD or patients with EBV viremia who are at risk for EBV-LPD. Patients should have failed 1st line Rituximab +/- chemotherapy or be ineligible for rituximab, as determined by the investigator (for example, prior treatment with rituximab, CD20-negative LPD or chronic active EBV affecting NK or T lineages, contraindication) ** EBV-LPD is defined as a proven EBV-LPD documented 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 ** Failure is defined as a reduction of less than partial response (PR) by Cheson criteria (Cheson, et al. 2014, Fournier, Ammari et al. 2014) (less than 50% reduction at least 14 days after treatment, compared to the baseline [prior to initial rituximab administration] or a decrease of less than 1 log in EBV PCR after administrationof rituximab) OR * Patients with active, uncontrolled EBV viremia that failed standard therapy (i.e. reduction of immunosuppression, chemotherapy, or rituximab, unless ineligible) ** Failure is defined as: *** A reduction of less than 1 log in viral load in blood or other tissue since baseline after at least 14 days from initiating standard therapy *** Clear progression of end organ disease by clinical manifestations or greater than 0.5 log increase in EBV DNA levels from baseline *** Inability to tolerate the pharmacological treatment due to toxicities per primary referring team. *** Unable to reduce immunosuppression (ie; risk of graft rejection) *** Unable to receive chemotherapy (ie; poor organ function or functional status) *** Unable to receive Rituximab (ie; prior exposure, CD20 negative disease or contraindication) *** Patients with chronic active EBV affecting NK or T Cell lineages are eligble regardless of viremia level
• Recurrent or multiple viral infections: * Recurrent viral infection is defined as occurrence of more than one episode of reactivation that required intervention or symptomatic disease in recipient of allogeneic HCT that required standard of care treatment * Multiple viral infections are defined as more than one virus reactivating (defined by PCR positivity) or causing symptomatic systemic or end-organ disease. At least one of those viral reactivations required standard of care intervention. No standard of care therapy is defined for ADV and BK * Patients with multiple infections/reactivations will be eligible as long as at least one of those viral infections meet the criterium of “refractory”
• DONOR: Donors for allogeneic (i.e., human leukocyte antigen [HLA] matched or mismatched related or unrelated) stem cell transplants (Group A; if available) who have fulfilled eligibility for and consented to stem cell donation as per Columbia University Irving Medical Center (CUIMC) institutional guidelines (BMT SOP PBMT1002 or DS01; most current versions) who has been the original donor for the patient who would still meet original eligibility criteria upon re-evaluation. HLA tissue type testing will be conducted using a buccal swab or blood collection (buccal swab is a non-invasive collection of tissue from the cheek)
• DONOR: Haploidentical relative (sibling, parent or offspring) of the patient who is at least 5/10 match on molecular high resolution HLA typing A, B, C, DR, DQ (Group B and for SCT recipients enrolled in Group A if original SCT donor is not readily available) and meets the criteria established for the SCT donors per BMT SOP (donor selection, donor evaluation and donor deferral).
• DONOR: Donor must be in good health based on review of symptoms, results of physical examination, and routine testing per standards of good medical care
• DONOR: Women of child-bearing potential must have a negative pregnancy test and be non-lactating
• DONOR: More than one donor may be screened and enrolled in the study for treatment of each recipient

Exclusion Criteria

• Patients with other uncontrolled infections, except for CMV, EBV, ADV or BK. For bacterial infections, patients must be receiving definitive therapy and have no signs of progressing infection for 72 hours prior to the day of infusion. For fungal infections, patients must be receiving definitive systemic anti-fungal therapy and have no signs of progressing infection for 1 week prior to R-MVST infusion. 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
• Patients who receive corticosteroids at >= 0.5 mg/kg prednisone or equivalent
• Patients who received anti-thymocyte globulin (Anti-thymocyte globulin [ATG], alemtuzumab, [campath]), or other T-cell immunosupressive monoclonal antibodies in the last 28 days
• Patients who received methotrexate, or other antimetabolite-type immunosuppressants that are toxic to proliferating T cells in the last 7 days
• Patients who received extracorporeal photopheresis within the last 28 days
• Patients who received checkpoint inhibitor agents (e.g., nivolumab, pembrolizumab, ipilimumab) within 3 drug half-lives of the most recent dose to the infusion of R-MVST
• Received donor lymphocyte infusion in last 28 days
• Evidence of graft versus host disease (GVHD) >= grade 2
• Evidence of biopsy-proven acute rejection in SOT recipients
• Active and uncontrolled relapse of malignancy
• Patients who are pregnant, or breastfeeding
• Female of childbearing potential, or male with a female partner of childbearing potential, unwilling to use a highly effective method of contraception
• Uncontrolled intercurrent illness including, but not limited to symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Patients who have received investigational (IND) product within 14 days of infusion of the R-MVST cells
• DONOR: Donor exclusion criteria will be followed as per the most current BMT SOP (donor selection, donor evaluation and donor deferral)
• DONOR: Donors of 17 years of age or younger