The use of banked third-party VSTs is a feasible and safe approach to rapidly treat severe or intractable viral infections after stem cell transplantation

The use of banked third-party VSTs is a feasible and safe approach to rapidly treat severe or intractable viral infections after stem cell transplantation. of illness with one of these viruses after hematopoietic stem cell transplant. The cumulative rates of total or partial reactions at 6 weeks postinfusion were 74.0% (95% CI, 58.5%-89.5%) for the entire group (n = 50), 73.9% (95% CI, 51.2% -96.6%) for cytomegalovirus (n = 23), 77.8% for adenovirus (n = 18), and 66.7% (95% CI, 36.9%-96.5%) for EBV (n = 9). Only 4 responders experienced a recurrence or progression. There were no immediate infusion-related adverse events, and de novo graft-versus-host disease developed in only 2 individuals. Despite the disparity between the lines LRE1 and their recipients, the imply rate of recurrence of VSTs increased significantly postinfusion, coincident with stunning decreases in viral DNA and resolution of medical symptoms. The use of banked third-party VSTs is definitely a feasible and safe approach to rapidly treat severe or intractable viral infections after stem cell transplantation. This study is definitely authorized at while “type”:”clinical-trial”,”attrs”:”text”:”NCT00711035″,”term_id”:”NCT00711035″NCT00711035. Intro Viral illness is definitely a major cause of morbidity and mortality in immunocompromised individuals.1-5 After allogeneic hematopoietic stem cell transplantation (HSCT), up to a third of deaths may be related to viral infection.6 Pharmacologic treatments are available for individuals with some types of viral infections, but these often have limited effectiveness and significant adverse effects.7-9 One solution is to reconstitute the antiviral immunity of the recipient with virus-specific T cells (VSTs) derived from the stem cell donor. This approach appears effective as prophylaxis and therapy for refractory Epstein-Barr disease (EBV), cytomegalovirus (CMV), and adenovirus (AdV) infections, which are 3 common causes of viral morbidity and mortality after HSCT.10-15 Unfortunately, the need to generate specific T-cell lines for each individual patient renders this approach impractical for widespread or urgent use, and it is not an option when the donor lacks viral immunity (eg, after cord blood transplantation). The current limitations of T-cell therapy for viral infections could be overcome if it were possible to prepare off-the-shelf reagents; that is, a standard bank of VSTs that were generated from virus-immune individuals with common HLA polymorphisms and freezing and stored. Promising results have been acquired with this approach in the Rabbit Polyclonal to EPHA3/4/5 (phospho-Tyr779/833) treatment of EBV infections after solid organ transplants.16 Even though strategy may also be beneficial after HSCT,13 there remains the risk that these third-party, HLA-mismatched VSTs might also cause graft-versus-host-disease (GVHD) or graft rejection. It is also unfamiliar whether such T cells would be effective against CMV and AdV infections, which LRE1 happen more commonly than EBV in immunocompromised individuals, and it is not known whether the banked T cells would have adequate persistence for sustained protection. Therefore, we generated and stored a standard bank of T-cell lines LRE1 LRE1 specific for EBV, CMV, and AdV that were ready for immediate use and, inside a multicenter study, administered them to 50 individuals with severe, refractory CMV, AdV, or EBV infections. Methods Third-party T-cell standard bank We generated a standard bank of VSTs that were either retained from our recipient-specific medical study10 or were newly generated from donors with known antiviral activity, including HLA homozygous donors recognized by the National Marrow Donor System. To generate VSTs, we transduced up to 5 107 donor peripheral blood mononuclear cells (PBMCs) having a medical grade Ad5f35pp65 vector at a multiplicity of illness of 10 viral particles (vp) per cell after an over night adherence step.17 Starting on day time 10 posttransduction, the cells were restimulated weekly with irradiated EBV-transformed lymphoblastoid cell lines transduced at an multiplicity of illness of 100 vp with the same Ad5f35pp65 vector at a responder:stimulator (R:S) percentage of 4:1, if development was performed inside a 24-well plate, or at an R:S percentage of 1 1:5 if expanded in the G-Rex.17 After 2 to 4 stimulations, the VSTs were cryopreserved. All donors offered educated consent and met eligibility requirements. At the time of cryopreservation, each collection was microbiologically screened, immunophenotyped by circulation cytometry, and tested for disease specificity by interferon-gamma (IFN-) enzyme-linked immunospot (ELIspot) assay. A total of 32 lines were produced and characterized, 18 of which were administered to the 50 study individuals. The selection of lines for infusion was based on the specificity of the collection for the prospective disease through a shared HLA allele, as well as the overall level of HLA match. Therefore, a collection that only matched at 1 allele but with confirmed antiviral activity against the infecting disease through that shared allele would be desired to a collection that matched at 2 or 3 3 alleles but did not have confirmed antiviral activity through these shared alleles. Cells were transported cryopreserved inside a dry shipper fitted having a data logger to participating sites.