T cells for viral infections after allogeneic hematopoietic stem cell transplant

Abstract

Despite recent advances in the field of allogeneic hematopoietic stem cell transplantation (HSCT), viral infections are still a major complication during the period of immune suppression that follows the procedure. Adoptive transfer of donor-derived virus-specific cytotoxic T cells (VSTs) is a strategy to rapidly restore virus-specific immunity to prevent or treat viral diseases after HSCT. Early proof of principle studies demonstrated that the administration of donor-derived T cells specific for cytomegalovirus or Epstein-Barr virus (EBV) could effectively restore virus-specific immunity and control viral infections. Subsequent studies using different expansion or direct selection techniques have shown that donor-derived VSTs confer protection in vivo after adoptive transfer in 70% to 90% of recipients. Because a major cause of failure is lack of immunity to the infecting virus in a naïve donor, more recent studies have infused closely matched third-party VSTs and reported response rates of 60% to 70%. Current efforts have focused on broadening the applicability of this approach by: (1) extending the number of viral antigens being targeted, (2) simplifying manufacture, (3) exploring strategies for recipients of virus-naïve donor grafts, and (4) developing and optimizing "off the shelf" approaches.

Figure 1

VST manufacturing strategies. Donor blood is drawn and PBMCs are then manipulated using different approaches for the manufacture of VSTs for clinical use. (A) Direct selection utilizes either: (1) multimers specific for a virus-derived peptide in the setting of a class-I HLA molecule, or (2) column selection where T cells are stimulated with viral antigen followed by selection of IFN-γ or CD154–expressing T cells using antibody coated immunomagnetic beads. (B) Ex vivo T-cell expansion requires the in vitro stimulation and expansion of T cells using APCs pulsed, infected, or transfected with viral peptide(s)/protein(s), viral lysate, or viral vectors/plasmids, respectively. (C) Genetic modification requires the gene transfer of high affinity VST receptors or chimeric-antigen receptors to redirect specificity of T cells to viral targets. CAR, chimeric antigen receptor.