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 donorderived 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 EpsteinBarr 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. (Blood. 2016;127(26):3331-3340)

Engineering cord blood to improve engraftment after cord blood transplant

“…In addition, the strategy is HLA restricted and targeting a single viral epitope increases the risk of viral immune escape. However, a clinical trial is currently underway in the United Kingdom evaluating T cells transduced with a retroviral vector expressing a CMVspecific TCR for high-risk patients after HSCT (Morris et al) (97).…”

“…These T cells suppressed viral replication compared with unexpanded CD8 T cells, and CMV and EBV-specific T cells derived from the same HIV-seronegative donors. This holds promise in the CB setting and HIV-specific T cells manufactured this way are currently studies utilizing donor-derived HIV-specific T cells after allogeneic HSCT are being planned (97). Moreover, the group at Children's National is currently exploring the potential expanding HIV-specific T cells from CB using a non-HLA restricted GMP compliant approach (101).…”

Immunotherapy for transplantation-associated viral infections

“…Potential limitations include the need for additional donor leukapheresis to collect sufficient starting material, which can be burdensome, particularly in the unrelated donor setting. Additionally, this method has a requirement for circulating VSTs, and is therefore not available to virus-naive donors or CMV-seropositive donors who do not respond to pp65 or IE-1 stimulation (57).…”

“…In the post-HSCT setting, gross impairment of T cell function liberates EBV-infected B cells (usually donorderived) to outgrow, causing post-transplant lymphoproliferative disorder (PTLD). PTLD risk is particularly high in patients receiving enhanced immune suppression for the treatment of GVHD, and in those receiving anti-thymocyte globulin (57,67).…”

Recent advances in T‐cell immunotherapy for haematological malignancies

“…(Taylor et al 2015) The most immunogenic of these is post-transplant lymphoproliferative disease and many studies have shown that infusions of EBV-specific T-cells derived from an EBV seropositive normal HSCT donor can induce complete remission in over 70% of patients who develop this complication after HSCT. (Bollard and Heslop 2016, Doubrovina et al 2012, Heslop et al 2010) Initial manufacturing strategies for donor-derived EBV-specific T-cells were lengthy, because they used lymphoblastoid cell lines (LCLs) as a source of EBV antigen. With the availability of overlapping peptide libraries spanning individual EBV antigens, several groups have shortened the process and shown that rapidly expanded EBV-specific T-cells induce similar response rates.…”