Challenges of T cell therapies for virus-associated diseases after hematopoietic stem cell transplantation

IMPORTANCE OF THE FIELD: Hematopoietic stem cell transplantation (HSCT) is the treatment of choice for many hematological malignancies and genetic disorders. The majority of patients do not have a human leukocyte antigen (HLA) identical sibling donor, and alternative stem cell sources include HLA-matched or mismatched unrelated donors and haploidentical related donors. However, alternative donor HSCT are associated with three major complications i) graft rejection; ii) graft-versus-host disease (GvHD); and iii) delayed immune reconstitution leading to viral infections and relapse. AREAS COVERED IN THIS REVIEW: Graft rejection and the risk of GvHD can be significantly reduced by using intensive conditioning regimens, including in vivo T cell depletion as well as ex vivo T cell depletion of the graft. However, the benefits of removing alloreactive T cells from the graft are offset by the concomitant removal of T cells with anti-viral or anti-tumor activity as well as the profound delay in endogenous T cell recovery post-transplant. Thus, opportunistic infections, many of which are not amenable to conventional small-molecule therapeutics, are frequent in these patients and are associated with significant morbidity and high mortality rates. This review discusses current cell therapies to prevent or treat viral infections/reactivations post-transplant. WHAT THE READER WILL GAIN: The reader will gain an understanding of the current state of cell therapy to prevent and treat viral infections post-HSCT, and will be introduced to preclinical studies designed to develop and validate new manufacturing procedures intended to improve therapeutic efficacy and reduce associated toxicities. TAKE HOME MESSAGE: Reconstitution of HSCT recipients with antigen-specific T cells, produced either by allodepletion or in vitro reactivation, can offer an effective strategy to provide both immediate and long-term protection without harmful alloreactivity.