Author(s): Ifigeneia Tzannou [*] aff1 , Ann M Leen aff1
adoptive immunotherapy; hematopoietic stem cell transplantation; T cells; viral infections
Hematopoietic stem cell transplantation (HSCT) can be curative for a variety of malignant and nonmalignant hematologic conditions and congenital diseases [1-5 ]. However, serious viral infections remain a major cause of morbidity and are responsible for mortality in up to 39% [6-9 ]. An increasing array of viruses have been implicated in post-transplant infectious complications, due in part to more comprehensive patient screening using improved detection methods, but also to the extension of this therapeutic modality to higher-risk patients (i.e., individuals without a human leukocyte antigen [HLA]-matched sibling donor) who receive more extensively manipulated products and/or prolonged immunosuppression. Thus, reactivation of latent viruses including cytomegalovirus (CMV; 20-68%) [ 10,11 ], Epstein-Barr virus (EBV; 0.5-29%) [12 ], herpes simplex virus 1/2 (HSV 1/2; 80%) [12 ], human herpesvirus 6 (HHV-6; 33-48%) [11,13 ], varicella zoster virus (10-68%) [12 ], human herpesvirus 7 (HHV-7; 10-57%) [11,14 ] and BK virus (BKV; 10-25%) [15,16 ] are frequent, while infections associated with an array of community-acquired respiratory viruses, including influenza (1.3-44%) [ 17 ], parainfluenza (2-7%) [18,19 ], metapneumovirus (2.5-9%) [20 ], Adenovirus (AdV; 6-28%) [21 ] and respiratory syncytial virus (RSV; 0.3-12) [18,19 ] are increasingly reported [22-25 ]. T-cell therapies that restore virus-specific immunity in the HSCT setting are a viable alternative to the traditional and often toxic antiviral drugs. Here, we explore the immunotherapeutic strategies currently used to provide immediate and long-term antiviral protection to adult- and pediatric-HSCT patients.
Donor lymphocyte infusion
The first adoptive T-cell transfer approach utilized in the allogeneic HSCT setting involved the adoptive transfer of unmanipulated donor lymphocytes - termed donor lymphocyte infusions (DLI). DLI therapy was based on the assumption that unmanipulated lymphocytes isolated from seropositive donors should contain populations of virus-specific T cells that were able to expand in vivo and provide antiviral protection. DLIs have proven effective in treating EBV-associated post-transplant lymphoproliferative disease (EBV-PTLD) [ 26 ], an AdV urinary tract infection [27 ], CMV reactivation [28 ], HHV-6 encephalopathy [29 ] and persistent RSV pneumonia [30 ]. However, the efficacy of this approach is limited by the low circulating frequency of T cells directed against many acute viruses, while the substantially higher frequency of alloreactive T cells within the infused product significantly increases the risk of causing graft versus host disease (GvHD). Thus, in order to preserve the benefits and minimize the risks associated with DLI infusions, techniques to selectively deplete alloreactive T cells or to induce anergy have been investigated.
Selective ex vivo allodepletion
Ex vivo allodepletion involves the selective removal of T cells with alloreactive potential prior to adoptive transfer. In order to identify this particular T-cell subset, donor T cells are first exposed to recipient-derived antigen-presenting cells (APCs) including peripheral blood mononuclear cells (PBMCs), activated T cells, EBV-transformed lymphoblastoid cell lines (EBV-LCL), dendritic cells (DCs) and/or fibroblasts [31-35 ]. Subsequently, cells that are alloactivated upregulate markers such as CD25, CD69, CD71, CD134, CD137...