Adoptive T cell therapy for the treatment of viral infections

Allogeneic hematopoietic stem cell transplantation (HSCT) is curative for a variety of malignant and non-malignant hematological disorders. However, many features of transplantation, including the immunosuppressive drugs administered as pre-transplant conditioning as well as the agents administered post-transplant to prevent graft versus host disease (GvHD), serve to compromise the host immune system leaving patients vulnerable to an array of latent and lytic viruses including cytomegalovirus (CMV), adenovirus (AdV), Epstein-Barr virus (EBV), human herpes virus 6 (HHV6) and BK virus (1-4). Conventional therapy for these infections has relied largely upon the use of small molecule antiviral drugs such as ganciclovir (for CMV and HHV6), cidofovir (for AdV and BK) and foscarnet (for CMV) (5-7). However, prolonged use can lead to toxic side effects such as bone marrow suppression (8) and nephrotoxicity (9), as well as the emergence of drug-resistant mutants (10) (e.g., ganciclovir-resistant CMV). Furthermore, since none of these agents improve endogenous virus-specific T cell (VST) immunity, infections frequently recur upon treatment termination, highlighting the need for novel therapies. This has prompted a number of groups, including our own, to evaluate the therapeutic benefits associated with the adoptive transfer of in vitro expanded VSTs and since the mid-1990s we have undertaken a series of clinical trials using stem cell donor-derived T cell lines targeting one or more of these clinically problematic viruses (11,12). Our recent study (13) reports on our efforts to streamline our VST manufacturing platform, enabling the generation of clinical grade VSTs with specificity for AdV, CMV, EBV, BK virus and HHV6. In this editorial we will briefly describe the innovations that allowed the production of this broad spectrum anti-viral product and discuss the potential for extending this approach beyond the HSCT setting.