Antiviral cell therapy: is this the future?

Abstract

In this issue of Blood, Leen and colleagues report the first multicenter trial of third-party viral-specific T cells (VSTs) for the treatment of 50 patients with refractory viral infections (cytomegalovirus, adenovirus, and Epstein-Barr virus) after stem cell transplantation.¹

How is this paper different from the other articles on cell therapy for viral diseases published recently in Blood^2,3 and in other journals?^4,5 First, it is a multicenter study: the VST lines were generated in vitro at Baylor College of Medicine, but besides being administered at Baylor, the lines were shipped to and used in another 6 participating centers. Second, it is a therapeutic trial (as opposed to a trial using prophylactic treatment³); it is the largest study showing therapeutic use of the multi-VSTs developed by the Baylor group.⁶ Previous publications by these investigators have shown the prophylactic efficacy of bivirus (adenovirus and Epstein-Barr virus) cell lines in extremely immunocompromised children who had received transplants,² but this is the first time that so many patients with a variety of refractory viral infections were treated with the trivirus VSTs. Third, the fear of graft-versus-host disease (GVHD) caused by alloreactivity potentially present in the infused VSTs did not materialize (GVHD developed in only 8 patients, de novo in 2 patients, recrudescence in 6 patients, and grade 3 in only 1 patient), confirming previous observations.⁷ However, the most important feature is that the VSTs used were off-the-shelf, only partially HLA-matched cell lines previously generated from third party donors (the degree of HLA matching varied between 1 out of 6 and 4 out of 6 times); suitable cell lines were found for 90% of the screened patients with a small bank of only 32 lines. Finally, the fact that the efficacy was higher than 70% for the 3 viruses targeted and was persistent in 89% of the patients makes it even more compelling. This study clearly gets us closer to a practical therapeutic option for patients with refractory viral infections following allogeneic stem cell transplantation.

Is this the future of cell therapy for viral infections? It might well be, if a large-enough cell-line bank could be created. The different strategies to obtain cells with antiviral activity and their potential problems have been reviewed.⁸ The 2 competing options are separating the preexisting (and low-frequency) VSTs from donors by a variety of methods^4,5 or generating them in vitro.⁶ The advantage of the first method is that it may be fast; the disadvantage is that sometimes it may impossible for either logistical reasons (donor not available) or technical reasons (VSTs too low to detect or separate). The advantages of the VSTs generated in vitro include obtaining the desired antiviral specificity regardless of preexisting immunity and potentially treating several infections (and maybe even the malignant disease⁹) simultaneously. The disadvantage is time. Even with improved rapid expansion methods, at least 10 days separate the time it is decided that a cell line is needed and the infusion of the VSTs, usually 2 weeks or more.¹⁰ Depending on the clinical situation, time may not be available.

Prebanked, partially HLA-matched VSTs seem to offer significant advantages. If the lack of GVHD is confirmed in further studies, this approach will likely become the preferred first choice because it provides immediate efficacy and does not preclude obtaining cells from the stem cell donors by any of the other 2 methods, although the efficacy of the third-party VSTs seems already very promising.

The only caveat (which may be significant) is whether these VSTs will perform as effectively in the presence of more immunosuppression. The patients included in this study represent a highly selected subset of all of those who went on to have viral infections: patients were excluded if they had active, acute GVHD grades II to IV; had received T-cell–depleting monoclonal agents like anti-thymocyte globulin or alemtuzumab; or were receiving more than 0.5 mg/kg/day of prednisone. Even under these relatively favorable immunologic circumstances, 10 of the 50 patients died of viral infections. In practice, it is common for viral reactivation to occur in the midst of GVHD actively treated with higher doses of steroids and other immunosuppressive agents, which may affect both the efficacy and safety of the VSTs. These concerns, as well as the myriad of immunologic topics brought up by these data (eg, differential effects of the same VSTs on different viruses in different patients, antiviral activity in the absence of detectable circulating antiviral T cells) will be addressed in future trials. After this study, the promise of effective cellular therapy for refractory viral infections seems closer than ever.