Scheduled administration of virus-specific T cells for viral prophylaxis after pediatric allogeneic stem cell transplant

Abstract

Infections with double-stranded DNA viruses are a significant cause of morbidity and mortality in pediatric patients following allogeneic hematopoietic stem cell transplantation (HSCT). Virus-specific T-cell therapies (VSTs) have been shown to be an effective treatment for infections with adenovirus, BK virus, cytomegalovirus (CMV), and Epstein-Barr virus (EBV). To date, prophylactic regimens to prevent or mitigate these infections using conventional antiviral medications provide suboptimal response rates. Here we report on a clinical trial (NCT03883906) performed to assess the feasibility of rapid manufacturing and early infusion of quadrivalent VSTs generated from stem cell donors ("donor-derived VSTs") into allogeneic HSCT recipients with minimal or absent viremia. Patients were eligible to receive scheduled VSTs as early as 21 days after stem cell infusion. Twenty-three patients received scheduled VSTs. Twenty of 23 patients had no viremia at the time of infusion, while 3 patients had very low-level BK viremia. Two developed clinically significant graft-versus-host disease (GVHD), although this incidence was not outside of expected incidence early after HSCT, and both were successfully treated with systemic corticosteroids (n = 2). Five patients were deemed treatment failures. Three developed subsequent significant viremia/viral disease (n = 3). Eighteen patients did not fail treatment, 7 of whom did not develop any viremia, while 11 developed low-level, self-limited viremia that resolved without further intervention. No infusion reactions occurred. In conclusion, scheduled VSTs appear to be safe and potentially effective at limiting serious complications from viral infections after allogeneic transplantation. A randomized study comparing this scheduled approach to the use of VSTs to treat active viremia is ongoing.

Graphical abstract

Figure 1.

Preclinical testing of VST products infused into patients on this study. (A) Fold expansion of VSTs in culture. (B) Percentage of viable cells after thawing of cryopreserved products. (C) Ratio of CD4:CD8 T cells in each product. Lines in all panels represent median values.

Figure 2.

Increase in antiviral T cells in PB of patients after receiving scheduled VSTs. (A) Absolute lymphocyte counts at infusion (pre) and 30 days after VST infusion (post) in all recipients. (B,C) Baseline (preinfusion) and peak (any point postinfusion) quantitated antiviral T cells as determined by interferon-γ ELISpot in recipients without any viremia and with viremia that cleared without intervention, respectively. (D) Representative examples of ELISpots from nontreatment failure patients with viremia that resolved with corresponding curves showing the kinetics of viremia.