Donor-derived CMV-specific T cells reduce the requirement for CMV-directed pharmacotherapy after allogeneic stem cell transplantation

Abstract

Key Points• Infusion of CMV-specific T cells early posttransplant does not increase acute or chronic graft-versus-host disease.• CMV-specific T cells early posttransplant reduce the need for pharmacotherapy without increased rates of CMV-related organ damage.We investigated the use of adoptively transferred donor-derived cytomegalovirus (CMV) specific cytotoxic T lymphocytes (CTL) as immune reconstitution postallogeneic transplant in a phase 2 study. Fifty patients were infused with a single dose of 2 3 10 7 cells/m 2 after day 28 post-transplant. Twenty-six patients reactivated CMV posttransplant (only 5 post-CTL infusion) and 9 required therapy with ganciclovir or foscarnet (only 1 post-CTL infusion).There was 1 case of fatal CMV disease, attributable to high levels of antithymocyte globulin at the time of T cell infusion. We compared the patients in the phase 2 study with a group of contemporaneous controls also treated at the trial centers. There was no increase in acute or chronic graft-versus-host disease attributable to CTL infusion; overall and progressionfree survival were similar in both groups. There was a reduction in the percentage of patients who required CMV directed antiviral therapy (17% vs 36%, P 5 .01) and in the total number of treatment days in the cohort receiving CTL (3.4 days vs 8.9 days, P 5 .03) without a reduction in CMV reactivation rates. We postulate that adoptively transferred cells are able to expand in response to viral antigen, limit viral replication, and prevent progression to tissue infection. This study was registered on the Australian Clinical

Acute GVHD results in a severe DC defect that prevents T-cell priming and leads to fulminant cytomegalovirus disease in mice

“…Recent clinical studies have shown that infusion of CMVspecific T cells early posttransplant does not appear to increase GVHD, but reduces the requirement for CMV-directed pharmacotherapy. 11 Our adoptive transfer studies in a controlled model system support these findings and demonstrate that there is no difference in the efficacy of antiviral CD8…”

“…Indeed, CMV-specific CD8 1 T cells can be expanded in vitro and adoptively transferred to treat established CMV disease refractory to antiviral therapy, [15][16][17] or to reduce the need for antiviral pharmacotherapy. 11 Although this approach confirms the ability of appropriately activated T cells to limit viral replication, the cellular networks controlling virus after transplantation are poorly understood. In addition, it is clear that in the presence of GVHD, the ability to control CMV is dramatically inhibited, 5 but the relevant mechanisms remain unclear.…”

“…14,40 This concept has been advanced by recent studies showing that administration of virus-specific T cells reduces the need for antiviral pharmacotherapy. 11 Here, we show that polyclonal antigen-experienced T cells from CMV immune donors bypass the defects in DC priming and protect from CMV disease in a GVHD setting. In a nonhuman primate model, antigen-specific CD8 1 T-cell clones derived from central memory T cells showed preferential longevity after adoptive transfer, compared with effector memory T cells.…”

“…5,6 The control of CMV infection requires the concerted activities of innate and adaptive immune effectors, 7 with T-cell-mediated immunity critical to control CMV replication over time and to resolve disease arising from viral reactivation. 8 Data in the BMT setting demonstrate that the recovery from CMV disease correlates with reconstitution of the CD8 1 T pool, [9][10][11][12][13][14] and provide independent evidence for the crucial role of CD8 1 T cells in controlling CMV infection. Indeed, CMV-specific CD8 1 T cells can be expanded in vitro and adoptively transferred to treat established CMV disease refractory to antiviral therapy, [15][16][17] or to reduce the need for antiviral pharmacotherapy.…”

Treatment of CMV infection after allogeneic hematopoietic stem cell transplantation

“…One of the most significative experience on HSCT patients who received donor CMV-VSTCs and compared with a control group was reported in 2013 [96]. The endpoint was to evaluate if prophylaxis with CMVspecific T cells could provide short-and long-term protection against CMV infection.…”