Expansion of T cells targeting multiple antigens of cytomegalovirus, Epstein–Barr virus and adenovirus to provide broad antiviral specificity after stem cell transplantation

Abstract

Background aims Hematopoietic stem cell transplant (HSCT) is the treatment of choice for a proportion of patients with hematologic malignancies as well as for non-malignant diseases. However, viral infections, particularly Epstein–Barr virus (EBV), cytomegalovirus (CMV) and adenovirus (Ad), remain problematic after transplant despite the use of antiviral drugs. We have shown that cytotoxic T lymphocytes (CTL) generated against CMV-pp65, EBV and Ad antigens in a single culture are capable of controlling infections with all three viruses after HSCT. Although pp65-specific CTL have proved efficacious for the control of CMV infection, several reports highlight the importance of targeting additional CMV antigens. Methods To expand multivirus-specific T cells with activity against both CMV-pp65 and CMV-IE-1, peripheral blood mononuclear cells (PBMC) were transduced with the adenoviral vector (Ad5f35-IE-1-I-pp65). After 9–12 days the CTL were restimulated with autologous EBV-transformed B cells transduced with the same Ad vector. Results After 18 days in culture nine CTL lines expanded from less than 1.5 × 107 PBMC to a mean of 6.1 × 107 T cells that recognized CMV antigens pp65 [median 273 spot-forming cells (SFC), range 47–995] and IE-1 (median 154 SFC, range 11–505), the Ad antigens hexon (median 153 SFC, range 26–465) and penton (median 37 SFC, range 1–353), as well as EBV lymphoblastoid cell lines (median 55 SFC, range 9–301). Importantly, the T cells recognized at least two antigens per virus and lysed virus peptide-pulsed targets. Conclusions CTL that target at least two antigens each of CMV, EBV and Ad should have clinical benefit with broad coverage of all three viruses and enhanced control of CMV infections compared with current protocols.

CMV promotes recipient T-cell immunity following reduced-intensity T-cell–depleted HSCT, significantly modulating chimerism status

“…With this in mind, it remains crucial to develop effective antiviral treatments that can be used in the setting of virus-naive donors, and a number of strategies are being pursued in this regard, with encouraging preliminary results. [13][14][15][16][17][18] Our data illustrate 2 further important observations that deserve consideration. First, given the apparent protective effect of recipientderived CMV-specific T cells, it is reasonable to question the potential effect of subsequent DLIs on CMV-related complications.…”

Impact of immune modulation with in vivo T-cell depletion and myleoablative total body irradiation conditioning on outcomes after unrelated donor transplantation for childhood acute lymphoblastic leukemia

“…Cytotoxic T-lymphocyte therapy with donor T cells against CMV, EBV, and adenovirus has been used successfully to prevent and treat these infections. 22,23 The major limitation of the present observational study is that choice of treatment strategy, including whether to use in vivo T-cell depletion, was at the discretion of each transplantation center and was therefore subject to bias. We also lack data on ATG or alemtuzumab pharmacokinetics, which might more accurately determine the efficacy of T-cell depletion.…”

Monoclonal Antibodies in Conditioning Regimens for Hematopoietic Cell Transplantation

“…Strategies incorporating DLI to reduce disease relapse are logical and apparently effective [89]. Strategies that potentially could help reduce the incidence of infections such as CMV are emerging and might offer added benefits to preemptive CMV treatment approaches [102]. The optimal dose and administration schedule of alemtuzumab to maintain effective GVHD prophylaxis while avoiding prolonged immune paresis remain elusive.…”