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cells survived at least temporarily
[147]
. Importantly, no increase in infec-
tious complications occurred in comparison to similarly treated historical
controls that did not receive Treg.
At the University Hospital Regensburg, we also performed a small phase I trial
using freshly isolated Treg from the initial stem cell donors in nine patients
with high disease relapse risk after SCT (M. Edinger, unpublished). At our
institution, such patients are treated preemptively with donor lymphocyte
infusions if they remain GVHD-free after the withdrawal of the prophylactic
immunosuppressive medication. Within this trial, patients first received a
Treg-enriched DLI (up to 5 × 10
6
/kg body wt) containing 50-60% FOXP3
+
cells and an additional conventional DLI at the same dose 8 weeks later if no
GVHD occurred. In this phase I study, no adverse events were observed after
Treg transfusion despite the absence of pharmacologic immunosuppression
and no patient developed early GVHD or infectious complications. Thus,
Treg transfusions seemed safe and feasible in this setting, but the study was
not designed to prove efficacy as only few patients were included and all
patients subsequently received additional conventional donor T cells.
In contrast to these safety and feasibility studies, the SCT team in Perugia
immediately performed an efficacy trial for patients undergoing haplo-
identical SCT. As in the mouse models, they enriched donor Treg cells and
cotransplanted such cell products together with CD34-selected stem cells
as the sole immunosuppressive strategy. For this purpose, they performed a
leukapheresis from the stem cell donor before starting the stem cell mobi-
lization. They enriched Treg from these leukapheresis products by the mag-
netic bead-based selection of CD25
+
cells to an average of 69% FOXP3
+
cells
and administered the Treg products to 28 patients (
n
= 24 with 2 × 10
6
/kg
body wt,
n
= 4 with 4 × 10
6
/kg body wt) 4 days before SCT. Furthermore,
they even injected up to 2 × 10
6
Tconv cells/kg body wt together with the
stem cell graft, a donor T cell dose that is expected to induce severe GVHD
in all recipients in this clinical situation. Yet surprisingly, most patients
remained free of clinically relevant acute GVHD and only 2 of 26 evaluable
patients developed greater than or equal grade 2 acute GVHD. Importantly,
Treg-treated patients seemed to reconstitute their lymphoid compartment
much more rapidly and had fewer cytomegalovirus reactivation episodes
compared to historical controls and they showed improved anti-infectious
immune responses
in vitro.
These results suggest that the concepts devel-
oped in murine transplantation models may also hold true in haploidentical
SCT in humans. Yet, these promising findings now have to be confirmed in
larger multicenter studies and a benefit in overall survival has to be shown,
as the treatment-related mortality in this trial was still high despite the low
incidence of GVHD. The authors attributed the treatment-related mortality
to the severely pretreated patient population and the toxicity of their modi-
fied conditioning regimen, as they replaced anti-thymocyte globulin with
an additional course of cyclophosphamide for the Treg trial
[148]
.
259
In vitro
expansion of Treg cells
For GVHD prevention trials Treg enrichment is achieved by the magnetic
selection of CD25-expressing cells, and sufficient numbers for a single
administration of 1-5 × 10
6
cells/kg body wt can be achieved with such
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