Biology Reference
In-Depth Information
Analogous to these approaches, a number of transplant centers have
recently started to evaluate therapeutic vaccination of recipients with
hematopoietic mHags as an alternative to adoptive immunotherapy. Vac-
cination may offer objective advantages because the
in vivo
boosting
of mHag-specific T cells may generate more relevant CTLs than
ex vivo
generated CTLs which frequently lack the expression of proper homing
receptors and seemingly do not possess the capacity for long-term
in vivo
persistence. The main logistical advantage of vaccination above adoptive
immunotherapy is the relative convenience to expand vaccination trials by
inclusion of several mHags and by conducting multicenter trials.
Since the optimal mode of vaccination to effectively boost a GVT-associated
mHag-specific CTL response is not yet determined, various modes of vac-
cination are currently being evaluated. These strategies are briefly outlined
below. Notably, no results have been reported yet from these recently initi-
ated clinical phase I/II trials.
mHag-peptide vaccination
In this strategy, patients who do not enter complete remission after DLI
are vaccinated with the peptides of hematopoietic mHags to boost the
mHag-specific donor T cells that have already been primed by host APCs.
Current clinical trials evaluate the vaccination with HA-1 and HA-2 pep-
tides, since these mHags are highly immunogenic, and their emergence
and
in vivo
expansion after DLI strongly correlates with the induction of
complete remissions. To increase the safety of vaccination, mHag pep-
tides are injected into patients with a high level of donor chimerism,
which indicates the replacement of host APCs by that of the mHag-
negative donor.
49
Therapeutic vaccination with mHag-peptide-loaded host
or donor DCs
Recently, we have started a new clinical trial in which DLI-unresponsive
multiple myeloma (MM) patients are treated with a second DLI in combi-
nation with host DCs loaded with relevant hematopoietic mHags including
HA-1, HA-2, ACC-1, ACC-2 and LRH-1 (personal communication Lokhorst,
Mutis, Goulmy, Hambach). This approach is unique because it uses host
DCs rather than donor DCs, the latter generally considered as a safer
choice. The rationale for the choice of host DCs was three fold: (i) host APCS
are crucial, not only for the development of GVHD, but also for an effective
GVT response
[106-108]
; (ii) in two previous clinical trials, the vaccination
of the patients with peptide unloaded host DCs in combination with DLI-
induced objective anti- host T-cell responses but no GVHD
[109]
; and (iii) a
number of experimental and clinical observations suggests that a subclini-
cal GvH reactivity against broadly expressed (HLA class II restricted) mHags
may provide the necessary signals for licensing of the mHag-specific CTLs
induced by mHag-loaded DCs
[71]
. The results of this clinical trial are there-
fore highly relevant for future studies. Next to this approach, new trials are
now also including patients with various hematological malignancies to
apply mHag-specific vaccination after HLA-identical, mHag-mismatched
transplantation using mHag-peptide or mRNA-loaded donor DCs. These
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