Biology Reference
In-Depth Information
FIGURE 3.1
mHag-based immunotherapy strategies and pos-
sible hurdles yet to overcome. Main immunotherapy
options with mHags are adoptive immunotherapy
with donor recall antigen-specific T cells transduced
with mHag-TCR genes and therapeutic vaccination of
patients with mHag (peptide or gene)-loaded dendritic
cells (DCs). Both options are expected to provide
an effective immunity which attacks and eliminates
mHag-positive tumor cells. The challenges toward
achieving an effective anti-tumor immunity are:
[1]
to
establish a long-term memory that can be boosted (by
recall antigen loaded DCs);
[2]
to overcome immune
suppression by natural Tregs;
[3]
to overcome immune
suppression by mHag-specific Tregs;
[4]
to overcome
cytokine or receptor-mediated immune suppression
mediated by tumor cells and microenvironment;
[5]
to
overcome tumor microenvironment-induced immune
resistance, which renders tumor cells resistant toward
lysis by cytotoxic T cells (CTLs).
48
inserting mHag-specific TCRs into virus-
[102]
or recall antigen- specific
T cells
[93,103]
is particularly interesting, since such strategies may enable
the
in vivo
boosting of therapeutical T cells via their endogenous TCRs.
Nonetheless, the TCR-transfer approach also carries a number of risks such
as the development of potential harmful neoreactivity inducing allo- and
auto-reactivity or even lethal GVHD due to mispairing of the alpha and
beta chains of the transduced and native TCR
[104]
. Finally, it is important
to note that it is in any case not appropriate to introduce mHag TCRs into
unselected donor T cells due to the risk of GVHD induction via the recog-
nition of ubiquitous mHags via their native TCRs. The numerous efforts to
improve the safety of the TCR-transfer approach is, however, beyond the
scope of this chapter. Perhaps the main logistical drawback of the clinical
potential of mHag-specific therapy in an adoptive immunotherapy setting
is its technical difficulty and labor intensity to generate TCR-transduced
CTLs simultaneously against various mHags. Consequently, such adoptive
immunotherapy strategies are usually executed by targeting only one or at
most two defined mHags and are therefore difficult to complete within a
reasonable time frame, especially in a single center trial.
Mainly due to this reason, until now only one small clinical trial has been
conducted, in which seven leukemia patients were infused with
ex vivo
-
expanded mHag-specific CTLs
[88]
. The therapy seemed to augment GVT,
but there was no long-term persistence of the transferred T cells and all
patients eventually relapsed. Furthermore, toxicity was observed as well,
probably because the mHags were not strictly selected for hematopoietic-
restricted tissue expression.
mHag-based vaccination strategies
Over the past decade, therapeutic vaccination with TAAs has emerged as
a promising approach for patients with solid cancers, especially after the
development of clinical grade protocols for
ex vivo
culture of DCs
[105]
.
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