Biology Reference
In-Depth Information
BOX 3.1
The main modes of mHag-based adoptive
immunotherapy and vaccination strategies investigated
at different transplant centers
Adoptive immunotherapy:
• Donor-derived CTLs generated by
ex vivo
stimulation of mHag-loaded
DCs (Leiden, NL; investigation halted due to technical drawbacks)
• Recipient-derived unmodified T cells transduced with mHag-TCR (Leiden, NL)
• Donor-derived CMV-specific (Leiden, NL) - or recall antigen (tetanus-
toxoid)-specific (Utrecht, NL) - T cells transduced with mHag-TCR
Vaccination:
•
Recipient vaccination with mHag peptides (NY, USA; Hannover, Germany)
•
Recipient vaccination with mHag-peptide-loaded host DCs (Utrecht, NL).
•
Recipient vaccination with mHag-peptide-loaded donor DCs (Utrecht, NL)
•
Recipient vaccination with mHag-mRNA-loaded donor DCs (Nijmegen, NL)
mHag-based adoptive immunotherapy
47
Conceptually, treatment of recurrent malignancies is possible by adoptive
immunotherapy directed against hematopoietic-restricted mHags in a sim-
ilar setting to DLI. Indeed, it has been shown that infusion of CD8
+
as well
as CD4
+
mHag-speciic CTLs into tumor bearing subjects can effectively
eliminate the established human hematopoietic and non-hematopoietic
tumors in immune-deficient mouse models, depending on the site of
tumor localization
[92-94]
. Such experimental results also substantiate
the idea that adoptive immunotherapy directed at even a single, but highly
immunogenic mHag, may result in objective clinical responses. Adoptive
immunotherapy requires, however, the
ex vivo
generation of large num-
bers and strong cytolytic mHag-specific CTLs from the donor in a relatively
short time frame. Furthermore, the
ex vivo
generated CTLs should have
the capacity to migrate into tumor sites and to generate long-term
in vivo
memory.
Earlier studies demonstrated the feasibility of
ex vivo
generation of mHag-
specific CTLs from mHag-negative stem cell donors by repeated stimula-
tion of donor T cells with peptide-pulsed or gene-transduced DCs
[95]
.
Artificial APCs coated with MHC-mHag complexes, anti CD28 antibody
[96]
, or with CD80 and CD54
[97]
might also help to selectively enrich
mHag-specific CTLs for adoptive immunotherapy. Nonetheless, clinical
implementation of these
ex vivo
culture protocols is cumbersome and has
suffered from serious technical drawbacks
[98]
. Furthermore, the con-
sequences of long-term
in vitro
cultures are currently unknown for the
in vivo
survival of CTLs
[99]
.
Some of these drawbacks have been recently tackled by
ex vivo
stimula-
tion of tetramer-sorted mHag-specific CTLs through CD3/CD28-beads and
culturing with a combination of IL-7 and IL-15
[100]
. Also, the so-called
“TCR-transfer” approach has been studied by various groups: mHag-
specific T cells were generated by retroviral transfer of mHag-specific TCR
genes into unselected, cytomegalovirus (CMV)-specific CD8+ or tetanus
toxoid-specific CD4+ T cells
[93,95,101-103]
(
Figure 3.1
). The approach of
Search WWH ::
Custom Search