Tumor-associated antigens - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 154

the immune response that is elicited may overlap with antigens that are
presented on normal tissue, and therefore may lead to undesired autoim-
munity or tolerance. To demonstrate the safety of transfected DCs, van
Driessche et al. administered increasing doses of WT1-transfected DCs
to patients with AML in a phase I clinical trial and showed minimal side
effects with this approach [81] . In a phase I/II clinical study, Van Tandeloo
et al. showed the efficacy of WT1 mRNA-electroporated DCs in prevent-
ing relapse in 5 of 10 AML patients, with some responses lasting at least 3
years [82] .

Another approach that bypasses the difficulties that may be encountered
by cell transfection takes advantage of the physiological abilities of DCs
to cross-present antigen; cross-presentation is a process by which APCs
take up antigens and present them on MHC class I [83] . Leukemia derived
and normal DCs have been shown to efficiently cross-present TAAs from
leukemia blasts [1,84] . Although most of these studies were performed
in animal models and in vitro , there are a few reports that have shown
the safety and efficacy of this approach. Lee et al. administered leuke-
mia lysate-pulsed autologous monocyte-derived DCs to two patients
with AML [85] . Although immunological response was detected in both
patients, no clinical responses were achieved. In another report, Hus et al.
administered autologous DC pulsed with tumor cell lysates to 12 patients
with CLL. Clinical and hematological responses were reported in eight
patients; four patients demonstrated immunological responses with an
increase in TAA-specific CTL and a decrease in CD4 + CD25 + FOXP3 + T
regulatory cells [86] .

156

Enhancing effector cells

Since the process of generating an immune response depends on the
expansion of T cells with a high-affinity T-cell receptor (TCR) for the tar-
get antigen/HLA complex, and because detecting T cells with distinct anti-
gen-specific TCRs has been associated with favorable clinical outcomes
[87] , generating T cells with high-avidity antigen-specific TCRs has shown
promising results [88] . In the setting of metastatic melanoma, Morgan
et al. administered melanoma-associated antigen recognized by T cells-1
(MART-1) specific TCR-transduced peripheral blood lymphocytes to 15
patients with metastatic melanoma [89] and reported long-term remissions
in two patients. Similar promising results were also shown for gp 100 mela-
noma antigen and NY-ESO-1 cancer testis antigen [90,91] . TCR-transduc-
tion approaches have also been applied to leukemia, specifically targeting
WT1 antigen in preclinical studies [92] .

Despite promising results, a major limitation of this technology is the
mispairing of the introduced TCR with the endogenous TCR, which reduces
the expression of the transduced TCR and can generate TCR that causes
autoimmunity. In a recent study, Ochi et al. developed a system for silenc-
ing endogenous TCR in order to enhance the expression of WT1-transduced
TCR [93] . In that study, T cells transduced with silencing TCR genes demon-
strated specific antileukemia activities, while sparing normal hematopoi-
esis. Although promising, these methodologies are currently being further
investigated for the therapy of hematological malignancies.