INTRODUCTION
Neuroblastoma (NB) is the most common extracranial solid tumor in children. Although
the prognosis of lowand intermediate-risk NB with conventional treatment modalities
is excellent, the prognosis of high-risk NB with conventional treatment alone is very
poor. The current standard treatment for high-risk NB consists of induction treatment
(conventional chemotherapy and surgery with or without local radiotherapy), high-dose
chemotherapy and autologous stem cell transplantation (HDCT/autoSCT) as a consolidation
treatment, and 13-cis-retinoid acid to reduce relapse from minimal residual disease.
However, the event-free survival rates are only 30-40%, which is unsatisfactory. For
this reason, a few clinical trials of tandem HDCT/autoSCT, high-dose 131I-meta-iodobenzylguanidine
(MIBG) treatment incorporated into HDCT/autoSCT, and anti-GD2 treatment after HDCT/autoSCT,
are currently underway to improve the survival of high-risk NB patients. Furthermore,
because about half of high-risk NB patients still die from treatment failure, allogeneic
SCT (alloSCT) is being investigated as a potential curative option.
AlloSCT AFTER RELAPSE
Conventional chemotherapy is ineffective in patients who failed treatment, and they
cannot tolerate additional intensive treatment because they have previously received
intensive treatment. Therefore, in these patients, there is no realistic chance for
cure using conventional treatment options alone. For this reason, alloSCT is being
investigated as a potential curative treatment option, because it offers a graft-versus-tumor
(GVT) effect not observed in autoSCT. Although a GVT effect has been demonstrated
in patients with advanced NB who received alloSCT [1], regimen-related mortality following
standard alloSCT with an intensive myeloablative conditioning regimen may be extremely
high in patients who have already been heavily treated.
REDUCED-INTENSITY AlloSCT
In recent years, several groups of investigators have developed reduced-intensity
conditioning regimens that lead to engraftment of donor lymphoid and hematopoietic
stem cells without the extra-hematopoietic toxicities of standard myeloablative conditioning,
while conserving the graft-versus-leukemia (GVL) or GVT effect. The reduced regimen-related
toxicity may make reduced-intensity alloSCT (RI alloSCT) particularly suitable for
patients at high-risk of regimen-related mortality, especially previous HDCT/autoSCT
recipients. In adults, striking GVT effects after RI alloSCT have been described in
refractory breast cancer and renal cell carcinoma [2]. Currently, the number of studies
employing RI alloSCT for NB is very small. However, early studies have suggested that
it is a feasible approach and have shown GVT effects, which were confirmed by tumor
disappearance after induction of acute graft-versus-host disease (GVHD) through withdrawal
of immunosuppressive drugs or donor leukocyte infusion. However, control of GVHD using
immunosuppressive drugs caused NB reappearance. The GVT effect could not control tumor
proliferation, particularly in patients with a significant tumor burden at transplantation.
Furthermore, it is difficult to effectively reduce the tumor burden prior to transplantation
using conventional treatment modalities. Therefore, a new treatment modality to effectively
reduce tumor burden prior to transplantation, as well as a posttransplant adjuvant
treatment to increase the GVT effect are needed to improve the outcome after RI alloSCT.
REDUCTION OF TUMOR BURDEN PRIOR TO RI AlloSCT
Because the GVT effect was not sufficient to prevent tumor progression in patients
with significant tumor burdens, to effectively reduce tumor burden prior to transplantation,
a new treatment modality is needed to improve the outcome after RI alloSCT. Unfortunately,
an effective salvage regimen after relapse is not yet available. However, high-dose
131I-MIBG treatment might be an option for efficient reduction of tumor burden prior
to RI alloSCT, because it has no significant toxicity other than hematologic toxicity,
which can be overcome by alloSCT. Since investigators have successfully incorporated
high-dose 131I-MIBG treatment into HDCT/autoSCT, a few investigators have begun to
incorporate high-dose 131I-MIBG treatment into RI alloSCT and have shown that it is
a feasible approach (Fig. 1) [3, 4].
STEM CELL SOURCE
Stem cell source is also an important issue to enhance the GVT effect. For many years,
HLA-matched donors were the only types of donor routinely employed; however, recently,
mismatched SCT was also shown to be feasible. Stronger GVHD and possibly stronger
GVT effects are expected in unrelated or mismatched SCT than in related or matched
SCT. Therefore, unrelated or mismatched SCT might be a preferred option, and not an
alternative to related or matched SCT in specific subpopulations of patients, such
as those with recurrent NB. Killer cell immunoglobulin-like receptor (KIR) ligand-mismatched
SCT is also a possible option to enhance the GVT effect in NB, because NB cells do
not express HLA class I antigens; therefore, NB cells could be an excellent target
for NK cell alloimmunity.
POST-SCT ADJUVANT TREATMENT
Post-SCT adjuvant treatment might be another approach to increase the GVT effect.
Donor leukocyte or NK cell infusion, NB-specific antibody treatment, or cytokine treatment
after SCT might be options for enhancing the GVT effect against NB cells. The NK cell-
or complement-mediated immune response might be more important than the T cell-mediated
immune response because NB cells generally do not express HLA class I antigens. Recently,
Pérez-Martínez et al. reported their experience using KIR ligand-mismatched haploidentical
SCT for 3 refractory metastatic solid tumors, including 1 NB [5]. This approach was
feasible, and the GVT effect was also demonstrated.
CURRENT CLINICAL TRIALS EMPLOYING RI AlloSCT
A few different clinical trials employing combinations of the strategies mentioned
above are currently underway (Table 1) [6-9]. Although the number of patients enrolled
is small and follow-up duration is short, the preliminary results are encouraging.
However, at present, we do not know which is the best strategy for achieving a successful
outcome. Further studies will yield an answer.
AlloSCT FOR NEWLY DIAGNOSED HIGH-RISK NB
In the 1980s and the early 1990s, alloSCT was used as an alternative to autoSCT when
autologous bone marrow had not been cleared of tumor or was impossible to harvest.
Both the Children's Cancer Group and the European group reported no difference in
relapse between those treated with autoSCT and alloSCT, but they reported a higher
toxic death rate in the group treated with alloSCT. Since then, alloSCT has been largely
abandoned. However, interest in alloSCT has been recently renewed by successful reports
of RI alloSCT in solid tumors, and some promising experimental studies demonstrated
a measurable antitumor immune response against NB. Recently, as an alternative to
autoSCT, a few groups have studied alloSCT in an attempt to harness an immunotherapeutic
effect. Early studies of alloSCT in children with newly diagnosed high-risk NB suggest
that it is a feasible approach that may improve outcome. Colleagues at Nagoya University
developed a novel SCT protocol to treat newly diagnosed very high-risk NB patients;
KIR ligand-mismatched cord blood SCT is given after autoSCT. This novel prospective
study is based on the hypothesis that the immunological effects of alloSCT will be
most beneficial in children with minimal tumor burden early in the disease process
prior to relapse.
CONCLUSION
Although RI alloSCT was shown to be feasible in patients who failed previous treatment,
alloSCT for recurrent or high-risk NB remains investigational, and there are still
many issues to be resolved. Therefore, at present, alloSCT is reserved for specific
clinical trials assessing its immunomodulatory effect even though the advent of RI
alloSCT has provided the expectation that it will reduce treatment-related mortality
and allow for the detection of a therapeutic benefit.