About half of high-risk NB patients still die from treatment failure even after tandem HDCT/autoSCT. The major cause of treatment failure is tumor relapse. Conventional chemotherapy has been ineffective after relapse in these patients, and they cannot tolerate additional intensive treatment because they had been intensively treated previously. There has been no realistic chance for cure with conventional options alone23)
, and therefore, a new modality of treatment is warranted for these patients. In this context, allogeneic SCT (alloSCT) is being investigated as a potential curative treatment option for patients who failed previous HDCT/autoSCT because it offers a graft-versus-tumor (GVT) effect not seen in autoSCT. AlloSCT results in recovery of properly functioning immune cells that can correct any functional defects that exist in their autologous counterparts, which may provide a beneficial GVT effect. The graft-versus-leukemia (GVL) effect is a widely accepted major component of alloSCT in leukemias24)
, and there is emerging evidence for a GVT effect in solid tumors25)
. A GVT effect has also been demonstrated in patients with advanced NB who received alloSCT26
. However, regimen-related mortality following standard alloSCT with an intensive conditioning regimen may be extremely high in patients who have already been heavily treated30
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 GVL or GVT effect. This reduced regimen-related toxicity may make reduced-intensity alloSCT (RI alloSCT) especially suitable for patients at high-risk of regimen-related mortality, particularly previous recipients of tandem HDCT/autoSCT. In adults, striking GVT effects after RI alloSCT have been described in refractory breast cancer and renal cell carcinoma25)
. However, reports concerning the possible GVT effect of RI alloSCT remain very limited in pediatric solid tumors.
Although the number of studies employing RI alloSCT for NB is currently very limited, early studies suggest that this is a feasible approach that has demonstrated GVT effects that were confirmed by the regression of tumor after induction of acute graft-versus-host disease (GVHD) by withdrawal of immunosuppressive drugs or donor leukocyte infusion (DLI). For many years, HLA-matched donors were the only types of donor routinely employed, however, more recently, mismatched SCT has also proved feasible. Jubert et al.33)
applied mismatched cord blood transplantation (CBT) for the treatment of refractory/relapsed NB patients. All patients were in partial response or less than partial response at transplant. CBT was feasible; however, relapse was rapid and there was not enough time to establish a GVT effect in patients with high tumor burden. Haploidentical SCT (haploSCT) also proved to be feasible. In 2003, Inoue et al.26)
first described a boy with refractory NB who received CD34-positive haploSCT after myeloablative conditioning. The tumor ultimately regressed and the authors stressed the possibility of a GVT effect against NB. Lang et al.27)
evaluated the feasibility and toxicity of haploidentical T- and B-cell depleted RI alloSCT with high numbers of NK cells and showed the feasibility and low toxicity of this approach even in intensively pre-treated NB patients. Sung et al.34)
also reported the results of RI alloSCT for NB patients who failed previous tandem HDCT/autoSCT. Regimen-related short-term toxicity was manageable and a GVT effect was observed in 2 of 6 patients after induction of acute GVHD; however, it was not sufficiently strong to control tumor progression in patients who had a significant tumor burden at transplant.
Early studies of RI alloSCT, including haploSCT, suggest that this is a feasible approach. They also demonstrated GVT effect that was confirmed by regression of tumor after induction of acute GVHD. However, the control of GVHD by immunosuppressive drugs resulted in the reemergence of NB. GVT effect was not enough to control tumor proliferation, particularly in patients who had a significant tumor burden at transplant. However, it was difficult to effectively reduce tumor burden prior to transplant with conventional treatment modalities. Therefore, a new modality of treatment to effectively reduce tumor burden prior to transplant along with post-transplant adjuvant treatment to increase the antitumor effects is needed to improve the outcome after RI alloSCT.
For efficient reduction of tumor burden prior to RI alloSCT without significant toxicity, high-dose 131
I-MIBG treatment might be an option because it has no significant toxicity other than hematologic toxicity. Recently, investigators have incorporated high-dose 131
I-MIBG treatment into RI alloSCT and demonstrated that it is a feasible approach35
. Another approach is to develop a new salvage treatment regimen with new drugs; however, at present, an effective salvage regimen using new drugs is not available.
Stem cell source is also an important issue to maximize the GVT effect. More GVHD and probably a stronger GVT effect are expected in unrelated or mismatched SCT compared to related or matched SCT. Recently, unrelated or mismatched SCT have also proven to be a feasible approach. Therefore, in a specific subpopulation of patients, unrelated or mismatched SCT might be a preferred option, and not merely an alternative to related or matched SCT. Killer immunoglobulin-like receptor (KIR) ligand mismatched SCT is also a possible option to enhance GVT effect in NB because NB cells do not express HLA class I antigen, and therefore, can be an excellent target for NK cell alloimmunity.
Post-SCT adjuvant treatment to increase the GVT effect might be another approach. DLI or NK cell infusion after SCT and NB specific antibody treatment with or without cytokine treatment might be options to enhance the GVT effect against NB cells. NK cell- or complement-mediated immune response might be more important than T cell-mediated immune response because NB cells generally do not express class I antigen37)
Different clinical trials employing combinations of the strategies mentioned above are currently under evaluation. For example, Toporski et al.36)
incorporated high-dose 131
I-MIBG into haploSCT with T cell depleted graft, and donor leukocytes were infused if GVHD was absent. Lang et al.27)
recently proposed a multicenter study employing an anti-GD2-based immunotherapy combined with haploSCT. They reported that this approach was feasible in their pilot treatment. Pérez-Martínez et al.37)
have recently reported their experience using KIR ligand mismatched haploSCT in 3 refractory metastatic solid tumors including 1 NB. This approach was also feasible and GVT effect was demonstrated. A clinical trial that incorporates high-dose 131
I-MIBG treatment into RI alloSCT in patients who failed previous tandem HDCT/autoSCT is under evaluation at Samsung Medical Center. IL-2 infusion is administered if the tumor has progressed or persisted at 6 months after RI alloSCT. Preliminary results are encouraging. At present, we do not know which the best strategy for successful outcome is. Further study will provide an answer.