High-Dose Iodine-131-Metaiodobenzylguanidine with Haploidentical Stem Cell Transplantation and Posttransplant Immunotherapy in Children with Relapsed/Refractory Neuroblastoma

Abstract

We evaluated the feasibility and efficacy of using high-dose iodine-131-metaiodobenzylguanidine ((131)I-MIBG) followed by reduced-intensity conditioning (RIC) and transplantation of T cell-depleted haploidentical peripheral blood stem cells (designated haplo-SCT) to treat relapsing/refractory neuroblastoma (RRNB). Five RRNB patients were enrolled: 4 with relapse (3 after autologous SCT) and 1 with induction therapy failure. The preparative regimen included high-dose (131)I-MIBG on day -20, followed by fludarabine (Flu), thiotepa, and melphalan (Mel) from day -8 to -1. Granulocyte-colony stimulating factor (G-CSF)-mobilized, T cell-depleted haploidentical paternal stem cells were infused on day 0 together with cultured donor mesenchymal stem cells. A single dose of rituximab was given on day +1. After cessation of short immunosuppression (mycophenolate, OKT3), 4 children received donor lymphocyte infusion (DLI). (131)I-MIBG infusion and RIC were well tolerated. All patients engrafted. No primary acute graft-versus-host disease (aGVHD) was observed. Four children developed aGVHD after DLI and were successfully treated. Analysis of immunologic recovery showed fast reappearance of potentially immunocompetent natural killer (NK) and T cells, which might have acted as effector cells responsible for the graft-versus-tumor (GVT) effect. Two children are alive and well, with no evidence of disease 40 and 42 months after transplantation. One patient experienced late progression with new bone lesions (sternum) 38 months after haplo-SCT, and is being treated with local irradiation and reinstituted DLI. One patient rejected the graft, was rescued with autologous backup, and died of progressive disease 5 months after transplantation. Another child relapsed 7 months after transplantation and died 5 months later. High-dose (131)I-MIBG followed by RIC and haplo-SCT for RRNB is feasible and promising, because 2 of 5 children on that regimen achieved long-lasting remission. Further studies are needed to evaluate targeted therapy and immune-mediated tumor control in high-risk neuroblastoma.

Engraftment of unrelated cord blood after reduced-intensity conditioning regimen in children with refractory neuroblastoma: a feasibility trial

“…Indeed, transplanting patients with low minimal residual disease has been shown to be the best approach to take advantage of post transplant allogenicity. 11,32 Furthermore, the immunosuppressive prophylactic regimen was intensive, as exemplified by the absence of GVHD and the occurrence of a post transplant lymphoproliferative disease in one patient. We choose to use rabbit antithymocyte globulin in the conditioning regimen to maximize the NK cell GVT effect.…”

“…35 Finally, additional post transplant immunotherapy should be considered in future trials based on this combined RIC-UCBT approach. 11 Donor lymphocyte infusion is unavailable after UCBT, but several other modalities are under investigation to increase the GVT effect of allogeneic transplantation, as NK cell activation, 9,12 minor histocompatiblity Ag targeting 13 and the use of cytokines such as IL-2, IL-7, IL-15, GM-CSF and IFN-a. [14][15][16][17] In this model, we observed that NK cell recovered earlier than T-cell counts.…”

“…[14][15][16][17] Allogeneic hematopoietic transplantation thus appears to be not only an immunotherapeutic modality, but also as a platform for subsequent immunotherapy. 1,11,18 Second, reduced-intensity conditioning regimen (RIC) followed by PBSCT has been shown to induce rapid donor chimerism in adult patients with solid tumors, thereby providing a GVT effect without the toxicity of a myeloablative preparative regimen. 1 Third, partially HLA-mismatched unrelated cord blood transplantation (UCBT) has been shown in childhood hematological malignancies to have outcomes similar to those of HLAmatched BMT.…”

“…[4][5][6][7][8][9] However, progress has been made in allogeneic transplantation both from a better understanding of immunogenicity and decreased transplant toxicity. First, it has been shown that the GVT effect of allogeneic transplantation may be enhanced by several therapeutic modalities: rapid immunosuppression withdrawal, donor lymphocyte infusion, 10,11 natural killer (NK) cell alloreactivity, 9,12 minor histocompatiblity Ag targeting. 13 IL-2, IL-7, IL-15, GM-CSF and IFN-a are being examined to enhance this GVT effect.…”

Reduced‐intensity allogeneic stem cell transplantation for children with neuroblastoma who failed tandem autologous stem cell transplantation

“…Yanik et al [27] and Matthay et al [28] demonstrated that highdose 131 I-MIBG treatment could feasibly be incorporated into HDCT/autoSCT. High-dose 131 I-MIBG treatment has been recently used to reduce tumor burden prior to alloSCT [29,30]. A strategy employing a post-transplant adjuvant treatment to increase the antitumor effect might be another approach to improve the outcome.…”