Graft-versus-tumor effect in a patient with advanced neuroblastoma who received HLA haplo-identical bone marrow transplantation

Abstract

Summary:A 5-year-old boy received CD34-positive HLA haploidentical bone marrow transplantation from his father as treatment for refractory advanced neuroblastoma. He had residual disease in the para-aortic lymph nodes and multiple bones after the transplant. However, all of his residual disease had disappeared completely 3 years later. He developed grade I acute graft-versus-host disease (GVHD) but had no symptoms of chronic GVHD or any other complications. This case demonstrates the possibility of a graft-versus-tumor effect against neuroblastoma by HLA-mismatched allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplantation (2003) 32, 103-106. doi:10.1038/sj.bmt.1704070 Keywords: neuroblastoma; CD34; graft-versus-tumorThe therapeutic effect of donor lymphocyte infusion (DLI) for relapsed CML after allogeneic bone marrow transplantation (BMT) has been established, 1 and the immunotherapeutic aspect of allogeneic hematopoietic stem cell transplantation (HSCT) has recently been emphasized, especially since the introduction of a reduced-intensity preparative regimen followed by allogeneic HSCT. Successful nonmyeloablative allogeneic PBSCT for metastatic renal cell carcinoma was reported by Childs et al. 2Although similar trials have been ongoing for many kinds of solid tumors, 3 a graft-versus-tumor (GVT) effect against neuroblastoma (NBL) has not been reported. We describe a patient with refractory advanced NBL who showed tumor regression over 3 years after allogeneic SCT, despite persistent metastatic lesions after SCT. This is the first case suggesting a GVT effect in neuroblastoma. Case reportA 4-year-old boy was diagnosed with stage 4 NBL (INSS: international neuroblastoma staging system) involving his right adrenal gland, multiple para-aortic lymph nodes, bone marrow and multiple bones in April 1997. Tumor markers were abnormally elevated at the diagnosis. Urinary vanillymandelic acid (VMA) and homovanillic acid (HVA) were 313.6 (upper limit 16.0) and 251.0 (upper limit 35.0) mg/mg creatinine, respectively. Serum neuron-specific enolase (NSE) was beyond the range of measurement (41000 ng/ml, upper limit 10.0). The response for induction chemotherapy (modified A1: 4 vincristine, cyclophosphamide, pirarubicin and cisplatin, CPT-11) was partial and double megatherapy was performed (Figure 1) according to our strategy. The first megatherapy, consisting of ifosfamide (12.5 g/m 2 ) and LPAM (210 mg/m 2 ) followed by autologous CD34-positive BM cell rescue, was given in November 1997. CD34-positive cells were collected by the Isolex system (NEXELL, Deerfield, IL, USA) and cryopreserved during repeated first-line chemotherapy aimed at purging of tumor cells. Extirpation of the primary tumor with ipsilateral nephrectomy and biopsy of the para-aortic lymph nodes and a bone marrow were carried out after the first megatherapy in December 1997. Viable NBL cells were found histologically in the resected tumor, sampled lymph nodes and a bone specimen. Prognostic evaluations of the resected tumors were as ...

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

“…2,3 Given a higher rate of TRM with allogeneic hematopoietic SCT and the occurrence of GVHD, autologous is the preferred therapeutic option for those in need of hematopoietic SCT: only 25 allogeneic transplantations were therefore performed for neuroblastoma in Europe in 2006. [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.…”

Successful tandem (autologous-cord blood) SCT in advanced neuroblastomas with highly amplified MYCN

“…Recently, there were some clinical reports of a GVT effect against neuroblastoma as follows: minimal residual disease in BM disappeared after the cessation of immunosuppressant 13 or after donor lymphocyte infusion, 14 and abnormal uptake on MIBG imaging disappeared 3 years after haploidentical PBSCT from the patient's father. 12 In our case 1, the urinary HVA level became normal at 3 years after uCBT. During reconstitution of the immune system after CBT, T-cell recovery is very slow, but functional NK cells recover within 1 month, 15,16 suggesting that alloreactive NK cells might have an important role in the GVT effect particularly in the early phase after CBT.…”

“…10,11 However, allo-SCT was recently reported to induce a graft-versus-tumor (GVT) effect against advanced neuroblastoma in some cases. [12][13][14] We performed a tandem transplantation consisting of autologous PBSCT (auto-PBSCT) followed by allogeneic cord blood transplantation (CBT) in three consecutive pediatric patients with stage 4 neuroblastoma exhibiting high MYCN amplification. They are alive without disease recurrence for 37-60 months after CBT.…”

Fenretinide sensitizes multidrug-resistant human neuroblastoma cells to antibody-independent and ch14.18-mediated NK cell cytotoxicity

“…Unfortunately, alloreactive T-cells of the donor can recognize the recipient cells as "foreign" and attack them, resulting in the development of "graft versus host disease" (GvHD) and transplantation related mortality. Interestingly, GvHD is often associated with a graft versus tumor (GvT) effect, in which alloreactive T-cells induce destruction of the tumor cell [57].…”