Evaluation of the efficacy of using allogenic natural killer cells in the treatment of children with recurrent neuroblastoma after hematopoietic stem cell transplantation
Evaluation of the efficacy of using allogenic natural killer cells in the treatment of children with recurrent neuroblastoma after hematopoietic stem cell transplantation
Introduction: Neuroblastoma is the most common tumor seen in the first year of life, and is the most frequent extra cranial solid tumor of childhood. It is derived from neural crest cell, and may arise in the adrenal medulla or anywhere along the paraspinal sympathetic ganglia. Typically, neuroblastoma presents with bone pain, anemia, or in babies, hepatomegaly. It has a median age at diagnosis of 18 months. Nearly two thirds of patients present at diagnosis with evidence of metastatic disease and have poor long term survival due to residual disease, despite aggressive approaches, including high dose multi agent chemotherapy, surgery, radiation therapy and autologous stem cell transplantation.
Methods: The large retrospective study recently conducted by the center for international blood and marrow transplant research (BMTR) analyzed allogenic SCT from matched donors.
Results: The case of neuroblastoma is not well understood. The great majority of cases are sporadic and unfamiliar. Familial neuroblastoma in some cases is caused by rare germline mutation in the anaplastic lymphoma kinase (ALK) gene. Germline mutations in the PHOX2B or KIF1B gene have been implicated in familial neuroblastoma, as well. Neuroblastoma is also a feature of neurofibromatosis type 1 and the beck with Weidman syndrome. MYCN oncogene amplification within the tumor is a common finding in neuroblastoma. Neuroblastoma has been linked to copy-number variation within the NBPF10 gene, which results in the 1q21.1 deletion syndrome or 1q21.1 duplication syndrome. Tumor cells express surface molecules that either switch off or switch on NK cell mediated cytotoxicity. HLA class Ι molecules on tumors negatively regulate NK cell function by engaging immunoreceptor tyrosine based inhibition motifs (ITIM) bearing receptors. That include the inhibitory killer in kire receptors (KIRS, CD158), highly polymorphic clonally distributed receptors able to distinguish among different HLA-A, B and C allotypes, and CD94, NKG2A heterodimers, specific for non-classical HLA-E. KIR and CD94, NKG2A are differently expressed in CD56 bright CD16 and CD56 dull CD16+ NK cell subsets, which represent sequential stage of maturation. Tumor cells switch on NK cell function by expressing at the cell surface non-MHC class Ι, danger molecules that are recognized by and array of activating NK receptors. In vitro treatment of NB cells with IFV-γ induced up regulation of HLA class Ι expression although decreasing their susceptibility to autologous NK cells, this up regulation of HLA class Ι molecules could enhance t cell mediated recognition. Patients were considered missing KIR ligand if the lacked one or more HLA class Ι ligand for their inhibitory KIRs. In contrast, patients with all ligands present possessed all HLA class Ι ligands for their inhibitory KIR. 152 patients were missing KIR ligand were compare with patient who received chemotherapy without ASCT and those who received ASCT. Twenty-one patients suffered from grade 3 or 4 gastrointestinal side effect: mucositis in 81% and nausea in 50%. Seven patients exhibited elevated liver enzyme (serum glutamate oxaloacetate transaminase and glutamate pyruvate transaminase) 3 times the upper limit of normal (ULN) and/ or elevated bilirubin.
Conclusion: High risk patients who currently have a dismal prognosis could benefit from multidisciplinary therapeutic protocol that include novel NK cell based immunotherapeutic strategic. The latter will take advantage of our knowledge about the presence or absence of NB associated interacting with activating, inhibitory receptors expressed by NK cell.
Keywords: neuroblastoma, brain cancer, stem cell transplantation, NK therapy, hematopoietic.