Neuroblastoma is one of the most common extracranial solid tumors found in children and the most frequent malignancy in infancy. Neuroblastoma remains accounting for an estimated 8-10% of all childhood cancers. Neuroblastoma is a tumor originating from the sympathetic nervous system, and the primary location may be commonly developing along with paraspinal ganglia of the sympathetic nervous system or adrenal glands. To most frequently, its high risk often affects distant sites, such as lymph nodes, bone, bone marrow, liver, and subcutaneous tissue, which often results in treatment-resistant and a disproportionally high mortality rate. Most patients are asymptomatic with tumors or present with a palpable abdominal mass or abdominal distension. Some of the patients can present with generalized bone pain, massive hepatomegaly, and abdominal compartment syndrome leading to respiratory compromise.
The diagnosis of suspicion of neuroblastoma in children can be evaluated by cross-sectional imaging (CT scan or MRI). It can assess the extent of the primary tumor and evaluate for regional or distant spread. Neuroblastoma may be a stem cell disease that has striking tumor cell heterogeneity and the ability to relapse. A small subset of neuroblastoma cases spontaneously regresses or is cured with surgical management alone without cytotoxic therapies. Conversely, metastatic neuroblastoma tends to present with life-threatening tumors that have refractory and case a dismal prognosis.
The treatment for low or intermediate-risk metastatic neuroblastoma is often achieved remission by intensive multimodal chemotherapy, radiopharmaceutical treatment, and resection of the primary tumor. Some children with high-risk neuroblastoma also benefit from high-dose chemotherapy with autologous stem cell transplantation. Despite intensive multimodal treatment, most neuroblastoma progress relentlessly and poor prognosis, and relapse after transplantation because of the resistance to conventional therapy. Given the high incidence of resistance to conventional therapies and the high mortality, new therapeutic strategies are still a substantial need and a current clinical challenge, in which, oncolytic virotherapy has shown promise in treating neuroblastoma.
Fig.1 Clinical presentations of neuroblastoma. (Maris, 2010)
Adenovirus (Ad) has capable of infecting tumor cells based on several modifications of the Ad genome to change its tumor selectivity. The oncolytic adenovirus ICOVIR-5 is a retargeted oncolytic adenovirus for treating metastatic neuroblastoma. ICOVIR-5 exploits aberrant E2F expression, which regulates the expression of several target genes in high-risk neuroblastoma. This allows an enhanced tumor selectivity while exerting a potent antitumor effect in vitro and in vivo. Four children with refractory metastatic neuroblastoma received several doses of autologous MSCs carrying ICOVIR-5, under an approved preliminary study. The results showed that symptoms of all patients had complete remission in the clinical study.
Herpes simplex virus (HSV) has been used for treating patients with different tumors, which offers promise in treating neuroblastoma. HSV viruses are enveloped viruses with a large double-stranded DNA, which are rendered oncolytic by deleting some neurovirulence gene. HSV viruses are rendered the ability of oncolytic by deleting genes critical for viral replication in healthy cells but not necessary in tumor cells, for instance, the “neurovirulence” gene. Although no pediatric trials are employing engineered HSV, several preclinical studies of the treatment of neuroblastoma have shown promising. FusOn-H2 is a conditionally replicating oncolytic virus from type 2 HSV (HSV-2) that selectively targets tumor cells with an activated Ras signaling pathway and kills tumor cells by a direct cytolytic effect. The preclinical studies have shown that the oncolytic FusOn-H2 virus may kill the tumor-initiating cells and also induces a significant antitumor immune response after its injection in the model. Thus, these promising preclinical studies suggest that virotherapy has potential benefits for metastatic neuroblastoma disease.
Parvovirus such as H-1PV has been investigated for the cytopathic effects on different non-malignant cells as well as neuroblastoma cell lines. The results show that H-1PV induces lytic infection in neuroblastoma cells with high infection efficiency, rapid virus replication, and exhaustive lytic effects.
A novel and stable attenuated poliovirus (mono-crePV) has been designed replicating in neuroblastoma cells by engineering and is tested in a preclinical model of neuroblastoma. The results indicate that the attenuated poliovirus has the capacity to kill neuroblastoma cells and to induce a robust antitumor immune response developed after the infection and lysis of tumor cells. The preclinical studies suggest that the attenuated oncolytic poliovirus may be a promising candidate for the effective oncolytic treatment of human neuroblastoma.
Newcastle Disease Virus (NDV) is an RNA virus that belongs to the family Paramyxoviridae. The oncolytic ability of NDV against neuroblastoma has been studied in vitro and in vivo.
Due to their ability to replicate in vivo, oncolytic viruses are attractive anticancer therapeutics that have been shown efficacy and safety in clinical trials. Creative Biolabs has established a comprehensive well-established OncoVirapy™ platform for the development of the oncolytic virus. Based on the most advanced techniques and years of experience in the oncolytic virus therapy field, Creative Biolabs provides custom oncolytic virus construction services and oncolytic virotherapy development for neuroblastoma to achieve our customers' specific goals of clinical research.
Please feel free to contact us for a quote and further discussion with our scientists.