Treatment of metastatic neuroblastoma with systemic oncolytic virotherapy delivered by autologous mesenchymal stem cells: an exploratory study

Abstract

Treatment of metastatic tumors with engineered adenoviruses that replicate selectively in tumor cells is a new therapeutic approach in cancer. Systemic administration of these oncolytic adenoviruses lack metastatic targeting ability. The tumor stroma engrafting property of intravenously injected mesenchymal stem cells (MSCs) may allow the use of MSCs as cellular vehicles for targeted delivery. In this work, we study the safety and the efficacy of infusing autologous MSCs infected with ICOVIR-5, a new oncolytic adenovirus, for treating metastatic neuroblastoma. Four children with metastatic neuroblastoma refractory to front-line therapies received several doses of autologous MSCs carrying ICOVIR-5, under an approved preliminary study. The tolerance to the treatment was excellent. A complete clinical response was documented in one case, and the child is in complete remission 3 years after this therapy. We postulate that MSCs can deliver oncolytic adenoviruses to metastatic tumors with very low systemic toxicity and with beneficial antitumor effects.

Tat-PTD-Modified Oncolytic Adenovirus Driven by the SCG3 Promoter and ASH1 Enhancer for Neuroblastoma Therapy

“…The treatment was found to be safe and at 3 months, a bone marrow biopsy indicated a minimal number of tumor cells in a mostly healthy marrow (Pesonen et al, 2010). In the other study, four children with metastatic neuroblastoma refractory to first-line therapies received several doses of autologous mesenchymal stem cells loaded with oncolytic adenovirus (Garcia-Castro et al, 2010). The adenovirus used in this case was an Ad5 virus with an RGD peptide in the fiber knob, which binds to cellular integrin, and it had the 24-bp deleted (D24) E1A gene driven by the E2F-1 promoter.…”

“…Oncolytic adenoviruses have already been clinically used at two centers for the treatment of children with metastatic neuroblastoma (Garcia-Castro et al, 2010;Pesonen et al, 2010). In one study, a 6-year-old boy with lymph node and bone marrow metastases was treated by injection of Ad5/3-Cox2LD24 oncolytic adenovirus, which is an Ad5 virus with Ad3 fiber knob and a 24-bp deleted (D24) E1A gene driven by the cyclooxygenase-2 (COX2) promoter.…”

Development of Anti-Cancer Stem Cells as Theranostic Agents in the Treatment of Different Cancer Types: An Update

“…In short duration from now for active immunity against tumor will be introduced by modifying the use of MSCs and NSCs whose aim is the establishment of the safety and efficacy of MSCs that expresses IL-12 (GX-051) and the route of administration of these drugs are intra-tumorally in patients suffering from head and neck cancer. Garcia-Castro and their co-workers demonstrated that using auto-logous MSCs laden with oncolytic adenovirus (ICOVIR-5) in a sample of four children shows efficacy and safety with metastatic neuroblastoma in several doses via infusion administration [223]. A single case was documented about the reduction of disease in a child after three years of therapy.…”

Defining stem cell types: understanding the therapeutic potential of ESCs, ASCs, and iPS cells

“…MSCs were recruited and migrated into the tumor. In one of the young patients, the virus destroyed enough tumor cells to generate a CD8 cytotoxic response, the tumor disappeared and the patient was free of the disease (Garcia-Castro et al 2010). Improving oncolytic viruses and adjusting the doses of injected MSCs could therefore have potential as be an alternative therapy in some advanced cancers in the future.…”