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Oncolytic Viruses as Therapeutic Tools for Pediatric Brain Tumors.

ABSTRACT: In recent years, we have seen an important progress in our comprehension of the molecular basis of pediatric brain tumors (PBTs). However, they still represent the main cause of death by disease in children. Due to the poor prognosis of some types of PBTs and the long-term adverse effects associated with the traditional treatments, oncolytic viruses (OVs) have emerged as an interesting therapeutic option since they displayed safety and high tolerability in pre-clinical and clinical levels. In this review, we summarize the OVs evaluated in different types of PBTs, mostly in pre-clinical studies, and we discuss the possible future direction of research in this field. In this sense, one important aspect of OVs antitumoral effect is the stimulation of an immune response against the tumor which is necessary for a complete response in preclinical immunocompetent models and in the clinic. The role of the immune system in the response of OVs needs to be evaluated in PBTs and represents an experimental challenge due to the limited immunocompetent models of these diseases available for pre-clinical research.

SUBMITTER: Varela-Guruceaga M

PROVIDER: S-EPMC6071081 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Oncolytic Viruses as Therapeutic Tools for Pediatric Brain Tumors.

Varela-Guruceaga Maider M Tejada-Solís Sonia S García-Moure Marc M Fueyo Juan J Gomez-Manzano Candelaria C Patiño-García Ana A Alonso Marta M MM

Cancers 20180709 7

In recent years, we have seen an important progress in our comprehension of the molecular basis of pediatric brain tumors (PBTs). However, they still represent the main cause of death by disease in children. Due to the poor prognosis of some types of PBTs and the long-term adverse effects associated with the traditional treatments, oncolytic viruses (OVs) have emerged as an interesting therapeutic option since they displayed safety and high tolerability in pre-clinical and clinical levels. In th ...[more]

PMID: 29987215

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Project description:Abstract Atypical teratoid/rhabdoid tumors (ATRTs) and primitive neuroectodermal tumors (PNETs) are two rare primary embryonal brain tumors, which are among the most frequent solid brain tumors in infants under one year old. The outcome for these children remains dismal, especially in ATRTs which have a 2-year overall survival below 20%. Therefore, we need to find out new efficient and safe therapeutic options for these children. Delta-24-RGD (DNX-2401 in the clinic) is an oncolytic adenovirus that has already been tested in Phase I/II clinical trials in patients affected by recurrent glioblastoma (NCT00805376; NCT01956734), demonstrating anti-tumor effect without any evidence of severe side effect associated with viral administration. Of interest for pediatric brain tumors, an ongoing Phase I trial using Delta-24-RGD for the treatment of diffuse intrinsic pontine gliomas (NCT03178032) has also demonstrated a safe profile in these children. For these reasons, we propose to evaluate the anti-tumor effect of Delta-24-RGD in preclinical models of ATRT and PNET. The virus was able to infect and replicate in tumor cell cultures (three models of ATRT and four of PNET), inducing a potent cytotoxic effect. In addition, this cytotoxicity resulted in the released the immunogenic cell death markers Hsp70, Hsp90, HMGB1 and ATP, as well as an increased calreticulin exposure in the outer cell surface. Although not conclusive, the presence of these markers suggest the triggering of an anti-tumor immune response. Intratumoral administration of the virus extended significantly the overall survival of mice bearing ATRT or PNET xenografts, leading to up to 40% of long-term survivors. We are currently setting up an intraventricular model of disseminated disease, since most of patients with ATRT actually die due to the presence of metastases. In conclusion, these results demonstrate that Delta-24-RGD could be a feasible therapeutic option for children with PNETs and AT/RTs.

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Oncolytic Viruses as Therapeutic Tools for Pediatric Brain Tumors.

Publications

Oncolytic Viruses as Therapeutic Tools for Pediatric Brain Tumors.

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