Available online 13 April 2023

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Diffuse intrinsic pontine glioma (DIPG) is the most frequent brainstem glioma and the most lethal brain tumor in childhood. Despite transient benefit with radiotherapy, the prognosis of children with this disease remains dismal with severe neurological morbidity and median survival less than 12 months. Oncolytic immunovirotherapy is emerging as a potential therapeutic approach in neuro-oncology. The oncolytic adenovirus Delta-24-RGD has shown efficacy in adult patients with recurrent GBM. Our group has demonstrated that Delta-24-RGD has oncolytic activity and triggers immune response in preclinical models of DIPG, and has a synergistic effect with radiotherapy in animal models of this disease. In this scenario, we conducted a first-in-human phase 1 clinical trial to evaluate the safety and efficacy of intratumoral injection of Delta-24-RGD in pediatric patients with newly diagnosed DIPG prior to standard radiotherapy. The study confirmed the feasibility of this treatment with an acceptable safety profile and encouraging efficacy results. Correlative analyses showed a biological activity from Delta-24-RGD in DIPG. Further advanced trials are needed to validate these results. Meanwhile, plenty of opportunities to increase the potential contribution of oncolytic viruses in the management of devastating tumors with no current effective treatment such as DIPG need to be explored and exploited.

Section snippetsOverview of diffuse intrinsic pontine glioma

Brainstem gliomas are a heterogeneous group of tumors with varying degrees of aggressivity and prognosis depending on their clinical presentation, location, and molecular characteristics. Most of them arise within the pons, the majority of which are poor prognosis high-grade infiltrative tumors. On the contrary, pediatric tumors located in other areas of the brainstem, such as the mesencephalic tectum or the cervicomedullary junction, are more likely to be low-grade well-circumscribed tumors

Immunovirotherapy in neuro-oncology

Oncolytic immunovirotherapy is emerging as an alternative therapeutic approach for cancer. One of the rationales behind the use of genetically engineered or attenuated naïve viruses to treat cancer is their ability to selectively replicate in tumor cells and induce their lysis. In addition to this intrinsic tumor cytolytic effect, oncolytic viruses are capable of promoting inflammation and eliciting both innate and adaptative antitumor immune responses [20] (Fig. 1).

In the past years, various

Preclinical development of immunovirotherapy for DIPG

The aforementioned data on the safety and potential efficacy of Delta-24-RGD in adult patients with GBM and the need for new and more effective treatments in children suffering from the devastating DIPG, led our group to narrow the focus and explore this innovative therapy in such a pediatric cancer population.

The first step for this purpose consisted of developing a reproducible and frameless in vivo DIPG model that allows for rapid evaluation of tumorigenicity and efficacy of intratumorally

Translation to clinics: phase I clinical trial

These encouraging results obtained in the preclinical field motivated the translation of Delta-24-RGD to the clinic in a dose-escalation phase I clinical trial [38]. The study was conducted in 12 children and adolescents with newly diagnosed DIPG and was aimed at evaluating the safety and efficacy of the intratumoral injection of Delta-24-RGD prior to standard radiotherapy. A stereotactic biopsy was performed through the middle cerebellar peduncle, and thereafter the virus was intratumorally

Future directions

In addition to the observed safety and efficacy outcomes, this latter study has shown evidence of biological activity from Delta-24-RGD in DIPG. Altogether, these data provide the rationale for expanded testing in a multi-center phase 2 trial designed to further evaluate and confirm the safety and efficacy of Delta-24-RGD and radiation therapy in children with DIPG.

In addition, the future landscape of oncolytic immunovirotherapy for DIPG and other gliomas appears encouraging, and plenty of

Disclosure of interest

The authors declare that they have no competing interest.

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