CANCELADO Oncolytic viruses for the treatment of pediatric brain tumors: The force awakens
Marta María Alonso Roldán
CIMA, Universidad de Navarra
Pediatric high-risk brain tumors remain the leading cause of cancer-related death in children. For the last 30 years, all treatment approaches for the most aggressive types of these tumors have failed, leaving a terrible prospect of survival at five years for these children virtually zero. Thus, it is clear that new therapeutic strategies are required that allow for more effective treatments of these tumors and defer the severe side effects derived from the current therapeutic choices. Oncolytic adenoviruses designed to replicate in and destroy tumor cells selectively represent a promising therapeutic strategy that could improve the outcome of this malignancy. Delta-24-RGD is a tumor-selective oncolytic virus that has been tested in several phase I clinical trials in adults with brain tumors with very promising results. The virus showed a lack of toxicity and some degree of efficacy due to the trigger of an immune response against the tumor. Taking advantage of the safety profile demonstrated by Delta-24-RGD in adult brain tumors during the last ten years, we have dedicated our efforts to characterize the preclinical and clinical efficacy of Delta-24-RGD in pediatric brain tumors. Preclinical studies demonstrated the virus's efficacy and allowed us to open the first-in-human clinical trial for diffuse intrinsic pontine glioma. Twelve patients were treated in this trial. The procedure was well-tolerated and safe. All patients displayed a reduced tumor volume after combined treatment. Lessons learned from the clinic allow us to engineer other viruses based on the Delta-24 platform to boost the immune response. The intratumoral administration of armed oncolytic viruses was safe and significantly increased the survival of mice bearing orthotopic pediatric murine tumors, leading to long-term survivors. We observed a significant increase in immune infiltration in the tumor with an active functional phenotype. These data indicate that incorporating positive immune modulators into the Delta-24-platform could improve the oncolytic effect of the virus by boosting the immune response while maintaining a safe profile in immunocompetent models offering a feasible option treatment for pediatric brain tumors. Our data underscore that oncolytic viruses are becoming a real option for treating these tumors.