Periodic Reporting for period 3 - ViroPedTher (Oncolytic viruses for the treatment of pediatric brain tumors: An integrated clinical and lab approach)
Période du rapport: 2022-03-01 au 2023-08-31
Childhood malignant tumors encompass a number of different diseases, all of them with the designation of orphan diseases. The prognosis for children with tumors has improved in the last decades. However, meanwhile the overall increase in survival has been a medical success, children with advanced or metastatic disease at diagnosis remain at risk with a poor prognosis, and relatively little improvement in outcome has been leveraged for this group of patients. Moreover, childhood brain tumors still present a challenge. Current curative therapies may leave children with significant long-term health issues, including neurocognitive dysfunction, endocrine deficits, and secondary cancers. Therefore, it is clear that novel and radically different therapeutic choices are needed to improve these children's survival and quality of life. Oncolytic adenoviruses engineered to replicate in and destroy tumor cells selectively represent a promising new therapeutic strategy that could improve the outcome of CNS tumors. Delta-24-RGD is a replication-competent adenovirus that has already shown efficacy in animal models of gliomas and the clinic. Preliminary results from the first trials revealed that the intratumoral injection of the virus instigated an initial phase of oncolysis followed by a delayed inflammatory response that ultimately resulted in tumor shrinkage with complete regression in a subset of the patients. Although tumor infection should lead to lymphocytic infiltration of the tumor, the immune-suppressive environment of cancer will inactivate any effective antitumor immune response in the majority of the cases. These results emphasize the urgent need to improve further this therapy and the suitability to translate it to pediatric solid tumors. This proposal aims to integrate clinical and lab-based research to develop tumor-targeted oncolytic adenoviruses with the capacity to elicit a therapeutic immune response in those tumors. Our research uses relevant models to accomplish the experimental aims. In our specific approach, we propose understanding the immune microenvironment of DIPGs and the response to viral therapy in the context of a clinical trial phase I conducted at our institution. Moreover, that knowledge is leveraging the design of Delta-24-based adenoviruses to recruit lymphocytes to the tumor with the competence of different ligands to activate the tumor-infiltrating lymphocytes. I expect that this innovative combinatorial treatment will efficiently challenge the profound and inherent tumor immunosuppression and, in turn, will elicit a robust antitumor immune response resulting in the significant improvement of the prognosis and quality of life of patients with pediatric brain tumors. This project has the potential to produce a vertical advance in the field of pediatric oncology.
During these first years, we have performed the following research according to the action objectives
Aim 1: We have demonstrated the feasibility and efficacy of the oncolytic virus Delta-24-RGD (DNX-2401 in the clinic) for newly diagnosed DIPGs. Most importantly, we have learned how these patients respond to the viruses and delve into potential resistance to this therapy.
Aim 2: We engineered several new, improved viruses, and we are currently evaluating their safety, efficacy, and mechanism of action in DIPGs.
Aim 3: We have set up several immunocompetent models that recapitulate key features of other pediatric brain tumors such as AT/RTs and PNETs. We are working on translating our therapeutic tools for these tumors as well.
Aim 1: We have demonstrated the feasibility and efficacy of the oncolytic virus Delta-24-RGD (DNX-2401 in the clinic) for newly diagnosed DIPGs. Most importantly, we have learned how these patients respond to the viruses and delve into potential resistance to this therapy.
Aim 2: We engineered several new, improved viruses, and we are currently evaluating their safety, efficacy, and mechanism of action in DIPGs.
Aim 3: We have set up several immunocompetent models that recapitulate key features of other pediatric brain tumors such as AT/RTs and PNETs. We are working on translating our therapeutic tools for these tumors as well.
Thanks to the ERC, we have shown the feasibility and effectiveness of oncolytic viruses for pediatric brain tumors. We expect to provide several viruses with a safe profile but with an improved efficacy effect. Additionally, we hope to have enough data to propel a phase I trial for recurrent pediatric brain tumors with the best candidate of these viruses by the end of the project.