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Updated: Sep 27, 2025
Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
Exploiting 4-1BB immune checkpoint to enhance the efficacy of oncolytic virotherapy for diffuse intrinsic pontine
Virginia Laspidea1,2,3, Montserrat Puigdelloses1,2,3, Sara Labiano1,2,3
1Health Research Institute of Navarra, Pamplona, Navarra, Spain.
Abstract:
Diffuse intrinsic pontine gliomas (DIPGs) are aggressive pediatric brain tumors, and patient survival has not changed despite many therapeutic efforts, emphasizing the urgent need for effective treatments. Here, we evaluated the anti-DIPG effect of the oncolytic adenovirus Delta-24-ACT, which was engineered to express the costimulatory ligand 4-1BBL to potentiate the antitumor immune response of the virus. Delta-24-ACT induced the expression of functional 4-1BBL on the membranes of infected DIPG cells, which enhanced the costimulation of CD8+ T lymphocytes. In vivo, Delta-24-ACT treatment of murine DIPG orthotopic tumors significantly improved the survival of treated mice, leading to long-term survivors that developed immunological memory against these tumors. In addition, Delta-24-ACT was safe and caused no local or systemic toxicity. Mechanistic studies showed that Delta-24-ACT modulated the tumor-immune content, not only increasing the number, but also improving the functionality of immune cells. All of these data highlight the safety and potential therapeutic benefit of Delta-24-ACT the treatment of patients with DIPG.
Insights
The oncolytic adenovirus Delta-24-ACT shows promise in treating diffuse intrinsic pontine gliomas (DIPGs) by boosting the immune system. This therapy improved survival in mice and demonstrated safety, offering hope for new pediatric brain tumor treatments.
Area of Science:
- Oncolytic virotherapy
- Immunotherapy
- Pediatric neuro-oncology
Background:
- Diffuse intrinsic pontine gliomas (DIPGs) are aggressive pediatric brain tumors with limited treatment options and poor prognosis.
- Existing therapies have not significantly improved patient survival, highlighting the critical need for novel therapeutic strategies.
Purpose of the Study:
- To evaluate the efficacy and safety of Delta-24-ACT, an oncolytic adenovirus engineered to express 4-1BBL, against DIPG.
- To investigate the mechanism by which Delta-24-ACT enhances antitumor immune responses in DIPG models.
Main Methods:
- Delta-24-ACT was engineered to express the costimulatory ligand 4-1BBL.
- In vitro studies assessed 4-1BBL expression and T-cell costimulation.
- In vivo studies utilized murine DIPG orthotopic tumor models to evaluate survival, toxicity, and tumor-immune microenvironment modulation.
Main Results:
- Delta-24-ACT induced functional 4-1BBL expression on infected DIPG cells, enhancing CD8+ T lymphocyte costimulation.
- Treatment with Delta-24-ACT significantly improved survival in mice with DIPG orthotopic tumors, leading to long-term survivors with tumor-specific immunological memory.
- Delta-24-ACT demonstrated safety, with no observed local or systemic toxicity, and modulated the tumor-immune content by increasing immune cell number and function.
Conclusions:
- Delta-24-ACT exhibits significant anti-DIPG effects by potentiating virus-driven antitumor immunity.
- The therapy is safe and effective in preclinical models, demonstrating potential for treating pediatric brain tumors.
- These findings support the further clinical investigation of Delta-24-ACT for DIPG treatment.
