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Updated: May 2, 2026
Combination Radiotherapy in an Orthotopic Mouse Brain Tumor Model
Published on: March 6, 2012
Combination of locoregional radiotherapy with a TIM-3 aptamer improves survival in diffuse midline glioma models
Iker Ausejo-Mauleon1,2,3, Naiara Martinez-Velez1,2,3,4, Andrea Lacalle1,2,3
1Health Research Institute of Navarra (IdiSNA), Pamplona, Navarra, Spain.
Abstract:
Pediatric diffuse midline gliomas (DMG) with altered H3-K27M are aggressive brain tumors that arise during childhood. Despite advances in genomic knowledge and the significant number of clinical trials testing new targeted therapies, patient outcomes are still poor. Immune checkpoint blockades with small molecules, such as aptamers, are opening new therapeutic options that represent hope for this orphan disease. Here, we demonstrated that a TIM-3 aptamer (TIM-3 Apt) as monotherapy increased the immune infiltration and elicited a strong specific immune response with a tendency to improve the overall survival of treated DMG-bearing mice. Importantly, combining TIM-3 Apt with radiotherapy increased the overall median survival and led to long-term survivor mice in 2 pediatric DMG orthotopic murine models. Interestingly, TIM-3 Apt administration increased the number of myeloid populations and the proinflammatory CD8-to-Tregs ratios in the tumor microenvironment as compared with nontreated groups after radiotherapy. Importantly, the depletion of T cells led to a major loss of the therapeutic effect achieved by the combination. This work uncovers TIM-3 targeting as an immunotherapy approach to improve the radiotherapy outcome in DMGs and offers a strong foundation for propelling a phase I clinical trial using radiotherapy and TIM-3 blockade combination as a treatment for these tumors.
Insights
This study shows that combining a TIM-3 aptamer with radiotherapy significantly improves survival in pediatric diffuse midline gliomas (DMG) models by boosting immune responses. This combination therapy offers a promising new treatment strategy for this aggressive childhood brain cancer.
Area of Science:
- Oncology
- Immunology
- Neuroscience
Background:
- Pediatric diffuse midline gliomas (DMG) with H3-K27M alterations are aggressive childhood brain tumors with poor prognoses.
- Current treatments and targeted therapies have limited efficacy, highlighting the need for novel therapeutic strategies.
- Immunotherapy, particularly immune checkpoint blockade using aptamers, presents a promising avenue for treating these rare and aggressive tumors.
Purpose of the Study:
- To investigate the therapeutic potential of a TIM-3 aptamer (TIM-3 Apt) as a monotherapy and in combination with radiotherapy for pediatric diffuse midline gliomas (DMG).
- To evaluate the impact of TIM-3 Apt on immune infiltration and the tumor microenvironment in DMG models.
- To establish a preclinical foundation for a clinical trial combining TIM-3 blockade with radiotherapy for DMG treatment.
Main Methods:
- Utilized two pediatric DMG orthotopic murine models.
- Administered TIM-3 Apt as monotherapy and in combination with radiotherapy.
- Assessed immune cell infiltration, specific immune responses, and overall survival rates.
- Analyzed myeloid populations and CD8-to-Tregs ratios within the tumor microenvironment.
- Conducted T cell depletion experiments to confirm the role of T cells in therapeutic efficacy.
Main Results:
- TIM-3 Apt monotherapy increased immune infiltration and elicited a specific immune response, showing a trend towards improved survival in DMG mice.
- Combination therapy of TIM-3 Apt with radiotherapy significantly increased median overall survival and resulted in long-term survivors in both DMG models.
- TIM-3 Apt treatment enhanced myeloid cell populations and increased the proinflammatory CD8-to-Tregs ratio in the tumor microenvironment post-radiotherapy.
- Depletion of T cells abrogated the therapeutic benefits of the combined treatment, underscoring the critical role of T cells.
Conclusions:
- TIM-3 targeting represents a viable immunotherapy approach to enhance radiotherapy outcomes in pediatric diffuse midline gliomas.
- The combination of TIM-3 Apt and radiotherapy demonstrates significant therapeutic potential, leading to improved survival and durable responses in preclinical models.
- These findings provide a strong rationale for advancing to a phase I clinical trial evaluating this combination therapy for DMG patients.
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