Adipose-Derived Stem Cells as Carrier of Pro-Apoptotic Oncolytic Myxoma Virus: To Cross the Blood–Brain Barrier and Treat Murine Glioma

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oncolytic virotherapy adipose tissue-derived stem cells glioblastoma blood–brain barrier apoptosis malignant tumors recurrence

Crossing the Blood–Brain Barrier: Study on Adipose-Derived Stem Cells as Carriers for Pro-Apoptotic Oncolytic Myxoma Virus in the Treatment of Murine Glioblastoma

Background and Objective

Glioblastoma (GBM) is among the most invasive and aggressive brain tumors, characterized by high recurrence rates and poor prognosis. Despite multimodal interventions, including surgery, chemotherapy, and radiotherapy, average survival rates remain below two years. The high recurrence is largely attributed to tumor stem cells, specifically brain tumor-initiating cells (BTICs), which exhibit strong immune evasion and drug resistance, contributing to tumor relapse and therapeutic resistance.

Recently, oncolytic virus (OV) therapy has emerged as a frontier in cancer treatment. OVs are weakly pathogenic viruses that selectively invade cancer cells and induce apoptosis. Modified myxoma virus (MYXV) has shown potential efficacy against various cancer types, including GBM. This study utilized a myxoma virus construct lacking the M011L gene (VMyx-M011L-KO/EGFP), capable of triggering apoptosis in BTICs. However, systemic delivery of OVs to brain tumors is limited by the blood–brain barrier (BBB) and host immune responses. To address this challenge, the research team proposed using adipose-derived stem cells (ADSCs) as Trojan horse carriers for systemic delivery of OVs to glioblastoma lesions. This study evaluates whether this therapeutic platform can effectively cross the BBB and achieve treatment efficacy in murine glioblastoma.

Study Source

This work was published in the International Journal of Molecular Sciences in 2024, authored by researchers from the Maria Sklodowska-Curie National Research Institute of Oncology, Poland, and Arizona State University, USA.

Study Design and Process

1. In Vitro Efficacy of Myxoma Virus Construct

In vitro assays evaluated the infectivity and cytotoxicity of VMyx-M011L-KO/EGFP across murine and human glioblastoma cell lines (GL261luc, LN18, T98G, U-251MG). Results showed that the virus effectively replicated and killed human glioblastoma cells but failed to multiply in GL261 murine cells due to rapid cytotoxic effects.

2. ADSCs Crossing an Artificial BBB

An artificial BBB model was developed to simulate the human blood–brain barrier structure. ADSCs loaded with VMyx-M011L-KO/EGFP successfully crossed the barrier and released the virus to infect glioblastoma cells. These findings demonstrated ADSCs’ potential as carriers for BBB penetration.

3. Local Delivery Efficacy in Animal Models

Using an orthotopic murine glioblastoma model, researchers injected VMyx-M011L-KO/EGFP-infected ADSCs locally into tumor lesions. Compared to controls, these injections significantly suppressed tumor growth and extended survival rates in treated mice.

4. Multi-Dose Therapeutic Strategy

Comparing single and multi-dose treatments, the latter demonstrated superior efficacy, extending survival and further inhibiting tumor growth. These results support the therapeutic potential of ADSCs as stable carriers in repeated treatments.

Key Findings

  1. Pro-Apoptotic Efficacy of VMyx-M011L-KO/EGFP: The virus construct successfully induced apoptosis in glioblastoma cells, evidenced by the activation of apoptosis-related proteins such as Caspase-3 and cleaved PARP.

  2. BBB Penetration by ADSCs: ADSCs crossed the artificial BBB and released the virus, allowing it to infect and kill glioblastoma cells.

  3. In Vivo Antitumor Efficacy: Locally injected virus-loaded ADSCs suppressed tumor progression and extended survival in murine glioblastoma models.

  4. Improved Outcomes with Multi-Dose Treatment: Repeated dosing further enhanced survival rates and tumor suppression, highlighting the platform’s therapeutic viability.

Conclusion and Applications

This study introduces a novel systemic delivery method for oncolytic viruses, leveraging ADSCs as carriers. ADSCs not only protect the virus from host immune clearance but also successfully deliver it across the BBB to brain tumors. The combined platform of ADSCs and VMyx-M011L-KO/EGFP demonstrates potential as a minimally invasive therapeutic approach for glioblastoma. Future developments could further enhance targeting and therapeutic efficacy.

Potential advancements include: - Enhancing ADSC targeting by overexpressing CXCR4 receptors and leveraging its ligand CXCL12 in glioblastoma lesions. - Developing minimally invasive arterial delivery techniques to reduce treatment invasiveness. - Exploring combination therapies with radiotherapy or chemotherapy to maximize synergistic effects.

Highlights and Innovations

  • ADSC-Based Delivery: The study established ADSCs as effective carriers for oncolytic viruses, utilizing their immune evasion and tumor tropism capabilities.
  • BBB-Crossing Strategy: Successful penetration of the artificial BBB by ADSCs offers a promising avenue for non-invasive glioblastoma treatment.
  • Validated Multi-Dose Strategy: Demonstrating efficacy in repeated treatments establishes a therapeutic framework for future clinical applications.

Future Directions and Challenges

  1. Enhancing Tumor Targeting: Research into the CXCR4/CXCL12 axis may improve ADSC homing to glioblastoma lesions, increasing the specificity and efficiency of viral delivery.
  2. Advancing Non-Invasive Techniques: Developing arterial delivery methods could further reduce invasiveness and improve clinical feasibility.
  3. Combination Therapy: Incorporating this platform with other modalities could amplify therapeutic outcomes.

Clinical Significance

By leveraging ADSCs as carriers, this study overcame key challenges in oncolytic virus therapy for glioblastoma, including systemic delivery and BBB penetration. The platform holds promise for broader application in other treatment-resistant brain tumors and represents a significant step toward innovative, non-invasive therapeutic solutions for glioblastoma.