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Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
Multistage responsive microneedle delivery system loaded oncolytic virus for topical therapy of melanoma
Zhongjie Wang1, Zewei Yan2, Hanlin Chen1
1School of Medical Technology, Beijing Institute of Technology, Beijing 100081, China.
Abstract:
Melanoma, the most aggressive form of skin cancer, remains a formidable therapeutic challenge. While oncolytic viruses (OVs) exhibit promising antitumor potential, their efficacy is often limited by insufficient intratumoral viral replication, poor tissue penetration, and the immunosuppressive tumor microenvironment (TME). Herein, a multistage microneedle (MN-OJ) system designed to amplify both local oncolysis and systemic antitumor immunity mediated by oncolytic adenovirus (OA) in melanoma. The dissolvable MN base facilitates rapid OA delivery, inducing tumor cell lysis and subsequent release of tumor-associated antigens to prime T-cell responses. Concurrently, the degradable MN tip enables sustained release of JQ1, which enhances OA replication, modulates lactic acid levels and PD-L1 expression, thereby reprogramming the immunosuppressive TME to promote T-cell infiltration and cytotoxicity. In murine models, MN-OJ demonstrated potent inhibition of both primary and distal tumors, without systemic toxicity. This innovative platform combines immediate tumor destruction with sustained immune modulation, offering a promising clinical approach for melanoma therapy.
Insights
This study introduces a microneedle system delivering oncolytic adenovirus and JQ1 to treat melanoma. The system enhances viral replication and boosts anti-tumor immunity, effectively reducing tumors in mice.
Area of Science:
- Oncology
- Virology
- Immunology
- Biomaterials Science
Background:
- Melanoma is an aggressive skin cancer with limited treatment options.
- Oncolytic viruses (OVs) show promise but face challenges like poor delivery and an immunosuppressive tumor microenvironment (TME).
Purpose of the Study:
- To develop a novel microneedle system (MN-OJ) for enhanced melanoma treatment.
- To improve oncolytic adenovirus (OA) delivery, replication, and efficacy.
- To reprogram the TME and enhance systemic anti-tumor immunity.
Main Methods:
- A multistage microneedle system (MN-OJ) was designed for sequential delivery of OA and JQ1.
- The system utilizes dissolvable microneedles for rapid OA delivery and degradable tips for sustained JQ1 release.
- Efficacy was evaluated in murine melanoma models, assessing tumor inhibition, viral replication, TME modulation, and systemic toxicity.
Main Results:
- MN-OJ facilitated efficient OA delivery, leading to tumor cell lysis and antigen release.
- Sustained JQ1 release enhanced OA replication and modulated the TME by reducing lactic acid and PD-L1 expression.
- The treatment resulted in potent inhibition of primary and distal tumors with no observed systemic toxicity in murine models.
Conclusions:
- The MN-OJ system effectively combines direct tumor destruction with immune modulation for melanoma therapy.
- This innovative platform demonstrates significant potential for clinical application in melanoma treatment.
- The study highlights the synergy between oncolytic virotherapy and targeted drug delivery for overcoming treatment resistance.
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