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Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
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Durable antitumor response via an oncolytic virus encoding decoy-resistant IL-18
Yan Cheng1,2,3, Yuanhui Zhao1,2, Yu Liu4,5
1State Key Laboratory of Biotechnology, Medical School, Nanjing University, Nanjing, China.
Journal for Immunotherapy of Cancer
|December 4, 2024
Summary
Engineered Interleukin-18 (IL-18) delivered via oncolytic adenovirus (oAdDR18) shows enhanced anti-tumor immunity and efficacy. This cytokine-based therapy, combined with immune checkpoint inhibitors, offers a promising strategy for cancer treatment.
Area of Science:
- Oncolytic virotherapy
- Immunotherapy
- Cancer research
Background:
- Interleukin-18 (IL-18) is crucial for immune cell activation but has limited clinical efficacy due to IL-18 binding protein (IL-18BP).
- Decoy-resistant IL-18 (DR18) variants were developed to overcome IL-18BP inhibition.
- Oncolytic adenovirus (oAd) serves as a platform for delivering therapeutic agents like DR18.
Purpose of the Study:
- To evaluate the efficacy of DR18 delivered by oAd (oAdDR18) in syngeneic mouse tumor models.
- To compare oAdDR18 with recombinant DR18 protein (rDR18) and oAd carrying wild-type IL-18 (oAdwtIL-18).
- To assess the potential of oAdDR18 in combination therapy with immune checkpoint inhibitors.
Main Methods:
- Construction of oAd harboring DR18 (oAdDR18) using an Ad5/3 chimeric fiber backbone.
- Assessment of IL-18 and IFN-γ levels by ELISA.
- Evaluation of antitumor efficiency in various tumor-bearing mouse models, including metastasis and combination therapy studies.
- Analysis of immune cell phenotypes in the tumor microenvironment via flow cytometry and immunohistochemistry.
Main Results:
- oAdDR18 maintained stable IL-18 and IFN-γ production, outperforming rDR18.
- Intratumoral delivery of oAdDR18 significantly reduced tumor growth across multiple models, with efficacy dependent on T-cell infiltration.
- oAdDR18 demonstrated superior long-lasting antitumor activity against local and distant tumors, including reduced lung metastasis.
- Combination therapy with anti-PD-1 antibody significantly enhanced antitumor effects compared to monotherapy.
Conclusions:
- oAdDR18 exhibits enhanced antitumor activity by inducing robust local and systemic immunity and modulating the tumor microenvironment.
- This engineered cytokine delivery via oncolytic virotherapy represents a potent strategy for cancer treatment.
- Combining oncolytic virotherapy with cytokine engineering offers a promising avenue for developing novel cytokine-based therapeutics for various diseases.
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