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Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
An Engineered Self-biomineralized Oncolytic Adenovirus Induces Effective Antitumor Immunity and Synergizes With
Shibing Wang1,2, Xue Yang2,3, Ying-Yu Ma2,3
1Department of Clinical Laboratory, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, China.
Abstract:
Oncolytic adenoviruses (oADV) are promising cancer treatment agents. However, in vivo hepatic sequestration and the host immunologic response against the agents limit the therapeutic potential of oADVs. In this study, we present a combined method with a rational design for improving oADV infection efficiency, immunogenicity, and treatment efficacy by self-biomineralization. We integrated the biomimetic nucleopeptide W6p into the capsid of oADV using reverse genetics, allowing calcium phosphate mineralization to be biologically induced on the surface of oADV under physiologic conditions, resulting in a mineral exterior. This self-biomineralized, modified oADV (oADV-W6-CaP) enhanced infection efficiency and therapeutic efficacy in coxsackievirus and adenovirus receptor (CAR)-negative cancer cells wherein protecting them against neutralization by preexisting neutralizing antibodies. In subcutaneous mouse tumor models, systemic injection of oADV-W6-CaP demonstrated improved antitumor effectiveness, which was associated with increased T-cell infiltration and CD8+ T-cell activation. In addition, the anticancer immune response elicited by oADV-W6-CaP was dependent on CD8+ T cells, which mediated long-term immunologic memory and systemic antitumor immunity against the same tumor. Finally, the addition of PD1 or CD47 inhibition boosted the anticancer effects of oADV-W6-CaP and increased the rate of complete tumor clearance in tumor-bearing animals. The self-biomineralized oADV shifted the suppressive tumor microenvironment from a "cold" to "hot" state and synergized with immune checkpoint blockade to exert outstanding tumoricidal effects, demonstrating promising potential for cancer immunotherapy.
Insights
Self-biomineralization of oncolytic adenoviruses (oADVs) with W6p creates a mineralized oADV-W6-CaP. This enhanced oADV improves cancer cell infection, immune response, and tumor clearance, showing promise for cancer immunotherapy.
Area of Science:
- Biomedical Engineering
- Cancer Biology
- Immunology
Background:
- Oncolytic adenoviruses (oADVs) show therapeutic potential but face challenges like hepatic sequestration and immune response.
- Improving oADV infection efficiency and overcoming host immunity are critical for effective cancer treatment.
Purpose of the Study:
- To develop a self-biomineralization strategy to enhance oADV infection, immunogenicity, and therapeutic efficacy.
- To investigate the potential of mineralized oADVs in overcoming CAR-negative cancer cell barriers and pre-existing neutralizing antibodies.
Main Methods:
- Integration of biomimetic nucleopeptide W6p into oADV capsid via reverse genetics.
- Induction of calcium phosphate mineralization on oADV surface under physiological conditions, creating oADV-W6-CaP.
- Evaluation of oADV-W6-CaP in CAR-negative cancer cells and subcutaneous mouse tumor models.
Main Results:
- oADV-W6-CaP demonstrated enhanced infection efficiency and therapeutic efficacy in CAR-negative cancer cells.
- Systemic injection of oADV-W6-CaP in mouse models showed improved antitumor effectiveness, increased T-cell infiltration, and CD8+ T-cell activation.
- The immune response was CD8+ T-cell dependent, mediating long-term immunologic memory and systemic antitumor immunity.
- Combination therapy with PD1 or CD47 inhibition further boosted anticancer effects and tumor clearance.
Conclusions:
- Self-biomineralization of oADVs offers a novel strategy to enhance their therapeutic potential in cancer treatment.
- oADV-W6-CaP effectively targets CAR-negative tumors, evades antibody neutralization, and converts the tumor microenvironment from 'cold' to 'hot'.
- This approach synergizes with immune checkpoint blockade, highlighting its promise for advanced cancer immunotherapy.
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