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Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
Surface engineering of oncolytic adenovirus for a combination of immune checkpoint blockade and virotherapy
Peng Lv1, Xiaomei Chen1, Shiying Fu1
1State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics and Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen 361102, China. gangliu.cmitm@xmu.edu.cn.
Abstract:
Advances in the development of modern cancer immunotherapy and immune checkpoint inhibitors have dramatically changed the landscape of cancer treatment. However, most cancer patients are refractory to immune checkpoint inhibitors because of low lymphocytic tumor infiltration and PD-L1 expression. Evidence suggests that viral oncolysis and immune checkpoint inhibitors have a synergistic effect that can improve the response to immune checkpoint inhibitors. In this study, we developed bioengineered cell membrane nanovesicles (PD1-BCMNs) with programmed cell death protein 1 (PD-1) to harbor oncolytic adenovirus (OA) and achieve a combination of immune checkpoint blockade and oncolytic virotherapy in one particle for cancer treatment. PD1-BCMNs could specifically deliver OA to tumor tissue; the infectivity and replication ability of the OA was preserved in the presence of neutralizing antibodies in vitro and in vivo. Selective oncolytic effects with oncolytic adenovirus led to an up-regulated expression of PD-L1 in the tumor microenvironment, turning immunologically 'cold' tumors into immunologically 'hot' tumors, presenting more targets for further enhanced target delivery. Notably, PD1-BCMNs@OA could effectively activate tumor-infiltrating T cells and elicit a strong anti-tumor immune response. Thus, PD1-BCMNs@OA may provide a clinical basis for combining oncolytic virotherapy with checkpoint inhibitors, enhancing the oncolytic adenovirus targeted delivery and significantly enhancing T cell immune responses, resulting in a stronger antitumor immunity response.
Insights
Bioengineered nanovesicles carrying oncolytic adenovirus (OA) and PD-1 enhance cancer immunotherapy by targeting tumors and activating T cells. This combination therapy overcomes resistance to immune checkpoint inhibitors, improving anti-tumor immunity.
Area of Science:
- Oncology
- Immunotherapy
- Nanomedicine
- Virology
Background:
- Cancer immunotherapy, particularly immune checkpoint inhibitors, has advanced cancer treatment.
- Many patients do not respond to immune checkpoint inhibitors due to low tumor lymphocytic infiltration and PD-L1 expression.
- Viral oncolysis combined with immune checkpoint inhibitors shows synergistic effects.
Purpose of the Study:
- To develop bioengineered cell membrane nanovesicles (PD1-BCMNs) loaded with oncolytic adenovirus (OA).
- To combine immune checkpoint blockade (PD-1) and oncolytic virotherapy in a single particle for cancer treatment.
- To enhance targeted delivery of OA and improve anti-tumor immune responses.
Main Methods:
- Development of PD1-BCMNs engineered to carry oncolytic adenovirus (OA).
- Evaluation of OA infectivity and replication in the presence of neutralizing antibodies.
- Assessment of PD1-BCMNs@OA in modulating the tumor microenvironment and activating T cells.
Main Results:
- PD1-BCMNs specifically delivered OA to tumor tissues, preserving OA infectivity and replication.
- Oncolytic adenovirus selectively caused oncolysis, up-regulating PD-L1 expression and converting 'cold' tumors to 'hot' tumors.
- PD1-BCMNs@OA effectively activated tumor-infiltrating T cells, eliciting a robust anti-tumor immune response.
Conclusions:
- PD1-BCMNs@OA represent a novel strategy for combining oncolytic virotherapy and checkpoint inhibition.
- This approach enhances targeted delivery of oncolytic adenovirus and boosts T cell-mediated anti-tumor immunity.
- The findings provide a potential clinical basis for improved cancer treatment strategies.
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