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Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
Engineering Oncolytic Vaccinia Virus to redirect Macrophages to Tumor Cells
Felicia Cao1,2,3, Phuong Nguyen1,4,5,6, Bangxing Hong1
1Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, TX, USA.
Abstract:
Oncolytic virotherapy has been tested in numerous early phase clinical studies. However, the antitumor activity of oncolytic viruses thus far has been limited. Numerous strategies are being explored to enhance their antitumor activity by activating the adaptive arm of the immune system. We reasoned that it might also be possible to engineer oncolytic viruses to redirect tumor-associated macrophages to tumor cells for therapeutic benefit. We engineered an oncolytic vaccinia virus (VV) to disrupt the CD47/SIRPα interaction by expressing a chimeric molecule that consists of the ectodomain of SIRPα and the Fc domain of IgG4 (SIRPα-Fc-VV). SIRPα-Fc-VV readily replicated in tumor cells and redirected M1 as well as M2 macrophages to tumor cells in vitro. In contrast, control VVs that either encoded YFP (YFP-VV) or SIRPα (SIRPα-VV) did not. In vivo, SIRPα-Fc-VV had greater antitumor activity than YFP-VV and SIRPα-VV in an immune competent osteosarcoma model resulting in a significant survival advantage. Pretreatment with cytoxan further augmented the antitumor activity of SIRPα-Fc-VV. Thus, arming oncolytic viruses with SIRPα-Fc may present a promising strategy to enhance their antitumor activity for the virotherapy of solid tumors.
Insights
Engineered oncolytic vaccinia virus (VV) redirects macrophages to tumor cells, enhancing antitumor activity. This novel strategy shows promise for solid tumor virotherapy.
Area of Science:
- Oncolytic virotherapy
- Immunotherapy
- Cancer research
Background:
- Oncolytic viruses show limited antitumor activity in early clinical studies.
- Strategies to enhance oncolytic virus efficacy often focus on activating the adaptive immune system.
- Tumor-associated macrophages (TAMs) can be engineered for therapeutic benefit.
Purpose of the Study:
- To engineer an oncolytic vaccinia virus (VV) to disrupt the CD47/SIRPα interaction.
- To assess the ability of the engineered virus to redirect tumor-associated macrophages (TAMs) to tumor cells.
- To evaluate the in vivo antitumor activity and survival advantage of the engineered virus.
Main Methods:
- Engineered an oncolytic vaccinia virus (VV) to express a chimeric SIRPα-Fc molecule, disrupting CD47/SIRPα interaction.
- Assessed viral replication and macrophage redirection in vitro using M1 and M2 macrophages.
- Evaluated in vivo antitumor efficacy and survival in an immune-competent osteosarcoma model, with and without cyclophosphamide pretreatment.
Main Results:
- The engineered SIRPα-Fc-VV replicated in tumor cells and effectively redirected both M1 and M2 macrophages in vitro.
- Control viruses (YFP-VV and SIRPα-VV) did not exhibit these effects.
- SIRPα-Fc-VV demonstrated superior in vivo antitumor activity and a significant survival advantage compared to controls.
- Cyclophosphamide pretreatment further enhanced the antitumor effects of SIRPα-Fc-VV.
Conclusions:
- Engineering oncolytic viruses to disrupt the CD47/SIRPα interaction by expressing SIRPα-Fc is a viable strategy.
- This approach enhances viral oncolysis by redirecting TAMs to tumor cells, leading to improved antitumor activity.
- Armed oncolytic viruses represent a promising therapeutic avenue for solid tumors.
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