Recombinant Vaccinia Viruses With Reduced Immune Neutralization
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Solution Overview
Problem
Existing oncolytic vaccinia viruses face challenges due to strong immune responses that neutralize the virus, hindering their effectiveness in cancer treatment.
Innovation Solution
Recombinant vaccinia viruses with inactivating mutations, such as B2R, and heterologous nucleic acids encoding interferon regulatory factor 3 (IRF3) and cytokines/chemokines like CXCL9 and IL-12, are engineered to reduce immunogenicity and enhance anti-tumor activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If oncolytic vaccinia viruses are used for cancer treatment, then anti-tumor activity is improved, but immune response neutralizes the virus reducing effectiveness
Solution Approach 1:
The patent extracts and removes the B2R gene from the vaccinia virus genome, creating a recombinant virus that lacks this immunogenic component. This extraction eliminates the harmful immune response triggered by B2R while preserving the virus's oncolytic capabilities, directly resolving the contradiction between anti-tumor activity and immune neutralization
Solution Approach 2:
The patent introduces heterologous genes encoding immune modulatory proteins (such as PD-1, PD-L1, CTLA-4) as intermediaries that mediate between the virus and the host immune system. These intermediary proteins actively suppress or modulate the immune response, allowing the virus to maintain its anti-tumor activity while evading immune neutralization
2Object-affected harmful factors
If viral genes are disrupted to reduce immunogenicity, then immune activation is reduced, but anti-tumor properties may be compromised
Solution Approach 1:
The patent applies local quality by selectively disrupting only the B2R gene while leaving the rest of the viral genome intact. This localized modification reduces immunogenicity specifically through B2R elimination without affecting other viral genes responsible for oncolytic properties, thus resolving the contradiction between reduced immune activation and maintained anti-tumor properties
Solution Approach 2:
The patent merges the attenuated virus (with B2R disruption) with heterologous immune modulatory genes to create a composite virus that combines the benefits of reduced immunogenicity from gene disruption with enhanced immune evasion capabilities from the added heterologous proteins, maintaining both reduced immune activation and strong anti-tumor properties
Data Source
AI summary
Provided herein are clonal strains of a vaccinia virus that exhibits enhanced anti-tumor properties and/or reduced immunogenicity, and recombinant vaccinia virus derived from the same. Also provided herein are recombinant oncolytic virus strains that include an inactivating mutation in one or more viral genes, and/or one of more heterologous nucleic acids each encoding one or more heterologous gene products. The viruses, e.g., vaccinia viruses, provided herein, including recombinant vaccinia viruses, can be used as an oncolytic virus therapy, e.g., an oncolytic vaccinia virus therapy, for treating cancer. Also provided herein are pharmaceutical compositions and methods and uses of the viruses, e.g., vaccinia viruses, for treating cancer, as well as nucleic acids encoding the viruses.