Chimeric Newcastle Disease Viruses Expressing Immune Modulators
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Solution Overview
Problem
Current Newcastle disease virus (NDV)-based therapies for cancer have shown only marginal success in clinical trials for advanced human cancers, necessitating the development of more effective NDV strains that can enhance immune cell activation and inhibit immune suppression.
Innovation Solution
Engineering chimeric Newcastle disease viruses (NDVs) to express agonists of co-stimulatory signals and antagonists of inhibitory signals of immune cells, along with mutated F proteins for increased fusogenic activity, to enhance their ability to infect cancer cells and stimulate an immune response.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If naturally-occurring NDV strains are used for cancer therapy, then the virus can infect cancer cells, but the immune stimulation is insufficient leading to only marginal success in clinical trials
Solution Approach 1:
The patent modifies the NDV genome to express modified immune checkpoint proteins with altered binding affinities or functions. Specifically, the ICOS ligand is engineered to have enhanced co-stimulatory activity, and PD-L1 is modified to have reduced binding affinity for PD-1, thereby changing the immunomodulatory parameters of the virus to overcome immune suppression
Solution Approach 2:
The patent creates a composite viral construct by incorporating multiple modified immune-related proteins into a single NDV genome. The virus simultaneously expresses modified ICOS ligand and modified PD-L1, combining multiple immunomodulatory functions into one therapeutic agent to achieve both immune activation and suppression of inhibitory pathways
2Productivity
If the F protein is mutated to increase fusogenic activity, then the virus can better infect and spread between cancer cells, but the risk of enhanced pathogenicity increases
Solution Approach 1:
The patent introduces specific localized mutations at the F protein cleavage site (e.g., adding polybasic sequences) to enhance fusogenic activity only at the critical cleavage region, while leaving the rest of the F protein structure intact. This localized modification allows controlled enhancement of infectivity without globally increasing pathogenicity
Solution Approach 2:
The patent carefully adjusts the cleavage site sequence parameters of the F protein to optimize fusogenic activity. By modifying specific amino acid residues at the cleavage site, the virus achieves enhanced cell-to-cell spread capability while maintaining controlled pathogenicity through precise parameter tuning rather than extensive structural changes
Data Source
AI summary
Described herein are chimeric Newcastle disease viruses engineered to express an agonist of a co-stimulatory signal of an immune cell and compositions comprising such viruses. Also described herein are chimeric Newcastle disease viruses engineered to express an antagonist of an inhibitory signal of an immune cell and compositions comprising such viruses. The chimeric Newcastle disease viruses and compositions are useful in the treatment of cancer. In addition, described herein are methods for treating cancer comprising administering Newcastle disease viruses in combination with an agonist of a co-stimulatory signal of an immune and/or an antagonist of an inhibitory signal of an immune cell.