Researchers have developed a method to repurpose influenza viruses as therapeutic platforms for infectious diseases and cancer.
The findings, published in the journal Engineering, detail a system that uses engineered viruses designed to replicate only under specific controlled conditions.
Platform Mechanism
The platform incorporates non-canonical amino acids (ncAAs) into viral proteins through premature termination codons (PTCs). This creates "PTC viruses" that require a specific orthogonal tRNA/aminoacyl-tRNA synthetase pair and the matching ncAA to replicate. In tests on XH 293 cells, the PTC viruses replicated only in the presence of the matching ncAA and did not replicate in unmodified mammalian cells, even when ncAA was supplemented.
Applications for Vaccines
Animal studies in mice, ferrets, and guinea pigs indicated that PTC viruses induced stronger immune responses compared to a commercial inactivated influenza vaccine. All immunized mice survived challenge with wild-type influenza.
Applications for Cancer Therapy
The platform has been adapted for cancer therapy as the chimeric antigen peptide (CAP) Flu system. This system links tumor-associated antigens to viral hemagglutinin, includes a CpG-rich TLR9 agonist, and an anti-PD-L1 nanobody gene. In a lung metastasis model, intranasal administration of CAP Flu enhanced dendritic cell recruitment and activation and suppressed tumor growth.
Comparisons to Other Vectors
According to the researchers, compared to adenovirus and vesicular stomatitis virus (VSV) vectors, the PTC influenza system offers orthogonal and genetically stable attenuation, strong mucosal immunity, and consistent stoichiometric antigen display.
Challenges
The researchers identified several challenges for the platform:
- Preexisting immunity to influenza may limit vector spread.
- Biosafety evaluations of ncAAs are required.
- Tumor-targeting specificity for non-pulmonary tumors requires optimization.
Publication Details
The paper, authored by Demin Zhou, Dezhong Ji, and Jiandong Jiang, is published in Engineering and is available at: https://doi.org/10.1016/j.eng.2025.12.007