Scientists at Peking University have developed an innovative method for delivering therapeutic cancer vaccines using an engineered influenza virus.
Genetic mutations that occur in tumor cells generate neoantigens that can induce tumor-specific immune responses. Although many neoantigens have been identified, delivery of these neoantigens for tumor-specific immunotherapy remains a challenge. Various forms of neoantigens, such as protein- and peptide-based as well as nucleic acid-based vaccines, are currently in clinical trials.
Scientists have developed a variety of methods to deliver neoantigens, including dendritic cell-based vaccines, viral vector vaccines, and biomaterials/nanomaterials-based vaccines. However, these approaches are limited by problems such as poor uptake and presentation of neoepitopes and low immunogenicity. In addition, solid tumors have an immunosuppressive microenvironment that raises the threshold for immune activation.
On May 25, 2023, Demin Zhou's team at Peking University published a research paper titled "An engineered influenza virus to deliver antigens for lung cancer vaccination" in the Nature Biotechnology subjournal.
The study developed a chimeric antigenic peptide influenza virus system, CAP-Flu, to deliver antigenic peptides conjugated to influenza A virus via inhalation to the lung for the treatment of lung cancer and prevention of metastasis of multiple tumors to the lung. More importantly, this engineered influenza A virus can bind to any tumor neoantigen of interest to generate new therapeutic lung cancer vaccines.
In December 2016, D.M. Zhou's team published a paper in the journal Science based on the phenomenon that bionic influenza viruses are much less likely to reinfect normal humans in the short term after infection, and on the theory that viral synthetic biology-terminated codons encode unnatural amino acids-to modify influenza viruses to carry premature termination codons (PTCs) that are fully infectious but unable to replicate in conventional cells. Such PTC-carrying viruses induce robust humoral, mucosal and T-cell immune responses in mice, guinea pigs and ferrets, protecting them from influenza attack.
In this latest work, the research team adapted this live influenza virus into a therapeutic tumor vaccine and validated it in a mouse tumor model.
Previous studies have observed that influenza A virus infection leads to tumor remission, but the severe respiratory complications that can result limit the translation of IAV into cancer therapies. In this latest study, the team developed a novel strategy to generate chimeric antigenic peptide influenza virus from live but non-replicating IAV.
The team chimerized the immune adjuvant CpG oligonucleotide with cholesterol molecules on the lipid membrane of a previously developed PTC virus and coupled chemically synthesized small peptide molecules to the HA protein of the lipid membrane via a click chemistry reaction. By exploiting the natural lung habitat of the influenza virus, the antigenic peptide is efficiently absorbed through the respiratory tract, uniformly distributed and tightly attached to the lung cells, making the influenza virus an excellent delivery system for the antigenic peptide. Antigenic peptides chimerized on PTC viruses can efficiently activate dendritic cells of antigen-presenting cells.
The team demonstrated that CAP-Flu delivers the tumor model antigen ovalbumin (OVA) to the lung, where it is able to induce robust antigen uptake, trigger innate and adaptive immune responses, and remodel the tumor microenvironment into a transient inflammatory state, thereby promoting tumor-specific cytotoxic T-cell infiltration into the tumor.
The research team further engineered the influenza virus genome to introduce a gene encoding anti-PD-L1 antibody into the PB2 gene sequence, which after inhalation was able to efficiently express anti-PD-L1 antibody only at the site of infection and further eliminate the immunosuppressive microenvironment and synergistically enhance the anticancer effect in a murine melanoma lung metastasis model.
In addition, the study showed that tumor neoantigen replacement could achieve the same therapeutic effect in lung metastasis models of colon and breast cancer tumors. Transformation provides a versatile strategy for synthetic peptide-guided, tumor-specific and personalized immunotherapy.