Every year, more than 49,000 people in the UK are diagnosed with lung cancer, and about a quarter of those tumours carry mutations in the KRAS gene. Current mRNA-based personalised vaccines are injected into the skin or muscle, but for lung cancer, delivering the vaccine directly to the airway could produce stronger, longer-lasting immunity. The problem is that the lung is built to expel inhaled material, and mRNA is fragile, so airway delivery has never been achieved for cancer vaccines. This project tests a new approach: biodegradable polymer particles, modified with peptides that bind to receptors in the lung, to carry mRNA encoding mutated KRAS proteins directly into the airway. The researchers will first confirm that cells in the lab correctly produce and display the neoantigens from the delivered mRNA, then check that the airway delivery triggers an antibody response in living animals. If successful, this early-stage validation will raise the technology’s readiness level and open the door to testing the platform in lung cancer models. The work is fundamental—it asks whether the delivery system works at all—but without that proof, no clinical application can follow.
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Each year in the UK, more than 49,000 people are diagnosed with lung cancer and around a quarter contain mutations in the KRAS gene. Once considered 'undruggable', KRAS can now be targeted by advanced therapeutic approaches such as mRNA based personalised vaccines that can train the immune system to recognise mutated proteins (neoantigens) and eliminate the cancerous cells harbouring them. However, mRNA vaccines are typically injected into the skin or muscle but it has shown that for lung immunity, local delivery to the airway may enhance long-term protection. Delivery of mRNA to the airway faces many hurdles including formulation stability, mucosal clearance and barrier function of the lung which acts to expel inhaled materials. Consequently, airway delivery of personalised cancer vaccines has not yet been demonstrated. We have previously developed biodegradable polymeric vectors that enabled the first nebulisation of mRNA to the airway. To improve potency and reduce mucosal clearance, we have built on this platform to generate prototype peptide modified materials to bind to receptors in the lung and have shown enhanced mRNA delivery in barrier epithelium of reporter proteins compared to unmodified polymers. To progress our technology towards clinical application, we propose to deliver mRNA encoding mutated KRAS with the peptide-polymers in an airway delivery platform. The airway plays an important role in immune regulation, functioning as sentinel immunoregulators providing an excellent therapeutic target for our technology. The proposed work in this grant will be critical at this early stage to validate the peptide-polymers for; 1. Production of mRNA encoded neoantigen production in vitro and correct presentation. 2. Generation of antigen specific antibody response in vivo following airway delivery Achieving these defined aims will increase technology readiness level by confirming that mRNA encoded neoantigen presentation is possible our airway delivery platform and move towards a specific clinical application. The MRC Developmental Pathway Gap Fund provides an appropriate framework to de-risk the technology for future funding to investigate efficacy in lung cancer models for further product development.
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