LOCATE: Local Oesophageal CAncer Treatment Engineering to advance the understanding and treatment of oesophageal adenocarcinoma.

Every year ~9000 people are diagnosed with oesophageal cancers in UK, and this disease is responsible for 5% of cancer-related deaths. Research efforts must continue to discover new therapies, in particular for oesophageal adenocarcinoma (OAC, the most common subtype of oesophageal cancers in Western Countries), because even cancers diagnosed at an operable stage have 50% of risk to recur after surgery and chemotherapy and the survival at 5 year from diagnosis and treatment remains very low (10-15%) (https://www.cancerresearchuk.org/about-cancer/oesophageal-cancer). Therefore, Cancer Research UK and Medical Research Council have described OAC as having urgent unmet need.

New medicines that boost the immune system against cancer (immunotherapies) can prolong life of patients with OAC and are effective in average for 10-20% of patients. One of the reasons why many cancers defy these medicines is related to a local immune-suppression that shuts the anti-cancer responses down. The research of our group has identified one of the critical mechanisms by which cancers shut the anti-cancer responses down, hence we are proposing a new strategy to release the brakes of the anti-cancer defences. We propose to use an RNA therapeutic, which requires to be prepared into nanomedicine similar to the COVID19 mRNA vaccines. Since adding up many systemic drugs (oral or intravenous medicines) to treatment protocols can significantly increase toxicity while retaining diluted effects where they are needed (e.g. inside the cancer), we also propose to perform an in-depth engineering study combined with bespoke biochemical technologies to allow this novel RNA-based nanomedicine to be delivered optimally inside the cancer, targeting a specific group of cells responsible for hampering the anti-cancer immunity. In our engineering, physics, biochemistry and immune-biology labs in London, Edinburgh and Manchester we will test if our ideas are feasible (Can engineering and physical simulations drive the creation of a new nanomedicine capable to achieve effective localised delivery and address a specific type of cells within the tumour? Can this new, very precise nanomedicine effectively restore anti-cancer immune responses?). If our results are demonstrated to be positive, this new therapeutic will bring new hope to OAC patients: although this proposal is for a proof of principle, early-stage preclinical study, our long-term plan is to move towards a clinical application (we will start to apply for funding for the necessary pre-clinical testing and identify funding and stakeholders for a Phase I clinical trial during Work Package 3). The results of our project will contribute not only to the engineering, biochemistry and immune-oncology academic knowledge, but also provide a potential useful tool against OAC for the medicine of the future. Also, our results would indirectly contribute to advance treatment of other cancers since our new strategy to design nanomedicines could be applied to other diseases.

Despite advances, outcomes of patients with oesophageal adenocarcinoma (OAC) remain bleak: survival for primary OAC remains at 10-15% 5 years after diagnosis. An immune-refractory microenvironment is a key reason for poor therapeutic response.

Systemic therapies cause severe toxicity and locoregional therapies are scarce: radiotherapy and radiofrequencies are mostly palliative and used in clinical trials with systemic therapies for inoperable patients, whilst oncolytic viruses are in clinical trials to enhance immunotherapy.

We propose a new way to engineer and deliver therapy for OAC. We will study in-depth the physical properties of the OAC tumour microenvironment. Using algorithms to analyse histological tissue and ultra-high-definition computed tomography we will model the fluid dynamics that determine diffusion in the tumour. Our simulation will drive our design of OAC-specific nanoparticles, so that their physics (e.g., dimension, shape, fluid viscosity) and chemistry (e.g., surface charge, embedding of monoclonal antibodies directed to cell-subset-specific targets) will optimise the diffusion, bioavailability and selectivity for a multi-level precision.

Then, we will synthesise nanoparticles in a controlled manner to maximise the delivery of a nucleic acid drug that we have identified as a novel immune-checkpoint, to a subset of "pro-cancer" immune cells to switch them from immune-suppressive to anti-cancer. We will use in-vitro data to select the nanoparticle with maximum selectivity and biological activity.

Last, we will inject the OAC surgical specimens from the patients with our nanoparticles to verify our prediction model. Thus, we will eventually tune our nanoparticles' parameters and adjust the design algorithms so that we can apply these to other clinical settings. If our proof of principle project is successful, we will design a phase I clinical trial to translate the results of our research into patients' benefit.