Public Funding for Deliver Biosciences Limited

Gene therapy covers a range of medicines which modify gene expression in cells to correct disease. This can be by stopping production of mutated genes, introducing normal, healthy ones or by providing completely new 'synthetic' genes. A limited set of approved gene therapies can already cure forms of blindness, muscular atrophy and cancer. It is generally necessary to confine gene therapy to a particular set of cells where it is necessary, as any modification to a cell may cause harm. For instance, expression of a synthetic gene designed to stimulate intracellular signalling on contact with cancer cells can help T-cells kill lymphoma (in Chimeric Antigen Receptor (CAR)-T therapy) but could be detrimental in other cell types. Hence therapies need to be targeted, and expression tightly controlled in time and space. Achieving such specific and efficient gene delivery to cells inside the body has not previously been possible, and therefore most approaches modify cells in a laboratory, before returning them to patients. This means traditional methods to get genes into cells can be used under controlled conditions, e.g. electroporation or viruses. However, this adds significant complexity and costs as it is difficult to safely maintain cells outside the body and has limited the reach of gene therapies, as current examples cost from £300,000-£1.8M and can only be dosed in a handful of specialist centres. Therefore gene therapies for rare diseases, or those for which a cure might be preferable but non-essential, may not pass cost-benefit thresholds. _In vivo_ gene therapy, where off-the-shelf delivery vectors are dosed into patients and modify cells inside them, can solve these issues. However, to realise this we desperately need safe, efficient and specific delivery vectors for gene payloads. Deliver Biosciences is focussed on engineering these technologies, and has started with a targeted lipid nanoparticle (tLNP) to deliver CARs specifically to T-cells. We have developed a novel safe gene expression system we call EDGE to use inside these tLNPs. In this project, we want to build a screening process to speed up our discovery of EDGE constructs and new tLNPs. We have designed a powerful system that we will evaluate, and validate its capability by optimising new EDGE constructs for T-cells and two other types. This will build better prototypes for Deliver's pipeline and a screening process to quickly engineer and derisk new synthetic biology constructs to fulfil industry needs and open new markets for gene therapy.

The immune system contains many different cells with different properties, and recently, technologies have been developed that empower immune cells against specific diseases. An example where immune cells are modified to make them effectively kill cancer cells is CAR-T therapy. These therapies hold the promise of selectively destroying cancer cells by finding these cells throughout the body (unlike surgery/radiotherapy) and have been successful against previously incurable blood cancers. However, these life-changing treatments are **prohibitively expensive** to the NHS (~250 patients per year allowed within the NHS cancer budget, and 5000 UK patients diagnosed annually) because of their current external manufacturing process. The production can take 60 days, requiring expert labour, and expensive facilities/materials. **Costs exceed £280,000/dose, and only available at specialist centres.** It is clear that these therapies **cannot become mainstream medicines in current form**. This delays their transformative potential in many common diseases which could benefit millions. ImmTune has developed a **nanoparticle-based technology** (similar to the one used in Pfizer's COVID vaccine) for the purpose of making these therapies **inside patients**. Our product will be a simple injection allowing rapid dosing to all the patients in need in a way that's faster, affordable and more effective. **Our technology would democratise these powerful therapies, and remove barriers of inequality in accessing these treatments**. We have demonstrated the potential of our technology for a subset of immune cells, T cells by creating CAR-T cells using our technology, and are now expanding the reach of our platform to a wider set of patients by testing it in a different immune cell subtype; natural killer (NK) cells. These cells have shown to be more potent at addressing more blood cancer, and solid tumour conditions. A successful project outcome would lead to us catering to a wider patient population. Dr Bakul Gupta is one of the **founders/CEO** and has years of experience in working with such nanoparticle-based technologies. Her knowledge and domain e**xpertise has laid the foundation** for the technology being built by the company. She is a **young first-time scientist turned entrepreneur who aspires to create affordable therapies for all patients using her skill set and the most cutting-edge scientific developments, and also be a trailblazer for women founders in the biotech sphere.** She has been leading the company for 3 years, and wants to continue doing this effectively by tapping into different expertise via IUK and KTN networks if awarded this grant.

ImmTune Therapies is developing a revolutionary new method of immune cell therapy, whereby patients' cells can be genetically modified inside their bodies to endow them with cancer-fighting properties. Our first focus is in CD19 Chimeric Antigen Receptor (CAR) T-cell therapy, a game-changing cancer treatment where patient's immune cells are modified to express a CAR, which directs them towards a molecule named CD19, which is expressed on cancer cells in many types of B-cell lymphoma. Our product is a targeted nanoparticle gene-delivery technology, called NanoCART-19, designed to deliver CARs to T-cells in the body. Our groundbreaking method will offer major advantages over current and developing CAR-T technologies, which rely on manufacturing the CAR-T cells outside the body. The currently approved process causes the treatments to cost \>£250,000pp and take 6-8 weeks to reach patients, which renders over 75% of NHS patients in need ineligible to receive therapy. With our method, treatment can become as quick as a **one-step off-the-shelf injection**, and **5-10 fold cheaper**, allowing treatment of **many more patients** and **lowering the burden** on healthcare systems such as the NHS. Our **rigorous customer discovery** (over a 12-month period) has highlighted the significant market desire for such a technology, from **pharmaceutical to medical professionals**. However, a robust demonstration of the capability of our technology is needed to secure investment and accelerate development. This project will demonstrate the potential of NanoCART-19 in treating B-cell lymphomas, by experimental validation in preclinical models and will compare CAR-T cells generated by NanoCART-19, to those currently used in the clinic. We will also build a supporting case to take this innovative method of cell therapy into humans for the first time, by engaging with regulatory bodies, investigating manufacturing scale-up and GMP compliance and working to position NanoCART-19 in the rapidly developing CAR-T market. ImmTune has gathered an **expert team** to deliver this ambitious project, including the **Cell and Gene Therapy Catapult** and **Dr Robert Koechl from King's College London**. The successful completion of this collaboration will drive ImmTune's product **towards the clinic and stimulate growth and investment,** allowing CAR-T therapy to benefit more patients in urgent need. Today, we are closer than ever to creating cancer treatments that don't just treat patients but can actually cure them, in a single treatment. ImmTune's technology is designed to make these cures available to many more patients who need them, **democratising cell therapy and opening new markets**.