Hard-to-treat cancers cause approximately 165,000 UK deaths annually. While cell-and-gene therapies (CGT) provide new hope compared to traditional treatments, they still face significant challenges. CGT treatments can offer patients an average of 5.8 extra years of good-quality life. However, the tumour microenvironment (TME) --- the area surrounding, created by the tumour --- often weakens a sufferer's immune system, making it difficult to mount a defensive-response to a tumour. Current therapies, such as CAR-T can lose effectiveness over time as tumour-associated-macrophages (TAMs) help protect the tumour and allow it to survive. One promising solution is gene-silencing technology, which aims to shut down certain genes that promote tumour-growth, thereby invigorating the immune response. However, existing gene-silencing methods have limitations: siRNA (small-interfering-RNA) works only for a short period before it degrades, shRNA (short-hairpin-RNA) can be switched off by changes in the cell, and miRNA-based therapies can also be inactivated, reducing their long-term effectiveness. To address these challenges, Laverock Therapeutics proposes a 21-month project to develop, test its novel gene-silencing platform called Non-disruptive scaffold-insertion (NDSI). This new technology affords improvements over existing approaches. It's a unique platform leveraging the natural process within a cell to regulate gene silencing. It provides long-lasting gene-silencing that can be dialled-in and-out of action when a cell needs it, which is matchless. Furthermore, the technology supports fine-tuning of the silencing effect, with access to a library of thousands of miRNA-based designs, enabling an optimum one to be found per treatment. Dialling-in-out gene silencing reflecting how the cell responds over time. A major advantage is that it can target multiple genes for silencing at once in a therapeutic cell. This is critical as cancer involves several genes working together to protect the tumour as it evades current therapy. This enables a cell-therapeutic to deploy counter-measures to immune-evasive-tumours. Silencing multiple gene-targets simultaneously increases the chances of overcoming the tumour's defences. This project will focus on using NDSI to target specific genes in TAMs. There are several known, and this project will discover more. After initial lab testing, studies will be conducted to assess how well it works in reducing tumours in living systems. Addressing current therapy weaknesses, this approach will strengthen the immune system's ability to fight tumours effectively, enhancing cancer treatment. Support from the Cell & Gene Therapy Catapult focuses on showcasing the project successes with the NHS and potential partners from the pharmaceutical industry to support post-project product development.

Cell therapy involves injecting, grafting, or implanting healthy cells into a patient to repair damaged tissue and/or cells, or to kill tumour cells. Currently, three cell therapies are NHS approved as a treatment for blood cancer (Kymriah, Yescarta, Tecartus), with many more in clinical evaluation. Cancer is a leading cause of mortality worldwide, accounting for nearly one in six deaths. Mortality is reduced when it's detected and treated early**,** though many cancer types including ovarian and the paediatric cancer, neuroblastoma, remain refractory even to patient targeted therapies. It is now known that soft-tissue cancers other than blood, exacerbate their own growth as they subdue normally effective immune cells, rendering them docile and unable to effectively eliminate the abnormal cancerous cells. Novel treatments are needed for these hard-to-treat cancers in women and children. A radical new solution is needed to reverse the subduing effect on immune cells, to turn the cells being coerced by the cancer into ones that can be invigorated to activate other immune effector cells and to kill the tumour. This project focusses on a radical new, cell therapy concept and if successful, will generate proof of concept data that the initial design works, and the highly innovative cell therapy idea can work by reactivating cancer-fighting immune cells, such as T-cells. The project is carried out by Laverock Therapeutics, a UK-based biotech company with a novel, patented innovation for conditional and safe turning off genes in cells and by this virtue can instil designer properties in a future therapy for cancer that is unprecedented. Laverock will perform the work but will work closely with a leading cancer research centre of excellence, funded by Cancer Research UK. They will perform a research service helping the company develop the concept via utilization of unique cancer-related laboratory tools. These, together with other preclinical assessments will prove valuable in maximising the company's gene engineering technology and delivering the laboratory data to support the cell therapy design. If successful, the project will deliver new exploitable innovation, derived from the unique combination of technologies and expertise. Experimental data will be published, disseminated to explain the beneficial prospects of the work to these communities affected by cancer. Data will be decision making for the company on how to further translate the project's output into a realizable safe, more durable and effective cellular immunotherapy for cancer. It will derive collaborative partnerships with cancer clinicians and companies.

Cell therapy involves injecting, grafting, or implanting healthy cells into a patient to repair damaged tissue and/or cells, or to kill tumour cells. Currently, three cell therapies are NICE approved, as a treatment for blood malignancies (Kymriah, Yescarta, Tecartus), with many more in clinical evaluation. Human cell therapy may be allogeneic (nonself/donor-derived) or autologous (self-derived). Allogeneic cell therapy is attractive because a single cell source can be used to treat multiple patients and diverse diseases. This enables manufacture at scale, significantly reducing per-patient treatment costs. In contrast, autologous, _ex vivo_-modified cell therapy is processed in individual batches for the patient being treated, making it expensive and difficult to scale. However, allogeneic cell therapy suffers from the significant drawback of eliciting a significant immune response from the patient, leading to immune rejection. This can be a major issue, requiring costly immunosuppressive therapy, which is often associated with serious and long-term side effects. State-of-the-art gene editing (GE) technologies attempt to reduce the immune response associated with the introduction of allogeneic cells. Human leukocyte antigen (HLA) is the main cause of immune-incompatibility. HLA genes encode the major histocompatibility complex (MHC) membrane-bound glycoproteins in humans. Through GE (e.g., CRISPR/Cas9 gene knockout), HLA proteins can be readily eliminated. However, this creates additional problems since the immune system can detect the lack of HLA expression on target cells, then deploying Natural Killer (NK) cells to attack HLA deficient grafts, unless other 'tolerizing' transgenes are expressed to suppress their activation, an approach which adds further complexity. Skylark Therapeutics has an exclusive licence agreement with Tropic Biosciences to develop their proprietary and patented cutting-edge gene silencing technology (GEiGS) in human therapeutics. GEiGS is a platform technology, which is already proven in plants and animals, but has yet to be fully tested in humans, although its core components (GE and RNA interference - RNAi) are already used as separate modalities in human therapies. GEiGS combines the strengths of both GE and RNAi approaches to deliver stable, tunable, and programmable gene expression regulation. GEiGS is uniquely suited to engineer cells that evade both T and NK cell responses after transplantation, and will therefore enable us to generate allogeneic cell therapies that are not rejected. GEiGS technology has the potential to revolutionise cell therapy, unlocking effective and accessible treatments for a wide range of diseases, including cancers, musculoskeletal disorders, and central nervous system disorders.