Public Funding for Theolytics Ltd

Annually 7,495 women in the UK are diagnosed with ovarian cancer (OC). \>75% of cases are diagnosed at an advanced stage (grade-III/IV) with poor long-term outcomes (<25% 5-year survival). Standard-of-care first-line treatments combine cytoreductive surgery, platinum-based chemotherapies, and paclitaxel. Although initially effective, most patients relapse and become resistant to platinum-based therapies. The are no effective treatments for platinum-resistant OC and patients have a life expectancy of less than 12-months. Whilst immunotherapies have shown great promise for many cancers, results for OC remain disappointing. This is believed to result from the heterogeneous and immune-suppressed nature of the tumour-microenvironment, and the high volume of cancer-associated-fibroblasts (CAFs), that create physical barriers to therapeutic- and immune-cell penetration, and promote tumour survival and proliferation mechanisms. Oncolytic viruses (OVs) are an emerging immunotherapy class that selectively infect cancer cells and induce immunogenic cell death, leading to tumour reduction, modulation of the tumour-microenvironment (lifting immune suppression), and stimulation of adaptive immune responses. Importantly, OVs demonstrate phenotypic selectivity, overcoming challenges of heterogeneity. However, existing OVs are primarily developed from seroprevelant wild-type viruses that are not evolved for oncolytic use, using simple cell-/animal-models that poorly model real tumour-/host-responses. Furthermore, OVs are unable to overcome CAF-associated extracellular barriers that hinder infection/spread. THEO-260 is a next-generation OV-therapeutic for the treatment of PROC, demonstrating world-first dual-efficacy (targeting both cancer- and CAF-cells), enabling effective treatment of stroma-rich tumours. IV-delivery enables THEO-260 to be incorporated seamlessly into standard-of-care practices. Step-advancements in features are achieved via Theolytic's revolutionary OV-platform. THEO-260 is anticipated to deliver a step-advancement in PROC treatment, significantly extending patient survival and quality-of-life.

Multiple myeloma (MM) is an incurable blood cancer affecting ~5,800 UK citizens each year. Prognosis is poor with a <29% 10-year survival rate. MM treatments are given in cycles of triplet chemo-, immuno-, and corticosteroid- therapeutic combinations. Periods of remission between cycles become increasingly shorter (from 2+ years to <6-months) as the disease builds resistance, until eventual death. The primary limitation of existing treatments is their targeted approach, acting on a specific molecular site/pathway. MM has several defences to such therapies (genomic variability/heterogeneity, phenotypic plasticity/adaptability, and immune suppression/resistance). Whilst novel advanced therapies (CAR T-cell etc.) are emerging, these are also targeted in nature and unlikely to offer a durable treatment/cure. A further limitation of existing treatments is their cost (£50K-£200K/therapy, £200K+/combination treatment, and £800K+/patient across 4/5-treatment cycles). Oncolytic viruses (OVs) are an emerging therapy offering hope for difficult to treat cancers such as MM. OVs selectively infect/lyse/kill cancer cells, whilst simultaneously stimulating strong immune responses (lifting cancer-associated immune suppression). Importantly, OVs attack the cancer based on its phenotype rather than molecular targets. This enables high potency against systemic heterogeneous cancers (whilst preventing evolved resistance/immunity), providing durable remission/curative potential (and reduced treatment cycles). However, existing OVs are primarily re-purposed seroprevalent laboratory/wild-type viruses, not evolved/optimised for combating human cancers, and thus demonstrate limited efficacy/systemic stability. Furthermore, existing development approaches utilise laboratory cell lines/animal models that poorly reflect real tumour/human responses, frequently de-selecting viruses with efficacy in patients. Theolytics overcome these challenges through a novel OV Platform.

Ovarian cancer (OC) is the 6th most common cause of cancer death. Annually \>7,443 women are diagnosed (\>240,000 globally). Mortality rates are \>65%, with most patients succumbing within 5-years. OC is frequently diagnosed at a late stage making it difficult to treat. Whilst initial response to chemotherapy is high, most patients (\>80%) quickly acquire (platinum-)resistance and relapse. Second-line chemotherapies/targeted-biologicals offer only marginal benefit in slowing progression. Emerging immunotherapies empower the patient's immune system to fight cancer and offer hope as effective second-line treatments. However, most (\>85%) OC tumours are devoid of essential immune cells/processes, making them unresponsive to immunotherapies. Oncolytic viruses (OVs) act by selectively infecting/destroying cancer cells, whilst simultaneously stimulating strong immune responses (recruiting immune cells/lifting cancer-associated immune suppression). A key strength of OVs is the ability to arm them with one/more synergistic therapeutic transgenes that may be expressed directly within the tumour (enhancing efficacy/bypassing toxicities). However, existing OVs are derived from re-purposed/common laboratory/wild-type viruses that are not evolved for oncolytic use nor systemic delivery, but instead developed/validated using laboratory cell-lines or mice that poorly reflect patient tumours. Typical arming strategies select 1-2 transgenes (from thousands of options) using a 'best-guess' approach on basic models (often de-selecting candidates with efficacy in real tumours, and poorly synergising with the virus). They give little attention to optimising transgene position within the virus (a critical variable for effective transgene expression). Theolytics seek to overcome these challenges through application of their disruptive OV Platform.