1283 Oncolytic immunotherapy THEO-260 enters readiness for first in human clinical trial in ovarian cancer patients

<h3>Background</h3> Ovarian Cancer (OC) is considered an immunologically cold tumour, characterised by a complex, suppressive tumour microenvironment (TME), abundant with stromal cancer associated fibroblasts (CAFs). THEO-260 is a novel oncolytic adenovirus capable of lysing both cancer cells and CAFs, triggering immunogenic cell death, and promoting T-cell activation. <h3>Methods</h3> Efficacy of THEO-260 was assessed in cell lines, <i>ex vivo</i> fresh OC patient samples and mouse models bearing subcutaneous and peritoneal human tumours (including CAFs). Safety was evaluated in a panel of primary human normal cells, and in immunocompetent CD-1 mice under GLP conditions. THEO-260 was manufactured at scale under GMP conditions. <h3>Results</h3> THEO-260 was highly efficacious in a panel of OC cell lines (n=8), different stromal rich tumour types (n=9) and a panel of fresh OC patient samples (n=33), killing cancer cells and CAFs. THEO-260 induced immunogenic cell death and T-cell activation (assessed by T-cell proliferation and IFN-𝛾 expression). In <i>in vivo</i> studies, THEO-260 demonstrated superior efficacy over paclitaxel in a subcutaneous platinum resistant high grade serous OC model (COV318) with human CAFs (MRC5). Intraperitoneally injected THEO-260 was capable of eliminating cancer cells (non-serous OC SKOV3-Luc) and inhibiting the formation of ascites in a peritoneal metastasis mouse model designed to mimic the OC TME. THEO-260 showed a strong safety profile, demonstrating selective replication in tumour cells with minimal levels of infectious virions produced across a range of normal primary human cells (n=17). It was well tolerated <i>in vivo</i> with no clinical signs, behavioural changes or body weight loss observed in a GLP toxicology study at planned clinical dose level equivalents. As expected following oncolytic virus delivery, THEO-260 caused a transient immune reaction <i>in vivo</i>. In preparation for clinical readiness, a desensitisation dosing regimen was developed to reduce immune related adverse reactions. Using this dosing regimen, the release of inflammatory cytokines were decreased by up to 11-fold in immunocompetent CD1 mice. Lastly, THEO-260 was successfully scaled up and GMP manufactured to high yields. <h3>Conclusions</h3> Preclinical data suggests that THEO-260 is efficacious and safe, and was successfully produced to large GMP scale. THEO-260 has gained regulatory approval for initiation of a first in human Phase I/IIa clinical trial in the UK, as an open-label, dose finding, safety, tolerability, and exploratory trial in patients with high grade serous or endometrioid ovarian cancer. <h3>Ethics Approval</h3> Human samples used in this research project were obtained from and approved by the relevant ethics committees including MCRC Biobank Research Tissue Bank Ethics, THE CHRISTIE NHS FOUNDATION TRUST Biobank and Imperial HealthCare Tissue Bank (approved by Wales REC3 22/WA/2836). In vivo studies were approved by the University of Oxford Animal Welfare and Ethical Approval Body (AWERB) and by the Home Office under Project Licence number P096ECC10. GLP toxicity study was approved by Barcelona Science Park Ethical Review Process (CEEA code 10379-P1).