enadenotucirev (ColoAd1)

Purpose/Objective: The CEDAR trial was a multi-centre phase 1 clinical trial (NCT03916510) in locally advanced rectal cancer patients which combined 25x2Gy chemoradiation with concurrent capecitabine and Enadenotucirev (EnAd), a tumourselective intravenous oncolytic adenovirus. S5230 Radiobiology - Microenvironment Interpatient microbial heterogeneity is greater than dynamic microbiome shifts through treatment in this study. Certain microbiome constituents may be associated with more favourable radiation responses. The absence of significant microbial variation during treatment suggests baseline microbiome features could be further explored as a predictive biomarker.

Enadenotucirev, a chimeric HAdV-11p/HAdV-3 adenovirus identified by bio-selection, is a low seroprevalence vector active against a broad range of human carcinoma cell lines...However, this information is very important, as it has a direct influence on the effectiveness of HAdV-11-based vectors. The aim of this work is to determine which of the two receptors, DSG2 and CD46, is involved in the attachment of the virus to the host, and what role they play in the early stages of infection.

CEDAR is the first trial to successfully combine an intravenous oncolytic adenovirus with radiation, demonstrating the feasibility and acceptability of this approach, and a new paradigm in radiosensitization in rectal cancer. Within this small Phase I study, EnAd demonstrated an acceptable safety profile with evidence of a higher-than-expected rate of response by mrTRG. Translation analysis of tissue, blood and microbiome for biological correlates of radiation synergy is underway.

P1, N=13, Completed, University of Oxford | Recruiting --> Completed | N=30 --> 13 | Trial completion date: Jan 2024 --> Feb 2023 | Trial primary completion date: Mar 2022 --> Feb 2023

Intravenously dosed enadenotucirev plus nivolumab demonstrated manageable tolerability, an encouraging overall survival and induced immune cell infiltration and activation in patients with advanced/metastatic epithelial cancer. Studies of next-generation variants of enadenotucirev (T-SIGn vectors) designed to further re-program the tumor microenvironment by expressing immune-enhancer transgenes are ongoing.

P1, N=51, Completed, PsiOxus Therapeutics Ltd | Active, not recruiting --> Completed | N=135 --> 51 | Trial completion date: Jun 2021 --> Oct 2021 | Trial primary completion date: Jun 2021 --> Oct 2021

P1, N=135, Active, not recruiting, PsiOxus Therapeutics Ltd | Recruiting --> Active, not recruiting | Trial completion date: Mar 2022 --> Jun 2021 | Trial primary completion date: Dec 2021 --> Jun 2021

We hypothesized that IV-deliverable T-SIGn cancer gene therapy vectors based on the oncolytic adenovirus enadenotucirev, which carry a transgene cassette encoding human immunomodulatory molecules to aid recruitment and activation of T-cells, could enhance the anti-tumor activity of human anti-EGFR CAR T cells in vivo...Since both agents were delivered systemically, this observation may reflect direct therapeutic activity at the metastatic sites. Taken together, these results indicate that combination therapy with a T-SIGn vector and CAR T cells holds great potential to be efficacious in humans with solid tumors.

Tumor-Specific Immuno-Gene (T-SIGn) cancer gene therapy vectors, which are based on the oncolytic adenovirus enadenotucirev, carry a gene cassette encoding combinations of human transgenes under control of the virus major late promoter (MLP) which restricts expression to tumor cells...Upregulation of IFNγ and Granzyme B in culture media indicated a strong activation of T-cells via expression of the bispecific T-cell activator. Cytotoxic T-cell activation also led to dose-dependent cell killing in NSCLC spheroids as shown by life/death analysis.Having established this proof of concept for functionality of T-SIGn viruses in PDOTS, ongoing studies are evaluating the immunomodulatory activities of a series of T-SIGn viruses expressing human IL-12 with or without other cytokine/chemokines.

Using intravital microscopy, a decreased perfused vessel volume was observed in infected tumour nodules upon systemic delivery of EnAd, encoding the oxygen-independent fluorescent reporter UnaG to a tumour xenograft grown under an abdominal window chamber. We conclude that the attenuation of the HIF pathway upon adenoviral infection may contribute to anti-vascular and immunostimulatory effects in the periphery of established infection foci in vivo.