enadenotucirev (ColoAd1) / Akamis Bio - LARVOL DELTA

Replication-Competent, Tumor-Specific Immuno-Gene Vectors Allow for Exchange of Transgenes and Lead to Viral Persistence Following IV Administration. (PubMed, J Immunother Precis Oncol) - "Enadenotucirev (EnAd) and successor transgene-armed Tumor-Specific Immuno-Gene (T-SIGn) vectors are replication-competent, blood-stable viral vectors that traffic to tumor sites following intravenous (IV) administration...The aggregated safety analysis revealed that safety and tolerability are defined by systemic viremia but not off-target or transgene-related toxicities. Nucleic acid and cytokine release from tumors and changes in the TME (e.g., CD8+ T cells), indicative of the mechanism of action of replication-competent viral vectors, constitute potentially valuable data to support the definition of a recommended phase 2 dose and the assessment of the benefit of multicycle administration."

IO biomarker • Journal • Oncology • Solid Tumor • CCL2 • CD8 • IFNG • IL17A • IL6

ASCENDING AORTIC THROMBUS: A CASE REPORT OF CATASTROPHIC SYSTEMIC EMBOLIZATION AND MANAGEMENT CHALLENGES - Enad Haddad (ACC 2025) - "AAT presents a significant treatment dilemma. Our case demonstrates the high embolization risk and highlights the need for thorough risk-benefit evaluation for surgical management of AAT."

Case report • Clinical • Hypertension • Interstitial Lung Disease • Pulmonary Disease • Respiratory Diseases • Thrombosis

Gut microbiome and gene expression changes during a Phase 1 trial of enadenotucirev and radiotherapy (ESTRO 2024) - P1 | "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."

P1 data • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Rectal Cancer • Solid Tumor • ATG5 • CDK1 • DSG2 • HPRT1

Phase I tolerability, persistence and pharmacodynamic (PD) profile of IV-administered next-generation adenoviral vectors supports clinical expansion in solid cancers (ESMO-TAT 2024) - P1 | "Methods The unarmed tumour-selective chimeric group B adenovirus enadenotucirev (EnAd) was evaluated in phase 1 studies in advanced/metastatic epithelial tumors and in locally advanced rectal cancer (LARC). Conclusions The sustained detection of vector DNA and persistence within tumors suggests next-generation T-SIGn vectors can be successfully administered IV. Preclinical studies support further clinical testing of targeted delivery of a CD40 agonist mAb with NG-350A to build on the intriguing results in the LARC pilot study and in disease-specific expansion cohorts in combination with CPIs."

Clinical • IO biomarker • P1 data • PK/PD data • Viral vector • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Rectal Cancer • Solid Tumor • CD80 • CD86 • IFNG

Toward the understanding of DSG2 and CD46 interaction with HAdV-11 fiber, a super-complex analysis. (PubMed, J Virol) - "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."

Journal • Infectious Disease • Oncology • CD46 • DSG2

A Phase 1 Trial of the Safety, Tolerability, and Biological Effects of Intravenous Enadenotucirev (EnAd), a Novel Oncolytic Virus, in Combination with Chemoradiotherapy in Locally Advanced Rectal Cancer (CEDAR). (PubMed, Int J Radiat Oncol Biol Phys) - P1 | "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."

Combination therapy • Journal • Metastases • Oncolytic virus • P1 data • Acute Kidney Injury • Colorectal Cancer • Gastrointestinal Cancer • Gastrointestinal Disorder • Nephrology • Oncology • Rectal Cancer • Renal Disease • Solid Tumor

Akamis Bio Highlights Data Showing Potential of its Adenovirus Vector Technology in Combination with Radiation to Treat Advanced Rectal Cancer (Businesswire) - P1 | N=13 | NCT03916510 | "Akamis Bio...shared data today from a Phase 1 study of its adenovirus vector technology in combination with radiotherapy that showed improved response rates relative to expectations for radiation alone in patients with locally advanced rectal cancer. The CEDAR study, sponsored by Cancer Research UK and Akamis Bio, found that Enadenotucirev (EnAd), a tumor selective, I.V.-administered oncolytic adenovirus (on which T-SIGn therapeutics are based), in combination with chemoradiotherapy, showed significantly higher response rates by MRI assessed tumor regression grade (mrTRG – 41.6%) and pCR/cCR (41.6%) than expected rates (~20%) for standard chemoradiation. In the two dose schedules with administration pre-CRT and post-CRT, mrTRG of 1 or 2 was observed in 5 out of 10 (50%) of the treated patients....Data from the CEDAR study will be presented today at the 2023 American Society for Radiation Oncology Annual Meeting in San Diego, CA."

P1 data • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Rectal Cancer • Solid Tumor

A Phase 1 Trial of the Safety, Tolerability, and Biological Effects of Intravenous Enadenotucirev (EnAd), a Novel Oncolytic Virus, in Combination with Chemoradiotherapy in Locally Advanced Rectal Canc (ASTRO 2023) - P1 | "Pre-clinical evidence of synergy with radiation warranted further clinical evaluation and assessment of safety in combination with chemoradiation (CRT), 25 x 2Gy and concurrent capecitabine. 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."

Clinical • Combination therapy • Metastases • Oncolytic virus • P1 data • Acute Kidney Injury • Colorectal Cancer • Gastrointestinal Cancer • Gastrointestinal Disorder • Nephrology • Oncology • Renal Disease • Solid Tumor

CEDAR: Chemoradiation With Enadenotucirev as a Radiosensitiser in Locally Advanced Rectal Cancer (clinicaltrials.gov) - P1 | N=13 | Completed | Sponsor: University of Oxford | Recruiting ➔ Completed | N=30 ➔ 13 | Trial completion date: Jan 2024 ➔ Feb 2023 | Trial primary completion date: Mar 2022 ➔ Feb 2023

Combination therapy • Enrollment change • Metastases • Oncolytic virus • Trial completion • Trial completion date • Trial primary completion date • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Rectal Cancer • Solid Tumor

Safety and efficacy of the tumor-selective adenovirus enadenotucirev, in combination with nivolumab, in patients with advanced/metastatic epithelial cancer: a phase I clinical trial (SPICE). (PubMed, J Immunother Cancer) - P1 | "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."

Clinical • Combination therapy • IO biomarker • Journal • Metastases • P1 data • P1 data • Cardiovascular • Colorectal Cancer • Gastrointestinal Cancer • Gastrointestinal Disorder • Head and Neck Cancer • Heart Failure • Hematological Disorders • Microsatellite Instability • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CD8 • IFNG • IL17A • MSI

[VIRTUAL] Prolonged overall survival (OS) in patients with metastatic colorectal cancer (mCRC) in SPICE, a phase I study of enadenotucirev in combination with nivolumab (SITC 2020) - P1, P3 | "Ethics Approval The study was approved by the Western Institutional Review Board, study approval number 1160755. A phase I multicenter study of enadenotucirev in combination with nivolumab in tumors of epithelial origin: an analysis of the metastatic colorectal cancer patients in the dose escalation phase."

Clinical • Combination therapy • P1 data • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • PD-1

Safety and tolerability of T-SIGn vectors when administered using “flat” versus “low-high-high” (LHH) dosing regimens. (ASCO 2022) - P1 | " Data were pooled from three Phase 1 dose-escalation studies in advanced/metastatic epithelial cancer: SPICE (EnAd + pembrolizumab/nivolumab; NCT02636036), FORTITUDE (NG-350A ± pembrolizumab; NCT03852511) and STAR (NG-641; NCT04053283). LHH dosing appears to induce a desensitization mechanism allowing higher cumulative doses of T-SIGn vectors to be given without the associated acute reactions to viral infusions. This finding may have implications for optimizing safety-efficacy profiles of viral vectors in cancer."

Clinical • Inflammation • Oncology • Solid Tumor • IFNG • IL6 • TNFA

NG-796A: A T-SIGn vector designed to reprogram the tumor microenvironment and drive anti-tumor immunity (SITC 2022) - "Background T-SIGn virus vectors are transgene-modified variants of enadenotucirev (EnAd), an Ad11p/Ad3 chimeric group B adenovirus, which retain all the functional and epithelial tumor-selectivity properties of EnAd, while also mediating the selective expression of transgenes by infected tumor cells...This data is consistent with the encoded transgenes supporting the infiltration and anti-tumor activity of T-cells in this solid tumor setting. Conclusions Due to its potential to reprogram the TME and support T-cell activity, NG-796A was selected as a candidate for progression into formal preclinical development activities in preparation for clinical evaluation."

Biomarker • IO biomarker • Tumor microenvironment • Oncology • Solid Tumor • CCL21 • IFNG • IL12A • IL15

Combining enadenotucirev and nivolumab increased tumour immune cell infiltration/activation in patients with microsatellite-stable/instability-low metastatic colorectal cancer in a phase 1 study (SITC 2021) - P1 | "Efforts are now focused on the development of next-generation variants of enadenotucirev designed to further re-programme the tumour microenvironment by expressing immune-enhancer transgenes (T-SIGn vectors); these studies are ongoing (NCT04830592, NCT04053283, NCT03852511). EudraCT number 2017-001231-39NCT number: NCT02636036"

Clinical • IO biomarker • P1 data • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CD38 • CD4 • CD8 • GZMB • IFNG • IL17A • MSI • PD-L1

NEBULA: A multicenter phase 1a/b study of a tumor-selective transgene-expressing adenoviral vector, NG-641, and nivolumab in patients with metastatic or advanced epithelial tumors. (ASCO 2022) - P1, P1a/1b | "Background: Tumor-Specific Immuno Gene Therapy (T-SIGn) vectors are next-generation transgene-armed variants of the adenoviral vector enadenotucirev that selectively replicate in epithelial tumor cells. Serial blood samples will be analyzed to study cytokine production and changes in peripheral immune cell subsets. Enrollment to the first dose-escalation cohort is ongoing."

Clinical • IO biomarker • P1 data • Gene Therapies • Inflammation • Oncology • Solid Tumor • CAFs • CXCL9 • FAP • IFNA1

A phase I study of enadenotucirev (EnAd), an oncolytic Ad11/Ad3 chimeric group B adenovirus, in combination with nivolumab in tumors of epithelial origin. (ASCO 2017) - P1; "Secondary endpoints include overall response, duration of response and progression free survival, assessed according to RECIST Version 1.1 and irRECIST Version 1. Enrollment to cohorts 3 & 4 began in January 2017."

Checkpoint inhibition • Combination therapy • Oncolytic virus • P1 data • Biosimilar • Bladder Cancer • Colorectal Cancer • Non Small Cell Lung Cancer

A multicenter phase 1a/b study of NG-641, a tumor-selective transgene-expressing adenoviral vector, and nivolumab in patients with metastatic or advanced epithelial tumors (NEBULA) (AACR 2022) - P1, P1a/1b | "Background: T-SIGn (Tumor-Specific Immuno Gene Therapy) vectors are transgene-expressing variants of the blood-stable adenovirus enadenotucirev. Analyses of serial blood samples will explore cytokine production and changes in peripheral immune cell subsets. Enrollment to the first dose-escalation cohort is ongoing."

Clinical • IO biomarker • P1 data • Oncology • Solid Tumor • CAFs • CXCL10 • CXCL9 • FAP • IFNA1

Safety and efficacy of the tumor-selective adenovirus enadenotucirev with or without paclitaxel in platinum-resistant ovarian cancer: a phase 1 clinical trial. (PubMed, J Immunother Cancer) - P1 | "Intravenously dosed enadenotucirev plus paclitaxel demonstrated manageable tolerability, an encouraging median PFS and increased tumor immune-cell infiltration in platinum-resistant ovarian cancer."

Clinical • Journal • P1 data • Hematological Disorders • Infectious Disease • Neutropenia • Oncology • Ovarian Cancer • Solid Tumor

SPICE: Phase I Study of Enadenotucirev and PD-1 Inhibitor in Subjects With Metastatic or Advanced Epithelial Tumors (clinicaltrials.gov) - P1; N=51; Completed; Sponsor: 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

Clinical • Enrollment change • Trial completion • Trial completion date • Trial primary completion date • Colorectal Cancer • Gastrointestinal Cancer • Head and Neck Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • PD-L1

[VIRTUAL] Prolonged overall survival (OS) in patients with metastatic colorectal cancer (mCRC) in SPICE, a phase I study of enadenotucirev in combination with nivolumab (SITC 2020) - P1, P3 | "Ethics Approval The study was approved by the Western Institutional Review Board, study approval number 1160755. A phase I multicenter study of enadenotucirev in combination with nivolumab in tumors of epithelial origin: an analysis of the metastatic colorectal cancer patients in the dose escalation phase."

Clinical • Combination therapy • P1 data • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • PD-1

OCTAVE: A phase I study of enadenotucirev, an oncolytic group B adenovirus, in combination with weekly paclitaxel in platinum-resistant epithelial ovarian cancer (ESMO 2019) - P1; "The combination of EnAd and Pxl has manageable tolerability. Favorable disease control is noted in this recurrent platinum-resistant population, which is worthy of further investigation. Clinical trial identification: 2013-001276-38."

Combination therapy • P1 data

Optimizing the tolerability of intravenous oncolytic viral immunotherapy administration: investigation of a low-high-high dose schedule of enadenotucirev (EnAd) administration (AACR 2019) - P1; "It is currently in combination studies with nivolumab and paclitaxel. Tolerability of EnAd is primarily determined by C1D1, correlating with the cytokine response across the patient cohort. The data from this in vivo pharmacology study support the concept of delivering a lower dose of enadenotucirev on Day 1 and administering higher doses thereafter, with the aim to deliver a higher viral load to tumour tissue and potentially optimise the overall risk:benefit of EnAd administration. This type of dosing regimen (low-high-high) has been successfully implemented in clinical studies of other systemically administered oncolytic viruses (Clin Cancer Res 2006;12:2555-2562) and is under clinical investigation as part of the ongoing combination study with nivolumab."

Oncolytic Virus

SPICE, a phase I study of enadenotucirev in combination with nivolumab in tumours of epithelial origin: Analysis of the metastatic colorectal cancer patients in the dose escalation phase (ESMO 2019) - "The combination of EnAd and nivolumab has a manageable toxicity profile supporting further investigation in study expansion. Favourable OS outcome in a highly refractory CRC population was noted and may suggest delayed immune antitumor activity in this population. Clinical trial identification: 2017-001231-39."

Clinical • Combination therapy • IO Biomarker • P1 data • PD(L)-1 Biomarker

A multicenter, open label, first-in-human study of an oncolytic viral vector expressing an agonistic anti-CD40 antibody (NG-350A) in patients with epithelial tumors (FORTITUDE). (ASCO 2019) - "Background: NG-350A is a transgene modified variant of the oncolytic platform virus enadenotucirev (EnAd) which expresses a fully human agonist anti-cluster of differentiation 40 (anti-CD40) antibody. Up to six patients are planned to undergo surgical resection of a tumor lesion to optimize translational research. Clinical conduct of the study was initiated in February 2019."

Clinical • Oncolytic Virus • P1 data

[VIRTUAL] T-SIGn cancer gene therapy and anti-EGFR CAR-T cells synergize in combination therapy to clear A549 lung tumor xenografts and lung metastases in NSG mice (AACR 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."

CAR T-Cell Therapy • Combination therapy • IO biomarker • Preclinical • Hematological Malignancies • Lung Cancer • Oncology • Solid Tumor • CXCL9 • IFNG • IRF1 • SOCS1 • TNFSF10