Phase 1 study of intravenous administration of the chimeric adenovirus enadenotucirev in patients undergoing primary tumor resection

Abstract

BackgroundEnadenotucirev (formerly ColoAd1) is a tumor-selective chimeric adenovirus with demonstrated preclinical activity. This phase 1 Mechanism of Action study assessed intravenous (IV) delivery of enadenotucirev in patients with resectable colorectal cancer (CRC), non-small-cell lung cancer (NSCLC), urothelial cell cancer (UCC), and renal cell cancer (RCC) with a comparator intratumoral (IT) dosed CRC patient cohort.MethodsSeventeen patients scheduled for primary tumor resection were enrolled. IT injection of enadenotucirev (CRC only) was administered as a single dose (≤ 3 × 1011 viral particles [vp]) on day 1, followed by resection during days 8–15. IV infusion of enadenotucirev was administered by three separate doses (1 × 1012 vp) on days 1, 3, and 5, followed by resection during days 8–15 (CRC) or days 10–25 (NSCLC, UCC, and RCC). Enadenotucirev activity was measured using immunohistochemical staining of nuclear viral hexon and quantitative polymerase chain reaction for viral genomic DNA.ResultsDelivery of enadenotucirev was observed in most tumor samples following IV infusion, with little or no demonstrable activity in normal tissue. This virus delivery (by both IV and IT dosing) was accompanied by high local CD8+ cell infiltration in 80% of tested tumor samples, suggesting a potential enadenotucirev-driven immune response. Both methods of enadenotucirev delivery were well tolerated, with no treatment-associated serious adverse events.ConclusionsThis study provides key delivery and feasibility data to support the use of IV infusion of enadenotucirev, or therapeutic transgene-bearing derivatives of it, in clinical trials across a range of epithelial tumors, including the ongoing combination study of enadenotucirev with the checkpoint inhibitor nivolumab. It also provides insights into the potential immune-stimulating properties of enadenotucirev.Trial registrationThis MOA study was a phase 1, multicenter, non-randomized, open-label study to investigate the administration of enadenotucirev in a preoperative setting (ClinicalTrials.gov: NCT02053220).Electronic supplementary materialThe online version of this article (doi:10.1186/s40425-017-0277-7) contains supplementary material, which is available to authorized users.

Oncolytic Viruses: Priming Time for Cancer Immunotherapy

“…However, it also poses a technical challenge depending on the tumor location, which can require specialized injection techniques via interventional radiology. On the other hand, the treatment of disseminated tumors using a systemically delivered OV may provide a greater chance of virus infection of multiple tumor nodules, as each tumor does not need to be directly injected [8,9]. Clinical responses in further clinical studies testing different routes of administration and doses will determine optimal conditions for oncolytic virotherapy.…”

Immuno-oncology: the next generation of breakthrough therapies. Highlights from The Society for Medicines Research Symposium. Oxford, UK - June 21, 2019

“…In cancer patients, EnAd has displayed a predictable and manageable safety profile following systemic (i.v.) dosing (20) as well as virus delivery and selective replication in tumor cell (21).…”

Cryo-EM structure of adenovirus type 3 fibre with desmoglein 2 shows a novel mode of receptor engagement

“…Desmoglein 2, a newly identified adenovirus receptor has been reported to be used by species B human adenoviruses such as HAd3, HAd7, HAd11 and HAd14 for cell infection 1 . As exemplified by HAd3 and HAd11, these viruses are used for cancer virotherapy 2,3,4 . The structure of the extracellular region of DSG2 containing four cadherin domains EC1 to EC4, has recently been solved by crystallography 5 .…”

“…The data presented here reveal a new mode of interaction for DSG2 interacting adenoviruses and provides new clues for the rational design of DSG2 interacting adenoviruses, subviral particles, or fibre knobs. Such vectors are currently undergoing a rapid development in therapy with HAd3, HAd11 being used in clinical trials 2,3,4 . Beside the use of oncolytic adenoviruses, HAd3 fibre-containing molecules such as penton-dodecahedron (symmetric particle harboring 12 fibres) or junction-openers (JOs) have been reported to act as enhancer of approved treatments in cancer therapies 1,10–12…”