RT Journal Article
SR Electronic
T1 Phase 1 study of intravenous administration of the chimeric adenovirus enadenotucirev in patients undergoing primary tumor resection
JF Journal for ImmunoTherapy of Cancer
JO J Immunother Cancer
FD BMJ Publishing Group Ltd
SP 71
DO 10.1186/s40425-017-0277-7
VO 5
IS 1
A1 Rocio Garcia-Carbonero
A1 Ramon Salazar
A1 Ignacio Duran
A1 Ignacio Osman-Garcia
A1 Luis Paz-Ares
A1 Juan M. Bozada
A1 Valentina Boni
A1 Christine Blanc
A1 Len Seymour
A1 John Beadle
A1 Simon Alvis
A1 Brian Champion
A1 Emiliano Calvo
A1 Kerry Fisher
YR 2017
UL http://jitc.bmj.com/content/5/1/71.abstract
AB Background Enadenotucirev (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.Methods Seventeen 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.Results Delivery 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.Conclusions This 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 registration This 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).Abbreviations:AEAdverse eventCDCluster of differentiationCRCColorectal cancerCTLCytotoxic T cellDSG2Desmoglein 2FoxP3Forkhead box P3GCPGood Clinical PracticeICHInternational Conference on HarmonisationIFNInterferonIgGImmunoglobulin GIHCImmunohistochemistryILInterleukinITIntratumoralIVIntravenousMCPMonocyte chemoattractant proteinMOAMechanism of actionMSIMicrosatellite instabilityNSCLCNon-small-cell lung cancerPD-1Programmed cell death 1PD-L1PD-1 ligand 1qPCRQuantitative polymerase chain reactionRCCRenal cell cancerSAESerious adverse eventTNFTumor necrosis factorTregRegulatory T cellUCCUrothelial cell cancervpViral particles