Nicola E Annels 1 , David Mansfield 2 , Mehreen Arif 1 , Carmen Ballesteros-Merino 3 , Guy R Simpson 1 , Mick Denyer 1 , Sarbjinder S Sandhu 4 , Alan A Melcher 2 , Kevin J Harrington 2 , Bronwyn Davies 5 , Gough Au 5 , Mark Grose 5 , Izhar Bagwan 1 , Bernard Fox 3 , Richard Vile 6 , Hugh Mostafid 1 , Darren Shafren 5 , Hardev S Pandha 7 Show Affiliations »
Abstract
PURPOSE: The CANON [CAVATAK in NON-muscle-invasive bladder cancer (NMIBC)] study evaluated a novel ICAM-1-targeted immunotherapeutic-coxsackievirus A21 as a novel oncolytic agent against bladder cancer. PATIENTS AND METHODS: Fifteen patients enrolled in this "window of opportunity" phase I study, exposing primary bladder cancers to CAVATAK prior to surgery. The first 9 patients received intravesical administration of monotherapy CAVATAK; in the second stage, 6 patients received CAVATAK with a subtherapeutic dose of mitomycin C, known to enhance expression of ICAM-1 on bladder cancer cells. The primary endpoint was to determine patient safety and maximum tolerated dose (MTD). Secondary endpoints were evidence of viral replication, induction of inflammatory cytokines, antitumor activity, and viral-induced changes in resected tissue. RESULTS: Clinical activity of CAVATAK was demonstrated by induction of tumor inflammation and hemorrhage following either single or multiple administrations of CAVATAK in multiple patients, and a complete resolution of tumor in 1 patient. Whether used alone or in combination with mitomycin C, CAVATAK caused marked inflammatory changes within NMIBC tissue biopsies by upregulating IFN-inducible genes, including both immune checkpoint inhibitory genes (PD-L1 and LAG3) and Th1-associated chemokines, as well as the induction of the innate activator RIG-I, compared with bladder cancer tissue from untreated patients. No significant toxicities were reported in any patient, from either virus or combination therapy. CONCLUSIONS: The acceptable safety profile of CAVATAK, proof of viral targeting, replication, and tumor cell death together with the virus-mediated increases in "immunological heat" within the tumor microenvironment all indicate that CAVATAK may be potentially considered as a novel therapeutic for NMIBC. ©2019 American Association for Cancer Research.
PURPOSE: The CANON [CAVATAK in NON-muscle-invasive bladder cancer (NMIBC)] study evaluated a novel ICAM-1 -targeted immunotherapeutic-coxsackievirus A21 as a novel oncolytic agent against bladder cancer . PATIENTS AND METHODS: Fifteen patients enrolled in this "window of opportunity" phase I study, exposing primary bladder cancers to CAVATAK prior to surgery. The first 9 patients received intravesical administration of monotherapy CAVATAK; in the second stage, 6 patients received CAVATAK with a subtherapeutic dose of mitomycin C , known to enhance expression of ICAM-1 on bladder cancer cells. The primary endpoint was to determine patient safety and maximum tolerated dose (MTD). Secondary endpoints were evidence of viral replication, induction of inflammatory cytokines, antitumor activity, and viral-induced changes in resected tissue. RESULTS: Clinical activity of CAVATAK was demonstrated by induction of tumor inflammation and hemorrhage following either single or multiple administrations of CAVATAK in multiple patients , and a complete resolution of tumor in 1 patient . Whether used alone or in combination with mitomycin C , CAVATAK caused marked inflammatory changes within NMIBC tissue biopsies by upregulating IFN -inducible genes, including both immune checkpoint inhibitory genes (PD-L1 and LAG3 ) and Th1-associated chemokines, as well as the induction of the innate activator RIG-I , compared with bladder cancer tissue from untreated patients . No significant toxicities were reported in any patient , from either virus or combination therapy. CONCLUSIONS: The acceptable safety profile of CAVATAK, proof of viral targeting, replication, and tumor cell death together with the virus-mediated increases in "immunological heat" within the tumor microenvironment all indicate that CAVATAK may be potentially considered as a novel therapeutic for NMIBC. ©2019 American Association for Cancer Research.
Entities: Chemical
Disease
Gene
Species
Year: 2019
PMID： 31273010 DOI： 10.1158/1078-0432.CCR-18-4022
Source DB: PubMed Journal: Clin Cancer Res ISSN： 1078-0432 Impact factor: 12.531