Phase I Trial of an ICAM-1-Targeted Immunotherapeutic-Coxsackievirus A21 (CVA21) as an Oncolytic Agent Against Non Muscle-Invasive Bladder Cancer.
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Embargo End Date
ICR Authors
Authors
Annels, NE
Mansfield, D
Arif, M
Ballesteros-Merino, C
Simpson, GR
Denyer, M
Sandhu, SS
Melcher, AA
Harrington, KJ
Davies, B
Au, G
Grose, M
Bagwan, I
Fox, B
Vile, R
Mostafid, H
Shafren, D
Pandha, HS
Mansfield, D
Arif, M
Ballesteros-Merino, C
Simpson, GR
Denyer, M
Sandhu, SS
Melcher, AA
Harrington, KJ
Davies, B
Au, G
Grose, M
Bagwan, I
Fox, B
Vile, R
Mostafid, H
Shafren, D
Pandha, HS
Document Type
Journal Article
Date
2019-10-01
Date Accepted
2019-06-27
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.
Citation
Clinical cancer research : an official journal of the American Association for Cancer Research, 2019, 25 (19), pp. 5818 - 5831
Source Title
Publisher
AMER ASSOC CANCER RESEARCH
ISSN
1078-0432
eISSN
1557-3265
Collections
Research Team
Targeted Therapy
Translational Immunotherapy
Translational Immunotherapy