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Viral targeting of non-muscle invasive bladder cancer and priming of anti-tumour immunity following intravesical Coxsackievirus A21

Annels, Nicola E, Mansfield, David, Arif, Mehreen, Ballesteros-Merino, Carmen, Simpson, Guy R, Denyer, Mick, Sandhu, Sarbjinder S, Melcher, Alan, Harrington, Kevin J, Davies, BronwYn , Au, Gough, Grose, Mark, Bagwan, Izhar N, Fox, Bernard A., Vile, Richard G, Mostafid, Hugh, Shafren, Darren and Pandha, Hardev (2019) Viral targeting of non-muscle invasive bladder cancer and priming of anti-tumour immunity following intravesical Coxsackievirus A21 Clinical Cancer Research.

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Abstract

Purpose: The CANON (CAVATAK in NON-muscle invasive bladder cancer) study evaluated a novel ICAM-1-targeted immunotherapeutic-coxsackievirus A21 as a novel oncolytic agent against bladder cancer.

Experimental Design: Fifteen patients enrolled on this 'window of opportunity' phase 1 study, exposing primary bladder cancers to CAVATAK prior to surgery. The first nine patients received intravesical administration of monotherapy CAVATAK; in the second stage, six patients received CAVATAK with a sub-therapeutic dose of mitomycinC, known to enhance expression of ICAM-1 on bladder cancer cells. The primary endpoint was to determine patient safety and maximum tolerated dose. Secondary endpoints were evidence of viral replication, induction of inflammatory cytokines, anti-tumour activity and viral-induced changes in resected tissue.

Results: Clinical activity of CAVATAK was demonstrated by induction of tumour inflammation and haemorrhage following either single or multiple administrations of CAVATAK in multiple patients, and a complete resolution of tumour in one patient. Whether used alone or in combination with mitomycinC, CAVATAK caused marked inflammatory changes within NMIBC tissue biopsies by up-regulating interferon-inducible genes including both immune checkpoint-inhibitory genes (PD-L1 and LAG3) and Th1-associated chemokines as well as induction of the innate activator RIG-I, compared to 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 tumour cell death together with the virus-mediated increases in "immunological heat" within the tumour microenvironment all indicate that CAVATAK may be potentially considered as a novel therapeutic for NMIBC.

Item Type: Article
Divisions : Faculty of Health and Medical Sciences > School of Biosciences and Medicine
Authors :
NameEmailORCID
Annels, Nicola E
Mansfield, David
Arif, Mehreenm.arif@surrey.ac.uk
Ballesteros-Merino, Carmen
Simpson, Guy RG.Simpson@surrey.ac.uk
Denyer, MickM.Denyer@surrey.ac.uk
Sandhu, Sarbjinder S
Melcher, Alan
Harrington, Kevin J
Davies, BronwYn
Au, Gough
Grose, Mark
Bagwan, Izhar N
Fox, Bernard A.
Vile, Richard G
Mostafid, Hughh.mostafid@surrey.ac.uk
Shafren, Darren
Pandha, HardevH.Pandha@surrey.ac.uk
Date : 4 July 2019
DOI : 10.1158/1078-0432.CCR-18-4022
Copyright Disclaimer : Copyright ©2019, American Association for Cancer Research.
Uncontrolled Keywords : Non-muscle; Bladder; Cancer; Oncolytic; Virus
Depositing User : Clive Harris
Date Deposited : 11 Jul 2019 15:26
Last Modified : 05 Jul 2020 02:08
URI: http://epubs.surrey.ac.uk/id/eprint/852248

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