The CANON trial, a window of opportunity phase I study of CAVATAK in non-muscle-invasive bladder cancer (NMIBC) has shown promising results. CAVATAK is a novel bio-selected formulation of coxsackievirus A21 (or CVA21). This study included 15 patients, the first 9 of whom received intravesical CAVATAK as monotherapy. The subsequent 6 participants received CAVATAK in combination with a subtherapeutic dose of mitomycin C. Primary end points were patient safety and maximum tolerated dose. Secondary end points were evidence of viral replication, inflammatory cytokine induction, antitumour activity and changes induced by the virus in resected tumour tissue. The induction of tumour inflammation and haemorrhage showed the clinical activity of CAVATAK after a single dose or multiple administrations; complete resolution was seen in one patient. CAVATAK had an acceptable safety profile, with no substantial toxic effects reported. Alone or in combination, CAVATAK caused notable inflammatory changes in NMIBC tissue, upregulating interferon-inducible genes including PD-L1 and LAG3. These data suggest that CAVATAK could be a novel therapeutic for NMIBC and can also increase immunological heat in NMIBC.