CAVATAK® is a novel, bio-selected Intercellular Adhesion Molecule 1 (ICAM-1) targeted immunotherapeutic Coxsackievirus A21 (CVA21). Surface ICAM-1 is up-regulated on NMIBC. CVA21 displays potent oncolytic activity against in vitro cultures of NMIBC cancer cells and ex-vivo human bladder tumor. Combining CVA21 with mitocycin C (MMC) synergistically enhances viral replication by increasing expression levels of ICAM-1.
The CANON study investigated the tolerance of escalating intravesical (IV) doses of CVA21 in 16 first-line NMIBC cancer pts. Stage 1 Cohort 1 (n = 3) and Cohort 2 (n = 3), pts received a single CVA21 administration at 1 x 108 and 3 x 108 TCID50, respectively. In Cohort 3 (n = 3), pts received 2 doses of CVA21 at 3 x 108 TCID50. Stage 2: Cohort 1 (n = 3), pts received a single CVA21 dose of 3 x 108 TCID50 and Cohort 2 (n = 3) with 2 doses of CVA21 at 3 x 108 TCID50, both in combination with MMC (10mg). Cystoscopy photography was performed before and after treatment (tx). IV tx was followed by TURBT surgery after 8-11 days, with tissues analysed for CVA21 replication, apoptosis, evidence of viral-induced changes immune cell infiltrates (multi-spectral imaging) and immune checkpoint molecules.
Data indicate tolerance of IV CVA21 tx. Serial cystoscopy identified viral-induced surface haemorrhage and immune inflammation of the tumor micro-environment. Virus replication within tumor was highlighted by detection of secondary viral load peaks in the urine. TURBT tissue analysis displayed marked tumor specific viral replication and evidence of viral-induced apoptotic cell death. NanoString analysis identified widespread increases in interferon (IFN), viral RNA and immune-checkpoint genes in CVA21-treated tissues compared to untreated historical controls.
Clinical activity of CVA21 was demonstrated by evidence of complete tumor response, viral replication and notable signs of tumor inflammation. The observed up-regulation of IFN/immune checkpoint genes provides evidence for the generation of both strong local and systemic anti-tumor immune responses.
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All authors have declared no conflicts of interest.