Phase I/II CANON study: oncolytic immunotherapy for the treatment of non-muscle invasive bladder (NMIBC) cancer using intravesical coxsackievirus A21

Background

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.

Methods

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.

Results

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.

Conclusions

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.

Clinical trial identification

VLA-012

Legal entity responsible for the study

Viralytics Ltd

Funding

Viralytics Ltd

Disclosure

All authors have declared no conflicts of interest.