A strain of the common cold virus has been found to potentially target, infect and destroy cancer cells in the majority of 15 patients with bladder cancer, a small UK clinical study reports, with no trace of the cancer was found in one patient.
Researchers from the University of Surrey and Royal Surrey County Hospital investigated the safety and tolerability of exposure to the oncolytic (“cancer-killing”) virus coxsackievirus (CVA21), a naturally occurring strain of the common cold, in fifteen patients with non-muscle invasive bladder cancer (NMIBC). NMIBC is found in the tissue of the inner surface of the bladder and is the tenth most common cancer in the UK with approximately 10,000 people each year diagnosed with the illness.
Current treatments for this cancer are problematic. Trans-urethral resection, an invasive procedure that removes all visible lesions, has a high tumour recurrence rate ranging from 50% to 70% as well as a high tumour progression rate between 10% and 20% over a period of two to five years. Another common course of treatment, immunotherapy with Bacille Calmette-Guerin, a live bacterium used to treat bladder cancer, has been found to have serious side effects in one third of NMIBC patients while one third do not respond to the treatment at all.
During this pioneering study fifteen NMIBC patients, one week prior to pre scheduled surgery to remove their tumours, received CVA21 via a catheter in the bladder. Examination of tissue samples post-surgery discovered that the virus was highly selective, targeting only cancerous cells in the organ and leaving all other cells intact. The virus was found to have infected cancerous cells and replicated itself causing the cells to rupture and die. Urine samples taken from patients on alternate days detected ‘shedding’ from the virus indicating that once virally infected cancer cells had died, the newly replicated virus continued to attack more cancerous cells in the organ.
Typically, tumours in the bladder do not have immune cells, preventing a patient’s own immune system from eliminating the cancer as it grows. Evidence suggests treatment with CVA21 inflames the tumour causing immune cells to rush into the cancer environment, targeting and killing the cancer cells. These tumours devoid of immune cells are known as ‘cold’ areas immunologically; however, treatment with the virus causes inflammation and immune cell stimulation to create ‘immunological ‘heat’. ‘Hot’ tumours in this way are more likely to be rejected by the immune system.
Following treatment with the virus cell death was identified in the majority of the patients’ tumours. In one patient no trace of the cancer was found during surgery.
Hardev Pandha, principal investigator of the study and professor of medical oncology at the University of Surrey, said: “Non-muscle invasive bladder cancer is a highly prevalent illness that requires an intrusive and often lengthy treatment plan. Current treatment is ineffective and toxic in a proportion of patients and there is an urgent need for new therapies.
“Coxsackievirus could help revolutionise treatment for this type of cancer. Reduction of tumour burden and increased cancer cell death was observed in all patients and removed all trace of the disease in one patient following just one week of treatment, showing its potential effectiveness. Notably, no significant side effects were observed in any patient.”
Dr Nicola Annels, research fellow at the University of Surrey, said: “Traditionally viruses have been associated with illness however in the right situation they can improve our overall health and wellbeing by destroying cancerous cells. Oncolytic viruses such as the coxsackievirus could transform the way we treat cancer and could signal a move away from more established treatments such as chemotherapy.”
Allen Knight, chair of Action Bladder Cancer UK, said in a BBC News report that the study findings were “very exciting”. Bladder cancer costs the NHS more per patient than nearly every other cancer, because of the high recurrence rate, he said. “If the safety, tolerability, and efficacy data can be confirmed in larger clinical studies and trials, then it could herald a new era in the treatment for non-muscle-invasive bladder cancer patients, like me, who often feel that innovations in cancer therapies pass us by.”
Dr Mark Linch, a bladder cancer expert at the Cancer Research UK Cancer Institute at University College London, said the initial results were “encouraging”.
“It will be really interesting to see how this new virus-based therapy fares in larger trials in people with non-muscle invasive bladder cancer, particularly in combination with newer immunotherapies,” he said.
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.
Nicola E Annels, David Mansfield, Mehreen Arif, Carmen Ballesteros-Merino, Guy R Simpson, Mick Denyer, Sarbjinder S Sandhu, Alan Melcher, Kevin J Harrington, BronwYn Davies, Gough Au, Mark Grose, Izhar N Bagwan, Bernard A Fox, Richard G Vile, Hugh Mostafid, Darren Shafren and Hardev Pandha