SURREY, U.K.—While the idea of a virus being helpful isn't entirely unheard of—adeno-associated virus vectors have been in use for years as vehicles for different therapies—the common cold is hardly what one would think of as anything other than a nuisance. But a particular strain of the cold virus, coxsackievirus (CVA21), could indeed join the ranks of viruses with a positive impact.
A team of researchers from the University of Surrey and Royal Surrey County Hospital explored the safety and tolerability of oncolytic CVA21 in patients with bladder cancer, and their results were published in Clinical Cancer Research in a study titled “Viral targeting of non-muscle invasive bladder cancer and priming of anti-tumour immunity following intravesical Coxsackievirus A21.”
The study was conducted in 15 patients with non-muscle invasive bladder cancer (NMIBC). A week before they were slated to undergo surgery to remove their tumors, the study participants received CVA21 via a catheter in the bladder, as explained in a University of Surrey press release by Natasha Meredith. Administration of CVA21 was found to be both selective and effective, according to Meredith's piece: “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.”
A majority of the patients all presented with cell death in their tumors as a result of CVA21 treatment. In the most impressive example of the effectiveness of this approach, one patient showed no trace of cancer during surgery.
“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,” Hardev Pandha, principal investigator of the study and Professor of Medical Oncology at the University of Surrey, said in a statement. “Coxsackievirus could help revolutionize treatment for this type of cancer. Reduction of tumor 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.”
As the authors reported in their abstract, “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.” MitomycinC is “known to enhance expression of ICAM-1 on bladder cancer cells,” as noted in the paper.
The increased inflammatory activity is promising, as Meredith's piece explains that tumors in the bladder generally lack immune cells. Increased inflammation attracts attention from the immune system, which increases the chances of the immune system detecting and killing the bladder cancer cells. Th1 cells activate macrophages, a key part of the immune system, and RIG-I can trigger apoptosis in cancer cells.
“The direct cytotoxic effect of oncolytic viruses is important, but it is now well recognized that the anticancer effects of oncolytic viruses also come from the activation of innate and adaptive tumor-specific immunity31, 32, 33, 34 and the immunogenicity of dying or dead cancer cells,” the authors wrote in their paper. “Understanding the mode of cancer cell death induced by particular oncolytic viruses is important when considering these agents for cancer therapy.”
Even though it was a small sample size, the effectiveness seen in this study—and the lack of toxic side effects—bodes well for the field of bladder cancer, which is in need of newer and safer therapies.
As noted in the 2018 Molecular Therapy Oncolytics paper “Oncolytic Immunotherapy for Bladder Cancer Using Coxsackie A21 Virus,” for which Pandha was an author, “Urothelial cancer of the bladder is the seventh most common cancer in the UK, with over 10,000 new cases annually in the UK.1 Superficial, non-muscle invasive bladder cancers (NMIBCs) are managed with cystoscopic transurethral resection of all visible lesions followed by intravesical chemotherapy and/or immunotherapy.2 The use of Bacillus Calmette-Guerin (BCG) as an immunotherapy for NMIBC and its proven effects of reducing recurrence and progression and improving disease-specific survival revolutionized the treatment of this malignancy in the 1970s. However, the potential for serious side effects of local and systemic BCG infection as well as the fact that there is a significant (30%) group of non-responder patients to BCG highlights the need to develop future immune-based therapies that overcome these problems.
“Treatment options and their outcomes in NMIBC have not changed significantly in decades. Whereas BCG continues to be the standard of care in patients with high-grade superficial disease, this is at a significant cost in terms of morbidity associated with BCG, the frequency and duration of treatments, and propensity to recur.”