Common cold virus could transform bladder cancer treatment
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A novel therapeutic approach that involves the oncolytic virus coxsackievirus showed potential among a small cohort of patients with nonmuscle-invasive bladder cancer, according to study findings published in Clinical Cancer Research.
One patient had no trace of cancer following treatment.
“Traditionally, viruses have been associated with illness. However, in the right situation, they can improve our overall health and well-being by destroying cancerous cells,” Nicola E. Annels, BSc, PhD, research fellow at the University of Surrey in the U.K., said in a press release. “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.”
Annels and colleagues sought to evaluate the intercellular adhesion molecule 1 (ICAM-1)-targeted coxsackievirus A21 (CVA21), a naturally occurring strain of the common cold, as a novel oncolytic agent before surgery among 15 patients with nonmuscle-invasive bladder cancer.
According to results of the phase 1 study, the agent showed potential as a therapeutic for this patient population.
Annels spoke with HemOnc Today about the study and the clinical implications of the findings.
Question: What prompted this research?
Answer: The idea of using viruses in cancer therapy dates to the 1800s, when physicians first reported observing some patients with cancer go into remission after a viral infection. More recently, the oncolytic virus therapy field has recognized the important role the immune response plays in the therapeutic outcome of this therapy. This was shown by the first oncolytic virus to receive FDA approval, talimogene laherparepvec, also called T-VEC (Imlygic, Amgen), which was used as treatment for melanoma. Injection of this genetically engineered oncolytic herpes virus into skin tumors resulted in shrinkage or complete remission of tumors, even in distant tumor sites, suggesting that not only can T-VEC activate the immune system locally, it also generates a “memory” in the patient’s immune system. Our group had previously demonstrated the susceptibility of bladder cancer cell lines to CVA21, a naturally occurring common cold-producing oncolytic virus known to be effective against a range of solid tumors. We showed the ability of CVA21 to enhance bladder cancer cell-killing by modulating the expression of the viral receptor ICAM-1 with low doses of mitomycin C treatment and the induction of immunogenic cell death in CVA21-treated cell lines capable of potentially generating long-lasting protective antitumor immunity in the bladder mucosa. These results provided the rationale for a phase 1/phase 2 clinical trial to investigate the therapeutic potential of CVA21 as an immunotherapy approach for the treatment of nonmuscle-invasive bladder cancer.
Q: What was the rationale for why this may work for this population of patients?
A: The bladder is a hollow organ that provides an ideal environment for the administration of oncolytic viral therapy. Local delivery to the isolated bladder environment can be achieved easily and directly via catheter, allowing the tumor to be exposed to large doses of virus with complete control of exposure duration and sequencing of repeat doses and/or combination treatments based on existing schedules used for Bacillus Calmette-Guérin. Further, this can be accomplished with limited exposure to the rest of the body and therefore reduced toxicity.
Q: How did you conduct the study?
A: We studied the tolerability and safety of escalating doses of CVA21. This virus binds to ICAM-1, which is overexpressed on the surface of many human cancer cells, including bladder cancer. In this “window-of-opportunity” study, 16 patients with untreated nonmuscle-invasive bladder cancer received CVA21 alone or in combination with mitomycin C (to upregulate the expression of the virus receptor ICAM-1) before undergoing transurethral resection of bladder tumor as part of their standard clinical care. The primary endpoint of this trial was to determine patient safety and maximum tolerated dose. Intravesical virus treatment was followed by surgery after 8 to 11 days, allowing us to assess the resected tumor tissues for viral replication, antitumor activity and viral-induced changes in immune cell infiltrates. Serum and urine were collected on days 1 (before virus instillation), 3, 5 and 8 after virus treatment.
Q: Can you elaborate on what you found?
A: This trial allowed investigators to analyze cystoscopic photographs of the bladder tumor before and after virus therapy, which showed evidence of anticancer activity in resected cancer, including one complete response for one of three patients receiving the highest dose of CVA21 alone. Tumor tissue samples obtained after surgery also confirmed the virus was highly selective, targeting only the cancer cells and leaving all normal cells unharmed. Urine samples taken from patients on alternate days following virus administration detected shedding from the virus, which indicated that once virally infected cancer cells had died, the newly replicated virus continued to attack more cancerous cells in the organ. One of the main aims of oncolytic virus therapy is to stimulate a patient’s immune system to fight the cancer cells. This study clearly showed that CVA21 was able to do this. By performing a detailed analysis of the resected virus-treated tumor tissue, we observed a high level of immune cells and immune markers within the bladder tumors. This finding was in contrast to untreated bladder tumors, which generally have low levels of these immune cells. Thus, the use of a virus to treat bladder cancer makes the cancer look foreign, triggering an immune response that normally would not be activated by the tumor itself.
Q: What is next for research on this?
A: Importantly, we observed an increase in immune checkpoint inhibitory genes — genes that can dampen or inhibit immune responses — within the bladder tumors in response to the virus treatment. Although this might seem to be a negative side effect, the efficacy of oncolytic virus therapy is expected to improve further when combined with immunotherapy using specific immune checkpoint inhibitors. The idea is that treatment of a tumor with a virus will increase the infiltration of immune cells, upon which the checkpoint inhibitors can work to keep the immune cells functioning against the cancer. Therefore, the next stage of clinical evaluation of CVA21 in nonmuscle-invasive bladder cancer logically would be in combination therapy, sequencing the checkpoint inhibitor after CVA21 to provide a potential alternative to standard Bacillus Calmette-Guérin. – by Jennifer Southall
Reference:
Annels NE, et al. Clin Cancer Res. 2019;doi:10.1158/1078-0432.CCR-18-4022.
For more information:
Nicola E . Annels , BSc, PhD, can be reached at the University of Surrey, Guildford, Surrey GU2 7XH, United Kingdom; email: n.annels@surrey.ac.uk.
Disclosure: Annels reports no relevant financial disclosures.