Cold virus could transform bladder cancer treatment

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September 23, 2019

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Nicola E. Annels, BSc, PhD

Nicola E. Annels

A new therapeutic approach involving the oncolytic virus coxsackievirus showed potential in a small cohort of patients with non-muscle-invasive bladder cancer, according to research results published in Clinical Cancer Research.

One patient had no trace of cancer after treatment.

“Traditionally, viruses have been associated with disease. In the right situation, however, they can improve our overall health and well-being by destroying cancer cells.” NicolaE. Annels, BSc, PhD, researcher at the University of Surrey in the UK, in a press release. “Oncolytic viruses such as the coxsackie virus could change the way we treat cancer and could represent a shift away from more established treatments, such as chemotherapy.”

Annels and colleagues sought to evaluate the intercellular adhesion molecule 1 (ICAM-1) targeting coxsackievirus A21 (CVA21), a naturally occurring cold strain, as a novel oncolytic agent before surgery in 15 patients with non-muscle-invasive bladder cancer.

According to the results of the phase 1 study, the drug showed potential as a therapeutic agent for this patient population.

Annes spoke to HemOnc Today about the study and the clinical implications of the findings.

Question: What reason for this research?

Answer: The idea of ​​using viruses in cancer therapy dates back to the 1800s, when doctors first reported that some cancer patients went into remission after a viral infection. More recently, the field of oncolytic viruses has recognized the important role the immune response plays in the therapeutic outcome of this therapy. This was demonstrated by the first oncolytic virus to be approved by the FDA, talimogene laherparepvec, also called T-VEC (Imlygic, Amgen), which was used as a treatment for melanoma. Injection of this genetically engineered oncolytic herpes virus into skin tumors resulted in shrinkage or complete remission of tumors even at distant tumor sites, suggesting that T-VEC can not only activate the immune system locally, but also generate a “memory” in the patient’s memory. . immune system. Our group had previously demonstrated the susceptibility of bladder cancer cell lines to CVA21, a naturally occurring cold-producing oncolytic virus, which is known to be effective against a range of solid tumors. We demonstrated 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 that may have long-lasting protective antitumor immunity. in the bladder mucosa. These results formed 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 non-muscle invasive bladder cancer.

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Q: What was the reason why this might work? in front of this patient population?

AN: The bladder is a hollow organ that provides an ideal environment for the delivery of oncolytic viral therapy. Local delivery to the isolated bladder environment can be achieved easily and directly via a catheter, allowing the tumor to be exposed to large doses of virus with full control over the duration of exposure and the order of repeated doses and/or combination treatments based on existing schedules used in front of Bacillus Calmette-Guerin. Furthermore, this can be achieved with limited exposure to the rest of the body and thus reduced toxicity.

Q: How did you conduct the research?

AN: We investigated the tolerability and safety of increasing 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 non-muscle-invasive bladder cancer received CVA21 alone or in combination with mitomycin C (to increase expression of the virus receptor ICAM-1) before undergoing transurethral resection of bladder tumor as part of of their standard clinical care. The primary endpoint of this study was to determine patient safety and maximum tolerated dose. Intravesical virus treatment was followed by surgery after 8 to 11 days, which allowed us to assess the excised tumor tissues for viral replication, antitumor activity and virus-induced changes in immune cell infiltrates. Serum and urine were collected on day 1 (before virus instillation), 3, 5 and 8 after virus treatment.

Q: Can you explain in more detail what you found?

AN: This study enabled researchers to analyze cystoscopic pictures of the bladder tumor before and after virus therapy, which showed evidence of anticancer activity in removed cancer, including one complete response for one of three patients who received only the highest dose of CVA21. Tumor tissue samples obtained after surgery also confirmed that the virus was highly selective, targeting only the cancer cells and leaving all normal cells unharmed. Urine samples taken from patients every other day after virus administration found that the virus was being shed, indicating that once virally infected cancer cells had died, the newly replicated virus continued to attack more cancer cells in the organ. One of the main goals of oncolytic virus therapy is to stimulate a patient’s immune system to fight the cancer cells. This study clearly showed that CVA21 was capable of this. By performing a detailed analysis of the excised virus-treated tumor tissue, we observed a high level of immune cells and immune markers in the bladder tumors. This finding was in contrast to untreated bladder tumors, which generally have low levels of these immune cells. So using a virus to treat bladder cancer makes the cancer look strange, triggering an immune response that wouldn’t normally be activated by the tumor itself.

Q: What’s next for research into this?

AN: Importantly, we observed an increase in immune checkpoint inhibitory genes – genes that can dampen or inhibit immune responses – in the bladder tumors in response to the virus treatment. While this appears to be a negative side effect, the efficacy of oncolytic virus therapy is expected to further improve when combined with immunotherapy with specific immune checkpoint inhibitors. The idea is that treating a tumor with a virus will increase the infiltration of immune cells, after which the checkpoint inhibitors can work to keep the immune cells functioning against the cancer. Therefore, the next phase of clinical evaluation of CVA21 in non-muscle-invasive bladder cancer would logically be in combination therapy, sequencing the checkpoint inhibitor after CVA21 to provide a possible 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: [email protected]

Revelation: Annes does not report any relevant financial disclosures.

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