Researcher Discovers New, Better Method of Treatment for Superficial Bladder Cancer

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David Zaharoff, University of Arkansas

FAYETTEVILLE, Ark. – A biomedical researcher at the University of Arkansas and his colleagues at the National Cancer Institute have discovered a superior method for treating superficial bladder cancer, which leads to muscle-invasive and then metastatic bladder cancer, the fifth most common form of cancer in the United States. David Zaharoff, assistant professor in the department of biological and agricultural engineering, combined Interleukin-12 (IL-12), a powerful cytokine, which is a type of protein, with chitosan, a biocompatible and adhesive polysaccharide, to successfully cure mice with bladder tumors.

“Intravesical chitosan/IL-12 is a well-tolerated, effective immunotherapy that deserves further consideration for testing in humans,” Zaharoff said. “We are very excited about this therapy as an alternative or complementary strategy for the management of superficial bladder cancer.”

Human clinical trials at the National Cancer Institute could begin as early as spring of 2010. The results were published in the August issue of Cancer Research, which may be found at http://cancerres.aacrjournals.org/.

In 2009, nearly 71,000 people in the United States will be diagnosed with bladder cancer, and slightly more than 14,000 people will die due to the disease. Global prevalence is estimated at greater than 1 million people and is steadily increasing.

For more than three decades, a drug known as BCG (bacillus of calmette-guerin, a type of bacteria) has been given intravesically – within the urinary bladder – as the immunotherapeutic, standard-of-care treatment for superficial bladder cancer. However, 20 to 30 percent of patients fail initial intravesical BCG therapy, and 30 to 50 percent of patients will develop recurrent tumors within five years. For the past several years, medical researchers have worked with Interleukin-12 as a potential alternative to standard cancer treatments, because it has shown an ability to eliminate tumors. But a recent clinical study using Interleukin-12 on patients with recurrent superficial bladder cancer did not demonstrate anti-tumor efficacy.

Aware of Interleukin-12’s potency, Zaharoff wondered why the therapy was unsuccessful. He hypothesized that the agent was not effectively delivered to the bladder tumor and underlying tissue. At the same time, he had been reading about chitosan, a natural, biodegradable polysaccharide derived primarily from the shells of shrimp and crab. Zaharoff knew that chitosan displayed adhesive properties, so he decided to combine it with Interleukin-12 and investigate whether the new formulation would adhere to the mucosal wall of mouse bladders and kill tumors.

He found that chitosan improved delivery and bio-adhesion of Interleukin-12. In their studies, 88 to 100 percent of mice with bladder tumors were cured after four intravesical treatments. In contrast, only 38 to 60 percent of mice treated with Interleukin-12 alone were cured. None of the mice treated with BCG alone were cured.

“Antitumor responses following chitosan/IL-12 treatments were durable and provided complete protection from intravesical tumor re-challenge,” Zaharoff said.

Urinary analysis showed that chitosan/Interleukin-12induced multiple cytokines – proteins that allow communication between cells and help regulate immunity – at levels significantly higher than either Interleukin-12alone or BCG. Immunohistochemistry tests following chitosan/Interleukin-12treatments revealed moderate to intense tumor infiltration by T cells, a group of white blood cells critical to the immune system, and macrophages, also a type of white blood cell. Bladder mucosa from cured mice contained residual populations of immune cells that returned to baseline levels after several months.

Zaharoff’s future work will focus on uncovering the specific immune responses that cause the tumors to die. His colleagues at the National Cancer Institute are planning human clinical trials. Zaharoff hopes that in five to 10 years chitosan/Interleukin-12 will be the standard-of-care therapy for patients with superficial bladder cancer.

Zaharoff is holder of the Twenty-First Century Professorship in Biomedical Engineering. He is director of the Laboratory of Vaccine and Immunotherapy Delivery.