Historical Studies of Cytokines in Urothelial Cancer

Arlene O. Siefker-Radtke, MD:In the 20 years that I’ve been treating bladder cancer, I’ve seen several unusual responses that we felt were induced by the immune system. Until now, we were unable to replicate the effects of immune therapy in impacting an immune response. If you look at the historical data, there has been a lot of use of intravesical therapies, including IL-2 and interferon. But the problem with cytokines is that they’re typically very short-lived, so they’re not around very long. And even when instilled in the bladder, once the patient relieves himself of the bladder distention, the cytokine is gone and the effects are minimized because of the lack of long-term benefit.

When we look in the metastatic setting, there have been trials trying to study inflammatory cytokines and their impact on chemotherapy and inducing an immune response. We did an early clinical trial that was published more than 15 years ago combining alpha interferon with 5-FU [5-fluorouracil] and cisplatin as the frontline treatment of metastatic bladder cancer. We did a randomized trial comparing it with traditional MVAC [methotrexate, vinblastine, doxorubicin, and cisplatin], and we found a regimen that had efficacy—there were definitely responses—but it was more toxic compared with traditional MVAC [methotrexate, vinblastine, doxorubicin, and cisplatin].

So the typical inflammatory cytokines have not had a toxicity profile that have allowed us to give them safely in a large number of patients. Imagine your frail, elderly grandmother or grandfather trying to go through toxic therapy that drops their blood pressure, makes them feel flu-like symptoms. There’s clearly a reason why the older style of inflammatory cytokines failed in this setting. With the use of this pegylated form targeting IL-2, it really has the toxicity profile that is needed to give it systemically, observe long-term effects through durable sustained expression of it in the circulation, and then target the immune response that is needed to attack cancer.

So I think these novel strategies play on a lot of our old hopes and failed treatments. But we’re now giving them in a more targeted fashion and a less toxic fashion, and as we’re seeing, early evidence shows that they have the potential to impact the lives of our bladder cancer patients.

Transcript edited for clarity.