Why Don’t Checkpoint Inhibitors Work for More Bladder Cancer Patients?

The local tumor microenvironment might offer clues

• Checkpoint inhibitors offer patients who have failed intravesical BCG an alternative to surgery
• This treatment produces only 15 to 25% response rates
• Cytokines or other molecules in the tumor microenvironment might inhibit the action of checkpoint inhibitors
• Researchers are studying new strategies that incorporate checkpoint inhibitors into combination therapies to increase efficacy

The FDA’s approval of the first checkpoint inhibitors for metastatic bladder cancer in 2014 ushered in a new era of treatment. This was the first class of new drugs to be approved for this indication in decades.

Checkpoint blockade “brought a lot of excitement,” Dr. Roger Li, urologic oncologist at the Moffitt Cancer Center in Tampa, FL, tells SurvivorNet Connect. For the first time, patients who had failed intravesical BCG had an alternative to cystectomy.

Yet despite initial optimism about checkpoint inhibitors, they only produce response rates of 15 to 25% in any setting — chemorefractory, metastatic, BCG-unresponsive. “The response rate is lower than what we would like to see,” Dr. Li says. “Why do 75 to 80% of the patients not respond to immune checkpoint blockade?”

Research in both bladder cancer and other cancer sites points to some explanations. For one thing, it’s possible that cytokines or other molecules produced in the local tumor microenvironment might inhibit the action of the checkpoint blockade, Dr. Li says. Another possibility is that the immune checkpoint blockade requires an ongoing immune response.

“Here at Moffitt and other cancer sites, we are actively investigating new strategies where we are using the immune checkpoint blockers as a backbone, but adding on to them different combination treatments,” he adds.