UF Health MedMatters

UF Researchers Work to Improve Response to Immunotherapy for Bladder Cancer

Immunotherapy has been used to treat bladder cancer for more than 20 years, with great success in some patients. Intravesical administration of bacillus Calmette–Guérin, or BCG, has been approved in the U.S. for stage I bladder cancer since 1990, and rates of complete response range from 55% to 70%. However, as many as 25% to 45% of patients do not respond, and an additional 40% ultimately relapse after initial response.

Dr. Paul Crispen speaking to a male patient and his spouseMore recently, multiple trials have demonstrated the efficacy of immune “checkpoint inhibitors” that target a protein called programmed cell death 1 (PD-1) or its ligand, PD-L1. In the U.S., two PD-1 inhibitors (nivolumab and pembrolizumab) and three PD-L1 inhibitors (atezolizumab, avelumab and durvalumab) are approved for treatment of advanced urothelial carcinoma. In the clinical trials that led to approval of these drugs, overall response rates were 15% to 29%.

“These results demonstrate how immunogenic bladder cancers are and that you can have great success in treating some patients with immunotherapy,” says Paul Crispen, MD, an associate professor of urology in the UF College of Medicine. “However, despite this success and the great gains we’ve made with the newer therapies, many patients fail therapy. The critical issue is trying to identify new mechanisms and new ways to improve existing immunotherapies. 

Researchers at UF are actively involved in this effort. They’re inviting patients with stage 1 bladder cancers to participate in a national clinical trial, being run by the Southwest Oncology Group, that’s investigating how to increase response to BCG. “We are priming the patient’s immune system with a BCG vaccine before patients receive therapy,” Crispen says. “This concept has been seen to improve response rates in retrospective studies, but this is the first prospective trial to try to prove that priming the immune system prior to BCG therapy can be effective.”

In patients with advanced cancers, UF researchers are examining specific changes within the tumor and the tumor microenvironment that may promote resistance to immunotherapy. “We are trying to identify the ways in which tumors are evading the immune system,” Crispen explains. “By doing that we can look for ways to counteract those mechanisms to make the tumors more susceptible to immunotherapy.”

Sergei Kusmartsev, PhD, an assistant professor of urology in the UF College of Medicine, is on the front line of this quest. “A tumor can evade the immune system in a number of ways,” he says. “One is to send out signals that directly block immune cells that come in to fight tumor cells naturally. Another is to recruit cells that shut down the immune response. Or it can happen in other ways or by a combination of mechanisms.” 

Kusmartsev’s team is taking blood and tumor samples from patients with bladder cancer and studying the interactions between the peripheral immune cells and the tumor, to try to identify mechanisms of “immune escape.”

“Although the mechanism varies, what we see in many bladder cancer patients is that the dominant factor is intratumoral degradation of hyaluronic acid,” Kusmartsev says. He notes that hyaluronic acid is normally produced by epithelial cells and is present in both normal bladder tissue and tumors. Normally, it has a very high molecular weight, but in patients with untreated bladder cancer, the molecular weight is much lower.

The accumulation of low-molecular-weight hyaluronic acid promotes angiogenesis (formation of new blood vessels) and immune escape. “Tumor-produced hyaluronic acid might be one of the most important targets for research in cancer therapy,” Kusmartsev says. 

There’s evidence that hyaluronic acid is metabolized differently by tumor cells than by normal cells, Crispen adds. Metabolism of hyaluronic acid by tumor cells may lead to recruitment of inhibitory immune cells and prompt those immune cells to send out additional signals to block immune response.

“This is just our initial work, it’s very early,” Crispen emphasizes. “But we’re trying to learn more about how this signal occurs — how this abnormal metabolism of hyaluronic acid is happening at the tumor level. If we can change it, we might be able to change the immune response in these patients with bladder cancer, and eventually remove one of the barriers to tumor response to immunotherapy.”

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University of Florida Health Shands Hospital has been recognized among the nation’s best hospitals in seven adult medical specialties. Overall, UF Health Shands Hospital was recognized as one of the best hospitals in Florida. In addition to being ranked among the nation’s top 50 hospitals in seven specialties, UF Health Shands Hospital also was listed as “high performing” in seven specialties, including abdominal aortic aneurysm repair, colon cancer surgery, COPD, heart failure, lung cancer surgery, neurology & neurosurgery and orthopaedics.