Study Investigates Hypomethylation Immunotherapy Combination in Bladder Cancer

Dr. Plimack
Elizabeth Plimack, MD, MS, had a paper about patients with bladder cancer accepted into Clinical Cancer Research.

PHILADELPHIA (May 12, 2023)—Immunotherapy has become a powerful tool to fight many cancers, but it still only works in some patients and researchers are looking for new options to help patients who become resistant.

A class of drugs called hypomethylating agents seemed like a promising new approach for patients with bladder cancer who weren’t responding to immunotherapy. However, a recent phase 2 clinical trial had to be stopped after no responses were seen and some patients saw their tumors start growing faster.

The paper, “A Phase II Trial of Guadecitabine Plus Atezolizumab in Metastatic Urothelial Carcinoma Progressing After Initial Immune Checkpoint Inhibitor Therapy,” was published recently in Clinical Cancer Research, a journal of the American Association for Cancer Research.

While the outcome is disappointing, researchers said the study still gives them new insights into why some patients with solid tumors become resistant to immunotherapy. They hope the data they gathered could still help them develop alternative treatments in the future.

“I’m incredibly grateful to the patients who were willing to enroll in this trial and try this novel approach,” said Elizabeth Plimack, MD, MS, a professor in the Department of Hematology/Oncology and Deputy Director at Fox Chase Cancer Center.

“Sometimes what we think will happen doesn’t, and that was the case here. But we are going to learn something from this, and the legacy of the patients who had the courage to enroll in this trial will move forward with future work,” added Plimack, who was a corresponding senior author on the study, which involved colleagues from Fox Chase and researchers from other institutions as well.

Methylation is a process that works like an “on-off” switch for DNA. Researchers hoped that by blocking methylation, they could turn off two DNA pathways. One pathway would help the immune system recognize and home in on tumor cells to more easily attack them. The second would reinvigorate “killer” immune cells, giving them more energy to fight the cancer.

Six patients were initially enrolled in phase 1 of the trial, which looked at a combination therapy of guadecitabine, a hypomethylating agent, and atezolizumab, an immunotherapy drug, in patients with metastatic bladder cancer. While the patients’ tumors didn’t shrink, they remained stable, and the patients had no unexpected side effects.

“They actually did quite well,” Plimack said. “We started off with a lot of enthusiasm.”

For phase 2 they expanded to add 15 patients. This time, while the patients again had no response to the therapy, four patients saw their tumors start growing faster than expected. The trial was then closed.

“It’s never a good feeling to have a study that doesn’t meet its endpoint,” Plimack said. But, she added, the study has some important findings, including the team’s earlier research into hypomethylation therapy that led to the trial.

A key takeaway for Plimack is that while hypomethylation therapy has been used with some success in liquid cancers like leukemia, it now seems unlikely to offer similar benefits in solid tumors. She noted that the new study is only the latest of many solid tumor studies to see disappointing results.

“I think if we were going to see activity in solid tumors, we would have by now,” she said. “I’m pessimistic that we’ll see meaningful results with currently available hypomethylating agents.”

However, she added that analyzing data gathered during the recent trial could yield new insights into why certain patients respond differently to treatment. Researchers now plan to take a closer look at the four patients whose cancers grew and look for clues in their tumor tissues, blood, or other characteristics that could explain their response. This could help scientists develop more personalized treatments in the future that may yield better results.

Fox Chase Cancer Center (Fox Chase), which includes the Institute for Cancer Research and the American Oncologic Hospital and is a part of Temple Health, is one of the leading comprehensive cancer centers in the United States. Founded in 1904 in Philadelphia as one of the nation’s first cancer hospitals, Fox Chase was also among the first institutions to be designated a National Cancer Institute Comprehensive Cancer Center in 1974. Fox Chase is also one of just 10 members of the Alliance of Dedicated Cancer Centers. Fox Chase researchers have won the highest awards in their fields, including two Nobel Prizes. Fox Chase physicians are also routinely recognized in national rankings, and the Center’s nursing program has received the Magnet recognition for excellence six consecutive times. Today, Fox Chase conducts a broad array of nationally competitive basic, translational, and clinical research, with special programs in cancer prevention, detection, survivorship, and community outreach. It is the policy of Fox Chase Cancer Center that there shall be no exclusion from, or participation in, and no one denied the benefits of, the delivery of quality medical care on the basis of race, ethnicity, religion, sexual orientation, gender, gender identity/expression, disability, age, ancestry, color, national origin, physical ability, level of education, or source of payment.

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