Immunotherapy has become a powerful tool to fight many cancers. However, it still only works in some patients, and researchers seek 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 II clinical trial had to be stopped after no responses were seen, and some patients saw their tumors start growing faster.

Elizabeth Plimack, MD, MS, is dedicated to finding a solution. Plimack’s 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 of the study is disappointing, it still is a step forward, providing fresh insights into why some patients with solid tumors become resistant to immunotherapy. Researchers 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 with 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 attack them more easily. The second would reinvigorate “killer” immune cells, giving them more energy to fight the cancer.

Six patients were initially enrolled in phase I 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 did quite well,” Plimack said. “We started with much enthusiasm.”

For phase II they expanded to add 15 patients. This time, while the patients had no response to the therapy again, 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 the reason 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.