New Hope For Bladder Cancer Patients

Northwestern Medicine researchers have created a biomarker signature test to predict which tumors will react to immunotherapy, which could increase the survival of bladder cancer patients. Only around 20% of bladder tumors respond to checkpoint immunotherapy medicines, which engage the body’s immune system to recognize a tumor. However, professionals are unsure which patients may benefit or why they aren’t more helpful for all patients.
Northwestern University Feinberg School of Medicine researchers discovered three types of tumors that could respond to immunotherapy and two that could not in a new study with many international colleagues.

The scientists also investigated the non-responsive malignancies using a mix of gene expression profiling, mutations, and spatial proteomics to find potential novel medications and therapies that may be utilized to make them responsive to immunotherapy.

The findings will be published in Nature Communications on April 27.

Bladder cancer, the fourth-most common cancer in men in the United States, is frequently fatal, and survival rates have not improved in the last 30 years.

“Immunotherapy has changed the way we treat bladder cancer, but it has significant limitations in that most patients will not respond to therapy,” said lead investigator Dr. Joshua Meeks, associate professor of urology at Feinberg and a Northwestern Medicine urologist. “Thousands of patients have their bladder removed every year, and treating these patients with immunotherapy could improve survival and potentially increase their chance of keeping their bladder rather than having it surgically removed.”

The researchers began with a Phase II trial of 82 patients who were given Keytruda (immunotherapy) before bladder removal. This was a one-of-a-kind trial in which the gene expression profile was assessed before and after Keytruda, with the capacity to fully measure the response to Keytruda after the bladder was removed. Keytruda and other immunotherapies are typically utilized in patients with advanced cancer, and the biological changes that occur in the tumor cannot be evaluated by tumor biopsies. Investigators were able to identify what traits were related to response or resistance by evaluating the transcriptome, DNA mutations, and spatial changes that occurred in tumors treated with Keytruda.

One-third of tumors, for example, was discovered to be in a subtype with very few tumor-infiltrating immune cells but enhanced expression of the oncogene pathway regulated by FGFR3 and a unique regulatory network of genes activated by an epigenetic regulator KDM5B. The researchers hope to re-activate an immunological response by targeting FGFR3 or KDM5B. Clinical trials combining new drugs and immunotherapy to combat immunological resistance will begin at Northwestern Medicine within the next year.

In addition, the study’s findings also provide “a more functional cancer genome atlas,” said Meeks, who also is the Edward Schaeffer, M.D., Ph.D. Professor of Urology and a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. “The current genome atlas looks at the fundamental building blocks of bladder cancer but doesn’t describe any treatment. That’s what makes this evaluation significant. This is about how bladder cancer responds to immunotherapy.”

The Cancer Genome Atlas is a cancer genomics study run by the National Cancer Institute that has molecularly described over 20,000 primary tumors. Dr. A. Gordon Robertson, the paper’s principal author, was also a lead scientist in the bladder cancer genome atlas.

The findings were the product of many cooperation with international groups that could conduct immunotherapy trials that were not available in the United States.

“Through team science endeavors, we were able to leverage different expertise and rare clinical trial specimens to answer important questions about which patients will respond to immunotherapy for the treatment of bladder cancer,” Meeks said.

Northwestern scientists worked with lead clinical investigators from Italy (Dr. Andrea Necchi) and the United Kingdom (Dr. Thomas Powles) to create a biomarker in collaboration with bioinformaticists from Canada and France (Clarice Groeneveld). The biomarker was subsequently validated in a third cohort of patients worldwide by the researchers.

The Polsky Urologic Cancer Institute of Northwestern University’s Robert H. Lurie Comprehensive Cancer Center at Northwestern Memorial Hospital, the AACR-Bayer Innovation and Discovery Grant, the United States Department of Defense, and the Veterans Health Administration all contributed significantly to the research.

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