Understanding that not all bladder cancers are the same, researchers at the University of North Carolina Lineberger Comprehensive Cancer Center have created a tool that may help them to uncover why only a fraction of patients responds to new immune-based treatments.

In the journal Cancer Research, researchers report they have developed a mouse model of luminal bladder cancer, one of the two subtypes of advanced bladder cancer. The researchers said this model might help them to determine which patients may respond to checkpoint inhibitors, a class of immunotherapy drugs that "remove the brakes" that can keep the immune system from attacking cancer cells.

Five checkpoint inhibitors have been approved for metastatic, or locally advanced, bladder cancer since May 2016, giving patients additional options after standard therapy failed. But studies have shown that less than a quarter of patients will respond to these drugs.

"Not all bladder cancers are the same, and until now, we didn't have the tools to understand biology or look at the therapeutic efficacy of drugs in luminal preclinical models," said Kim, an associate professor. "The biggest impact is that the scientific community now has a mouse model that can be used to understand the biology of these bladder tumors better, and to evaluate promising therapies."

Effectiveness of checkpoint inhibitors

The researchers used their newly created model and an existing model for basal-like bladder cancer, the other subtype of bladder cancer, to examine features that may determine the effectiveness of checkpoint inhibitors.

They studied the immune microenvironment—the immune cells in and around the tumor—for each subtype. They determined there were lower levels of immune cells in and around luminal tumors, and that this model did not respond as well to PD-1 inhibitors.

They also analyzed the level of the neo-antigens present on the two different bladder cancer subtypes. Neoantigens are proteins that sprout on the surface of cancer tumors as a result of DNA mutations or other alternations in cancer cells. Scientists are interested in using neoantigens to predict response to immunotherapy treatments, or as drug targets.

"We think neoantigens are at least a large reason for why there is an anti-tumor immune response—meaning the body uses the neo-antigens to recognize the tumor as foreign," Kim said. "There's a lot of interest in trying to leverage neo-antigens therapeutically, and so we wanted to see if our model expressed them."

Researchers found the luminal subtype had a lower number of markers that were highly immunogenic or had the ability to trigger the immune system. "Understanding how and why tumors are differentially immunogenic is critical for understanding how to best use therapies that target the immune system in the clinic," Vincent said.

Kim said a future line of research will investigate how neo-antigens help to elicit an immune response, and whether they can leverage their findings to augment the activity of checkpoint inhibitors.

"We are refining our understanding of cancers, and to make a parallel in another disease, I'd say to call breast cancer 'breast cancer' nowadays is not appropriate," Kim said "We call it HER2-positive breast cancer, or triple negative breast cancer, because these types are treated differently, and the biology underlying them is different. For bladder cancer, we now understand the same is true—that there are multiple subtypes of the disease. We should no longer refer to bladder cancer as a single disease"