Johns Hopkins Medical Institution

Researchers at The Johns Hopkins Greenberg Bladder Cancer Institute are researching new immunotherapies and methods to predict which patients will best respond to different types of immunotherapies.

For years physicians have tried to stimulate the immune system through vaccines or in bladder cancer patients using a bacterial product called BCG. More recently, scientists have discovered that immune cells themselves express molecules called checkpoints, or brake molecules. Blocking those molecules could increase the immune system’s ability to fight cancer. Johns Hopkins researchers Charles Drake, Suzanne Topalian and Julie Brahmer led early clinical trials of an investigational drug that blocks a brake molecule called programmed death-1 (PD-1) in kidney cancer, melanoma and lung cancer patients. In the trials, some patients who failed prior therapies achieved a complete response to their cancer from this checkpoint-blocking drug.

This type of immune-based therapy blocks a molecular pathway that shields tumor cells from the immune system. The pathway involves programmed death ligand-1 (PD-L1), which is expressed on cancer cells and its partner, PD-1 which is expressed on immune cells. The interaction of PD-L1 and PD-1 forms a sort of biochemical shield that protects tumor cells from being destroyed by the immune system, and blocking that pathway can allow the immune system to destroy tumor cells.  Some tumors express another version of PD-L1 called PD-L2.  This protein, discovered by researchers at Johns Hopkins in 2001, also can interact with PD-1 to turn off the immune response to cancer. 

On the Horizon

Not all cells use the same brake, however. Sometimes they use another brake, and sometimes they use other brakes in addition to PD-1. Johns Hopkins investigators plan to analyze immune cells from bladder cancer patients to better define the program that stops them from killing cancer. They also want to model brake molecules in mice to better understand how they work. Armed with this knowledge, they plan to go back to immunotherapy trials in humans potentially with drugs that block a combination of checkpoints, which should achieve a higher response rate for more patients. About 50 percent of patients that have PD-L1 in their bladder cancer, for example, respond to PD-L1 blocking immunotherapy; in patients with low PD-L1, the response rate is only about 10-15 percent.