Discovery
January 22, 2016

"Recent advances in our understanding of the immune system have resulted in a sea change in the treatment of aggressive malignancies," says Brady scientist Charles Drake, M.D., Ph.D. He should know; he is doing groundbreaking work on immunotherapy in prostate cancer. "In particular, we now know that in many patients, their immune cells have already seen the tumor and are poised to destroy tumor cells. However, those tumor- destroying immune cells are often held back by a series of molecules known as immune check- points." Normally, Drake explains, these checkpoints function to protect the body from auto-immune attack; "but in cancer, tumors hijack those pathways to protect themselves, instead."

The immune system is all about communication. For an immune cell – a foot soldier in the body's effort to protect itself against enemy invaders – to be activated, two signals need to be made. Signal 1 is controlled by the T cell, a white blood cell, that recognizes a tumor-specific protein, called an antigen, through its receptor. Think of Radar O'Reilly in MASH, listening to his headset and hearing something suspicious. Signal 2 comes from B7 molecules. Here's where the communication gets scrambled: In tumors, T cells often pick up a "checkpoint" molecule called CTLA-4, which sticks to B7 molecules like glue. This is bad, because it effectively hijacks Signal 2 – blocking the communication back to the foot soldier – and the T cell never gets the signal to "go fight the bad guy." A second and maybe even more important checkpoint is controlled by the interaction between PD-L1 on the tumor cell and PD-1 on the T cell.

The world of immunotherapy involves a lot of alphabet soup-sounding names. For example, the most important checkpoint pathway is controlled by two molecules that act on two different kinds of cells. The initials "PD" stand for "Programmed Death." PD-L1 is made by tumor cells, and PD-1 is on the corresponding immune cells called T cells. "When tumors are under attack, they crank up the production of PD-L1," says Drake, and this is a bad thing. "PD-L1 protects the tumor cells by binding to PD-1 on those invading white blood cells called T cells — effectively turning them off." Imagine a smoke alarm going off, and the home security system calls the fire department and says, "Don't worry, it's just a false alarm," so the house keeps on burning.

But scientists have figured out how to break this cycle — in other words, to call the fire department back and say, "Hurry up! We need you!"

Drake is excited about blocking another immune checkpoint that targets the molecule CTLA-4. Interestingly, blocking both of these checkpoints, CTLA-4 and PD-1, "leads to a higher response rate than blocking either one alone," notes Drake, and a Johns Hopkins team led by Emmanuel Antonarakis and Drake is planning a trial of dual-checkpoint blockade in men with advanced prostate cancer that expresses a mutated androgen receptor called ARV7 which makes them particularly resistant to androgen-targeting therapies.

Note: Not all men express AR-V7; there is a brand-new blood test, only available at Johns Hopkins, that can tell whether you are in this group.