Discovery 
November 30, 2017

Isaacs, Denmeade, and Brennen: New prodrug is a cellular “boulder-buster” that paves the way for immune cells to reach the tumor. This prodrug may work even better when combined with other forms of immunotherapy.

Prostate cancer makes it tough for the body’s immune system to fight it. One tactic it uses is to put T cells, the body’s enemy-fighting soldiers, to sleep (see story). Another is to set up barricades to keep these and other immune cells off the battleground.

“A major reason why the body doesn’t do a more successful job of fighting off prostate cancer, especially metastatic castration-resistant prostate cancer, is poor infiltration of immune cells,” says Brady scientist John Isaacs, Ph.D. “This is also a key reason why immunotherapy is not more successful in prostate cancer. We desperately need to find a way to remove this barrier and let the immune cells in.”

Isaacs, with Nathaniel Brennen and Samuel Denmeade, may have found a way to breach this roadblock. First, they identified the culprits here: mesenchymal stem cells (MSCs), immune-suppressing cells made in the bone marrow. “We discovered that prostate cancer recruits these MSCs,” says Isaacs, “which then infiltrate the sites of metastatic cancer and block the activity of many types of immune cells.”

Imagine you’re trying to get across a field, but it’s full of Stonehenge-sized boulders. That’s what’s happening to the body’s frustrated immune soldiers. But Isaacs, Brennen and Denmeade have come up with a cellular “boulder-buster.” They have designed and synthesized a new prodrug that “selectively depletes these immune-suppressive, tumor-infiltrating MSCs.” Based on their preclinical studies, published in Oncotarget, they propose that reducing the sheer number of MSCs “will restore the immune system’s ability to infiltrate sites of prostate cancer and kill cancer cells.”

Even more promising: “We expect the prodrug will have even greater antitumor effects when used in combination with other forms of immunotherapy, such as immune checkpoint inhibitors that will wake up the sleeping T cells,” says Isaacs.

The team’s findings may lead to development of a biomarker test, as well: One day, the presence or absence of MSCs “may help distinguish which men need immediate local treatment and which men do not.”