Checking the Checkpoint in Cancers

A new form of immuno-oncology therapy may show promise for cancer patients.

Cancer survives and thrives by working around the body’s natural defenses and turning off the immune system’s roadblocks before it can attack the disease. One way tumor cells flourish is by using the programmed death-1 (PD-1) receptor and programmed death-ligand 1 (PD-L1) pathway to dampen the immune system. Innovative new therapies are now tackling this pathway in an attempt to slow the progression of certain tumors

PD-1 is a “checkpoint,” which immune cells use to determine whether they should attack an enemy, such as a tumor cell or a cell infected with a virus, or shut themselves down. Cancers, though, have found ways to manipulate PD-1. For example, they make high levels of its ligand, PD-L1. So when immune cells approach tumors, they become anesthetized by the PD-L1 and lose their ability to attack.

New immunotherapy research is examining whether antibodies that block the PD-1/PD-L1 pathway can awaken and reactivate immune cells so they can once again kill tumor cells.

PD-1 and PD-L1 antibodies release the brakes on the immune system and can restore its natural antitumor response

There are other therapies designed to work with the immune system to combat cancer, but PD-1 and PD-L1 inhibitors may hold unique potential for some hard-to-treat cancers.

“PD-1 and PD-L1 antibodies release the brakes on the immune system and can restore its natural antitumor response,” said Robert Hershberg, Executive Vice President, Head of Business Development and Global Alliances, at Celgene Corporation,former Chief Scientific Officer and leader of the Immuno-Oncology Center of Excellence. “I think there’s very little doubt now that the future of oncology is inextricably linked to the immune system.”

While targeted therapies effectively shut down just one target within cancer cells, immunotherapy has more widespread effects — working with the body’s immune system as a whole to make it more difficult for the cancer to survive. Early clinical research suggests that a range of solid tumor cancers, including melanoma, lung cancer, bladder cancer, head and neck cancer (among others), respond to immunotherapy. Using sophisticated immune monitoring techniques to determine which patients respond to these immune-targeting agents remains a crucial endeavor at Celgene.

Disrupting the PD-1 checkpoint may also result in an unchecked immune response that may lead to adverse effects for some patients. Researchers are learning how to engineer these therapies to not only be more effective but also minimize molecular interactions that may have undesirable consequences.

Down the road, combination therapy with PD-1 and PD-L1 antibodies could be even more advantageous. “It’s a breakthrough and revolutionary, but really the tip of the iceberg,” Hershberg said.