Understanding Checkpoints: New Hope For Autoimmunity

(Posted on Wednesday, October 23, 2024)

A breakthrough in cancer therapy could unlock a whole new frontier in medicine. Scientists are now exploring an exciting possibility: using naturally occurring checkpoints in the immune system to treat autoimmune diseases such as lupus, rheumatoid arthritis, and type 1 diabetes. While checkpoints are targeted in cancer immunotherapies, this unexpected shift could also revolutionize how we treat these chronic conditions, giving hope that a therapy built to fight cancer might also calm an immune system in overdrive.

Checkpoints and Cancer

What are checkpoints and what do they do? To understand their value, let’s turn to our body’s defense system: the immune system.

The immune system constantly scans the body for threats like viruses, bacteria or cancer cells. But just like any sound security system, its activity must be carefully controlled. If too active, the immune system can damage healthy cells; if too inactive, it won’t recognize dangers lurking nearby.

Checkpoints help maintain this delicate balance. These proteins are found on the surface of immune cells and can tell the immune system to gear up or slow down. Many—but not all—checkpoints function as built-in brakes that prevent immune cells from overreacting and attacking healthy tissues.

But cancer complicates matters. Cancer cells cleverly hijack these brakes and trick the immune system into slowing down. These deactivated immune cells no longer detect the cancer cells growing unchecked.

This is where checkpoint inhibitors come in. This novel class of cancer immunotherapies sets these checkpoints straight. Each infusion contains antibodies that block checkpoint proteins like a hand over a light switch, preventing cancer cells from turning off the immune system. This allows your immune cells to recognize and attack the cancer cells they had overlooked. Rather than directly impacting cancer cells, these inhibitors empower the immune system to do what it’s naturally designed to do: fight off threats and protect your body. This breakthrough approach has become an invaluable therapeutic for several advanced forms of cancer, including melanoma and Hodgkin lymphoma.

Flipping the Script for Autoimmunity

How could checkpoint inhibitors, a drug that traditionally stimulates the immune system, benefit people with autoimmunity? Autoimmune diseases arise when overactive immune cells mistakenly attack the body’s own tissues, leading to inflammation and damage. For these patients, more immune activity would only worsen their condition. In fact, most people with autoimmune disorders rely on immunosuppressive medicines to quiet their immune systems.

But what if we flipped the script? What if we used checkpoints to calm the immune system instead of stoking it? This opposite strategy could unlock new ways of treating autoimmune diseases with therapies that, until now, were mainly reserved for cancer.

There are two potential ways to pursue this goal. The first is to use encourage checkpoints to suppress the immune system. One example of a strategy already in use is a drug called Abatacept, which taps into the immune-modulating power of checkpoints. Abatacept reduces immune activity by enhancing the activity of CTLA-4, a checkpoint receptor that tamps down T cell activation. By turning off immune responses through this mechanism, Abatacept helps reduce swelling and joint damage in people with autoimmune arthritis. It has proven especially valuable for patients who do not respond to other treatments. Interestingly, CTLA-4’s role in autoimmune treatment contrasts with its use in cancer therapies, where blocking the same checkpoint encourages immune cells to attack tumors more aggressively.

Agonists, drugs that mimic natural proteins, could achieve a similar effect with further exploration. These therapies could imitate checkpoint proteins and reduce excessive immune activity. In one preclinical study, NYU researchers suggest that activating an immune checkpoint called PD-1 could restore balance to the immune system, especially through strengthening mechanisms involving how the receptor forms pairs (or dimers). Interestingly, PD-1 is commonly blocked in cancer treatments to ramp up antitumor activity, but in autoimmunity, activating it may help suppress harmful immune activity.

A second potential approach involves creating a new class of checkpoint inhibitors—ones that work in reverse. These novel therapies would block immune-stimulating checkpoints, preventing them from activating immune cells and therefore lessening harmful immune activity. This contrasts existing checkpoint inhibitors for cancer, which stop cancer cells from engaging with immune-suppressing checkpoint proteins. Though still in the early stages, promising candidates include CD137 and CD40, which play roles in immune activation.

Looking Ahead

Checkpoint inhibitors, long celebrated for revolutionizing cancer treatment, are now sparking curiosity in a new direction: their potential to tame autoimmune diseases. This opposing strategy—calming the immune system rather than activating it—represents a bold reimagining of these therapies. Although this concept is just beginning to take shape, and we still don’t know the potential complications and limitations these drugs could have, this line of research holds exciting potential to reimagine how we approach immune-related conditions.

Read the original article on Forbes