By: Alex Oh

For years, drugs that release brakes on the immune system have been used to treat thousands of people with cancer “that were previously untreatable.” Unfortunately, these drugs, or checkpoint blockers, have failed in many patients as well and with certain types of cancers. The reason: our bodies’ immune systems can be slowed by more than one kind of brake.

Checkpoint blockers generally help the immune system by attacking a certain type of brake, which are the protein interactions that “disarm the body’s T-cells, allowing cancer to go unchecked.” Those protein interactions are not the only kind of brake: MDSCs, or myeloid-derived suppressor cells, are an immune cell population that also function as brakes. In fact, people with cancer often have high levels of MDSC.

According to Science News, MDSCs “are a mix of immature cells from the same family as neutrophils and macrophages, which act as general first responders in the immune system.” Their main purpose, according to William Carson III, a surgical oncologist at Ohio State University in Columbus, is “to slow things down.” Because of this, Carson suspected that disabling them might help the immune system fight cancer cells quicker and more effectively.

In 2016, a study was done on people who had received checkpoint blockers for advanced melanoma. In that study, the people with lower levels of MDSCs in their blood “responded better to the immune therapy and lived longer.” Carson and his colleagues theorized that removing these suppressor cells would allow the checkpoint blockers to work better. So, they found a type of drug that would do exactly that: Brd inhibitors.

Brd inhibitors are drugs that eliminate the protein Brd, which controls the activity of various genes in tumor cells, including the ones that “promote” MDSCs. Because of this, Brd inhibitors seemed to have the potential to help the checkpoint blockers in the immune system.

So, Andrew Stiff, a physician-researcher in Carson’s lab, decided to “conduct studies in mice with implanted breast tumors – a type of human cancer that responds poorly to checkpoint blockade.” In the study, among the mice that were treated with just the checkpoint blocker anti-PDL1, “tumor growth slowed in 3 of the 11 animals.” The results were even worse for the mice treated with just a placebo-drug or Brd inhibitor. However, among the 11 mice that received both the anti-PDL1 and a Brd inhibitor, tumors shrank in seven.

Another drug that has been used with anti-PDL1 is an anti-inflammatory peptide called trefoil factor 2, or TFF2. Timothy Wang, a gastroenterologist at Columbia University Irving Medical Center, found that giving mice TFF2 can “boost the immune system and slow tumor growth.”

Unfortunately, studies show that these drugs often have a different effect on mice than they do with human patients. For example, according to the Science News, while “anti-PD1 and anti-PDL1 therapies only modestly slowed tumor growth in mice”, they are “the cornerstone for immuno-oncology therapy in humans.”

Currently, over a thousand trials are testing checkpoint blockers along with other drugs. While some “are showing some promise,” , it seems like there is ’s still a long way to go. In fact, according to Li Peng, chief scientific officer at Palleon Pharmaceuticals, scientists are “just scratching the surface.”

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