Immune Altering Drug Hits Cancer in the Stomach

Working with an international team of collaborators, scientists at Columbia University have found a way to shift the balance of a type of white blood cell inside a stomach tumor, causing the immune system to recognize and attack the cancer instead of ignoring it. The work, published in the August issue of Cancer Cell, also sheds light on immune functions that may drive many other diseases.  

Gastric tumors stimulate and attract a population of immune cells called immunosuppressive neutrophils, which protect the tumor from being eliminated by the immune system. A protein called CXCR4 is critical for this process, recruiting the immunosuppressive cells and repelling T cells that would otherwise attack the tumor. Some researchers have tried developing drugs that block CXCR4 activity, with mixed results.  

Scientists at Columbia discovered that a naturally occurring protein called TFF2 binds and regulates CXCR4. “We went on to show that it was a partial agonist. When we stimulated cells expressing CXCR4 with TFF2, we could see some  low-level signaling, but when we added the normal ligand for CXCR4, the TFF2 would block its activity,” says Timothy Wang, MD, chief of digestive and liver diseases at Columbia and co-leader of the Tumor Biology and Microenvironment program at the Herbert Irving Comprehensive Cancer Center (HICCC). In other words, adding TFF2 could switch CXCR4’s activity from “high” to “low,” without turning it off completely. That, and results from experimental models of gastric cancer, suggested that TFF2 could help shift a tumor’s immune environment to turn on the cancer.  

Unfortunately, natural TFF2 is a short-lived protein, breaking down in a couple of days. Wang’s team set about modifying it in various ways, eventually engineering a version that lasts three weeks or more in an animal. In the new work, the investigators tried using their modified TFF2 to treat gastric cancers in an animal model of the disease.

“The TFF2-albumin peptide certainly suppressed the [immunosuppressive neutrophils] and inhibited cancer to some extent, but when we combined it with [other drugs], we got much more robust responses, and a significant improvement in survival,” says Wang, who is the senior author on the new paper. Adding TFF2-albumin to the current standard treatments for gastric cancer produced a robust immune response and withered the tumors.  

Analyzing the animals’ blood and bone marrow, the scientists found that tumor development causes a broad change in the composition of the immune system. “We saw that in gastric cancer, there’s a shift from what we call good neutrophils to bad neutrophils, and that this is corrected to a large extent by treatment with TFF2-albumin [in the animals],” says Wang. Data from patients with gastric cancer support the idea that the tumor also causes a major change in the overall immune response. By drawing “good” immunosuppressive neutrophils into the tumor and out of the bone marrow, where blood cells are made, the cancer disrupts the normal balance of blood cell production.  

Working with Tonix Pharmaceuticals in Chatham, NJ, Wang and his colleagues now hope to test TFF2-albumin in clinical trials. “The company right now is working on GMP production and toxicity testing. We’ve been in contact with the FDA, and received preliminary guidance,” says Wang. He adds that the team hopes at some point to move ahead to clinical trials.

The same approach may also work in colon cancer, which shares similar immune features, and the findings also suggest a broader strategy for addressing the chronic immune dysfunctions that underlie many other diseases, ranging from other cancers to obesity. “If you could find a way to keep these [immunosuppressive neutrophils] in the bone marrow when you’re not sick with an infection, it could help a lot of chronic diseases,” says Wang.