The innovation: Gut bacteria play key role in effectiveness of immune checkpoint inhibitors

Recent studies have uncovered a variety of intriguing ways that the gut microbiome of cancer patients may shape their response to cancer therapies. One of the most promising recent findings is that gut bacteria may be necessary for the effectiveness of immune checkpoint inhibitors (ICIs), a major player in the treatment of many cancers.

Andrew Y. Koh, M.D., Director of Pediatric Cellular and ImmunoTherapeutics Program at Children’s Health℠ and Associate Professor at UT Southwestern, led one of the first studies that showed melanoma patients who had a robust response to ICIs had certain types of gut bacteria. But Dr. Koh and other researchers pursuing this connection were puzzled by how microbiota in the gut could help fight cancers in the skin.

In a new study, Dr. Koh and his lab found clues that help solve this puzzle and bolster the theory that gut bacteria are critical for the effectiveness of ICIs like ipilimumab, nivolumab and pembrolizumab. They found that these immunotherapy drugs induce changes that allow certain gut bacteria to escape from the gut and travel to the tumor site and lymph nodes adjacent to the tumor where they help unleash the full force of the immune response against the tumor.

“We think these findings lay the foundation for a therapeutic approach that skips the gut and delivers specific parts of bacteria to lymph nodes and the tumor," Dr. Koh said. "We think this could be better than giving oral probiotics and relying on the bacteria to take hold in the gut before moving on."

The big picture: Understanding how gut bacteria can fight skin tumors

ICI therapy has revolutionized cancer treatment, but for reasons that are still unclear, only 20-40% of patients respond to ICIs.

One reason may be that patients lack certain gut bacteria. Two studies in 2015 found that ICI treatment failed to control the growth of melanoma and sarcoma tumors in lab mice that did not have gut bacteria or mice that had been pre-treated with antibiotics. But after animals received oral administration of certain bacterial strains, ICIs were able to rein in tumor growth.

Research by Dr. Koh and his colleagues at UT Southwestern (as well as other groups) found a similar connection between specific signatures of gut bacteria and ICI response in patients with skin, lung, and kidney cancer. But researchers were puzzled by the studies because they linked ICI response to a variety of types of gut bacteria and it was unclear if they could all have this effect. Subsequent studies also reported that tumors themselves harbored microbial communities, including small amounts of bacteria normally found in the gut.

“It’s a relief because our new study shows that many bugs in the gut can actually improve ICI response, and we also know how they are able to establish the tumor microbiomes,” Dr. Koh said.

Key details: Could an injected microbiome-derived therapy be safe and more effective than probiotics?

The Koh Lab found that six different types of gut bacteria (including Enterococcus and Escherichia bacteria) are selectively taken up inside dendritic cells (white blood cells that help activate the immune response). The ICI treatment prompts the dendritic cells to move from the gut to lymph nodes along the gastrointestinal tract (called mesenteric lymph nodes) and carry the bugs with them.

The study was the first to show that ICI treatment leads to restructuring of the mesenteric lymph nodes that allows bacteria to escape into the blood and travel to tumors and tumor-draining lymph nodes far from the GI tract. The bacteria identified in the study were able to activate dendritic cells, which in turn activated T cells to fight tumors.

“It’s like immune checkpoint inhibitors release the brakes on T cells to fight tumors, and then the bacteria hit the accelerator on the immune system,” Dr. Koh said.

The lab team also learned that gut bacteria have to break out of the gut to help prime the immune response. This discovery made them wonder if delivering components of gut bacteria directly into the blood, or even under the skin adjacent to lymph nodes, would be a more efficient way to boost ICI response. Preliminary unpublished data show this approach was safe in mice and had an antitumor effect similar to oral administration of the bacteria. They are now testing subcutaneous injections of bacterial-derived therapy in other preclinical cancer models.

“It may be easier to bypass the gut because so many things can perturb the gut microbiome, such as if the patient has to go on antibiotics or goes on a new diet,” Dr. Koh said.

How this could help patients: Finding ways to improve ICI response in pediatric cancer patients

An important takeaway from Dr. Koh’s research is that patients receiving ICIs should take antibiotics that don’t wipe out good gut bacteria. “We’re starting to realize that not all antibiotics are created equal in terms of how they impact the microbiome, and we should use microbiome-sparing antibiotics,” Dr. Koh said.

At this point, studies on the role of gut bacteria in ICI response have focused on adult patients, and the implications for pediatric cancer patients are still unclear. In general, response to ICI therapy is less robust in pediatric patients than adults, and there are fewer indications for this therapy in childhood cancers.

Dr. Koh is involved in an early-stage clinical trial of children with solid tumors, led by his colleague Matthew Campbell, M.D., Pediatric Hematologist/Oncologist and Assistant Professor at UT Southwestern, to see if combining ICI and chemotherapy is safe and enhances the benefit of ICI. Dr. Koh will analyze fecal and tumor samples from the participants to determine whether their microbiome profiles are associated with poor ICI response

“One thing we're considering is whether the gut microbiome of kids differs from adults in a way that makes it less able to activate the innate immune system. Kids may need certain bacteria to drive their ICI response," Dr. Koh said.