Probiotics and the response to immunotherapy for cancer

As mentioned earlier in this issue of TreatmentUpdate, emerging research suggests that bacteria that live in the gut can have an impact on several organ-systems, including the intestine, brain and immune system. There are teams of scientists around the world studying how bacteria in the gut can be manipulated to produce beneficial effects for the immune system and perhaps to help moderate certain conditions. In particular, some scientists hope to be able to decrease inflammation and immune activation with gut bugs. Other scientists hope to improve the anti-cancer response of the immune system when people with cancer are given an emerging class of drugs call checkpoint inhibitors. We will discuss checkpoint inhibitors later in this report, but first some background about the immune system is necessary.

Checkpoints within the immune system

During a typical response to an infection or tumour, the immune system needs to be mobilized. This mobilization is done through the release of chemical signals of inflammation. Certain cells of the immune system that fight microbes and tumours—including CD8+ T cells, natural killer cells and macrophages—become activated. Eventually, after an infection or tumour has been contained and destroyed, the immune system needs to dampen and shut down the response to the infection/cancer or else cells that remain activated could inadvertently injure healthy tissue. Also, excess inflammation could slowly degrade vital organs.

To help turn off these immune responses, cells of the immune system begin to display checkpoints. These are proteins on the surface of cells that signal to CD8+ and other cells to decrease and eventually cease their activity.

The interest in checkpoint inhibitors

Commonly studied checkpoints include PD-1 and PD-L1 (these are called programmed cell death protein-1 and programmed cell death ligand-1, respectively). Some research suggests that HIV infection causes cells of the immune system to display these and other checkpoints. It is possible that, in the vast majority of people, these checkpoints may play a role in the immune system’s inability to contain and clear HIV. Scientists in the U.S. are conducting small studies of checkpoint inhibitors in people with HIV as part of attempts at curing this infection.

Responders and non-responders

Some tumours also display checkpoints on their surface, thwarting the immune system’s ability to vanquish tumours. In some people with cancer, checkpoint inhibitors can be powerful; they can cause tumours to shrink, and, in some cases, tumours disappear entirely. This occurs because in some people, called “responders,” checkpoint inhibitors unblock the immune system, unleashing a robust immunological response against the tumour. Unfortunately, this immune response can sometimes get out of control and cause intense side effects.

Scientists are trying to find out which people with cancer will have a beneficial response when treated with checkpoint inhibitors. Such studies may one day be useful in HIV cure research.

Clues from cancer treatment

Research teams in France and the U.S. have been studying the gut bacteria of people with different cancers, all of whom were treated with checkpoint inhibitors. Participants were divided into responders and non-responders. Some of the most interesting aspects of this research came from the team in France with scientist Bertrand Routy, PhD. He and his colleagues studied participants who were receiving treatment with checkpoint inhibitors for the following cancers:

• non-small cell lung cancer
• renal cell carcinoma
• urothelial carcinoma

They found that when participants took antibiotics to treat infections, they had a relatively weak response to tumours elicited by checkpoint inhibitors. This finding suggests that some species of bacteria can interfere with the effectiveness of checkpoint inhibitors.

Routy’s team analysed the feces of participants (feces contain a representative sample of gut bacteria) and found that participants with a favourable response to checkpoint inhibitors against PD-1 had relatively high levels of the bacteria Akkermansia muciniphila. These bacteria are thought to have anti-inflammatory activity. In separate and unrelated experiments, researchers fed mice different diets and found that those mice fed a diet rich in fish oil had relatively high levels of these bacteria in their gut.

Engaging in fecal microbiota transplants

Culturing bacteria from the feces of healthy people or from people who are immune to certain bacterial infections, and then transferring these bacteria to other people is called fecal microbiota transplant (FMT). This technique has been used to treat some cases of severe and prolonged diarrhea caused by overgrowth of the bacteria C. difficile.

Routy, as well as another team of researchers in the U.S., cultured bacteria from the feces of cancer patients who were treated with checkpoint inhibitors. They then gave mice with human tumours FMT with these bacteria. Only the mice that received FMT from people who had responded to checkpoint inhibitors showed improved responses to those tumours when they too were treated with checkpoint inhibitors. The mice that showed poor responses despite FMT were then given supplements of A. muciniphila and their responses to checkpoint inhibitors improved.

These and other experiments strongly suggest that for checkpoint inhibitors to have beneficial effects, people with cancer may need to have the right mix of bacteria.

Readers should note that other scientists studying people with other cancers (such as malignant melanoma) found that other bacteria, such as Faecalibacterium, enhanced the activity of checkpoint inhibitors in subsequent studies with mice. Thus, it is possible, likely even, that there is no one ideal variety of gut bacteria that can help people who use checkpoint inhibitors. Rather, a mix of bacteria with one strain predominating may be useful in some cancers, while in others types of cancer, a diverse mix of bacteria may be more useful.

A difficult road ahead

The experiments with gut bacteria and checkpoint inhibitors are exciting and underscore the importance of such bacteria for the immune system. Now much work lies ahead in this aspect of cancer research. Scientists need to study precisely how friendly bacteria can help enhance the immune response in cases of cancer treatment with checkpoint inhibitors.

Also, as mentioned earlier in this issue of TreatmentUpdate, there are factors that can affect the mix of bacteria that live in the gut. It is one thing to study mice confined to cages, but another to study complex human beings with cancer and the many factors that can affect the composition of gut bacteria, including use of antibiotics and other medicines, diet, stress, use of supplements, and so on. Scientists have their work cut out for them as they try to move experimental results with mice to clinical trials with people with cancer being treated with checkpoint inhibitors. Due to the complex and poorly understood ways that gut bacteria can affect human health, it could take years before supplements of friendly bacteria are routinely used with checkpoint inhibitors or other immune-based therapy in clinical trials. In some cases, if scientists can uncover how gut bacteria exert their effects on the immune system, it may not be supplements of bacteria that are tested in clinical trials, but instead proteins derived from such bacteria.

HIV cure research

Researchers in France and the U.S. are conducting clinical trials of checkpoint inhibitors in people who have HIV and cancer. As checkpoint inhibitors can cause intense side effects, researchers are proceeding cautiously with these studies. If the results from these studies are positive, then researchers can plan on investigating the role of gut bacteria and checkpoint inhibitors in this population.

—Sean R. Hosein

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