Immune therapy for cancer needs the right gut stuff

| November 23, 2015
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When it comes to health, we don’t often think of having too much of a good thing. It’s very difficult, although not impossible, to get sick from eating too many carrots, for example, or drinking too much water. But the biological systems within our bodies are very familiar with the ‘too much’ idea and have evolved elaborate systems of checks and balances to prevent it.

The immune system is a great example of this. When a disease causing germ enters, the system launches an attack. But it shouldn’t attack forever. That would lead to a whole host of problems including fever, diarrhea, rashes and eventually death. And so there are molecules that keep tabs on the process and inhibit self-destruction.

But there are some cases when we’d like the immune system to go into overdrive. Cancer is one of them. And over the last decade researches have explored ways to shut down those inhibitory molecules and unleash more of the power of our immune system. There are several cancer drugs that do just that on or coming to the market soon.

Immune therapies are rather startlingly effective, but not for all patients. Some patients just don’t respond, or do so only at first. Doctors haven’t been able to pinpoint why, but a pair of studies suggest that its not just the drug that matters. The content of our guts and the kinds of bacteria that live there make a huge difference in whether the cancer-fighting drugs work.

The experiments in the two studies mostly involved mice. In one, researchers noticed that mice from one company responded really well to anti-cancer drugs compared to mice from another. And, when they put the mice together — and they shared and ingested each other’s feces — the non-responders did better at fighting cancer. So, researchers traced it back to one particular family of bacteria living in the gut.

A second study found that mice who were raised to be germ-free and have not gut microbiota did not respond at all to anti-cancer immune therapy. The gut species that mattered most were two species from the Bacteroids family. When they gave germ-free mice those bacteria, they responded to the cancer drug.

It might be counter intuitive to think of the gut, the immune system and cancer together. But the gut is really a proving ground for immunity. There the immune system has to identify and destroy bad bacteria that makes us sick while properly ignoring the many, many good families of bacteria that keep us healthy. The immune system also keeps our own cells from growing out of control, which is the genesis of any cancer.

Some patients mount a natural immune attack on their own cancers by sending a large number of t-cells to attack. T-cells are an immune cell that is programmed to recognize foreign invaders. Immunotherapy works by taking away some of the regulatory mumbo jumbo that keep T-cells from going to all out war. Those regulatory processes are really important when you’re healthy. When treating a patient for cancer, however, its worth the risk of disarming some of those properties in order to maximize cancer fighting.

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From this pair of studies it seems that in order to fight cancers, our immune systems need to be pre-programed by families of the good bacteria in our guts. As Anna Azvolinksy wrote at The Scientist, “[They’re] suggesting it is the immune system’s response to commensal microbes that readies it to fight tumors.”

When cancer immune therapies are given to a mouse or patient who has this pre-programmed microbial mix, tumors dissolve. But if that mix isn’t already in place the drugs don’t work as well. There is even some evidence that the relationship between gut bacteria, t-cells and immune therapies works both ways. Human patients who had immune therapy for cancers had increased numbers of these bacterial species after treatment. So, not only were the germs important for the efficacy of the treatment, but that the treatment itself seem to foster growth of the important species.

Scientists will now work to figure out the molecular mechanisms of the relationship. In one of the experiment, scientists increased the tumor-fighting response without even needing to transfer the bacteria. T-cells that had been programmed to recognize the good bacteria worked just as well.

This new evidence may also explain an interesting pattern in immunotherapy: it works for some people really well, but not for everyone. Physicians already know that patients who’s immune system send T-cells to cancers will best benefit from immune therapy. It seems like the gut microbes might be a necessary for that. Science writer Ed Yong wrote:

Although both studies were mainly done in mice, they hint at why checkpoint inhibitors work so absurdly well in a minority of patients, but not in everyone. That lucky minority may harbor gut microbes that make these drugs that much more effective.

And there is some thought that probiotics or even fecal transplants with these crucial micoorganisms could increase effectiveness without increasing risk of side effects. In order to identify which patients could benefit, everyone who might get the drug would need to have their gut microbes sequenced. That would come with a pretty hefty price tag. Some companies are already starting down that path to explore not only how gut bacteria affect current cancer care, but also how they could be manipulated to develop other treatment.

Meredith Knight is a contributor to the human genetics section for Genetic Literacy Project and a freelance science and health writer in Austin, Texas. Follow her @meremereknight.

The GLP featured this article to reflect the diversity of news, opinion and analysis. The viewpoint is the author’s own. The GLP’s goal is to stimulate constructive discourse on challenging science issues.

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