permaculture

[Lawrence London <lfljvenaura@gmail.com>]

https://www.nature.com/articles/d41586-018-05208-8?utm_source=fbk_nnc&utm_medium=social&utm_campaign=naturenews&sf204568270=1&fbclid=IwAR13egleq5zaZ8FYSztlihB1Tv5ZUTnpH7f7C4Ghhaly5GTXTSWYBK34z-8

NEWS FEATURE
23 May 2018
How gut microbes are joining the fight against cancer
The intestinal microbiome seems to influence how well some cancer drugs
work. But is the science ripe for clinical trials?
Giorgia Guglielmi

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Illustration by Ola Niepsuj
PDF version
<https://www.nature.com/magazine-assets/d41586-018-05208-8/d41586-018-05208-8.pdf>

Bertrand Routy earned a lamentable reputation with Parisian oncologists in
2015. A doctoral student at the nearby Gustave Roussy cancer centre, Routy
had to go from hospital to hospital collecting stool samples from people
who had undergone cancer treatments. The doctors were merciless. “They made
fun of me,” Routy says. “My nickname was Mr Caca.”

But the taunting stopped after Routy and his colleagues published evidence
that certain gut bacteria seem to boost people’s response to treatment1
<https://www.nature.com/articles/d41586-018-05208-8?utm_source=fbk_nnc&utm_medium=social&utm_campaign=naturenews&sf204568270=1&fbclid=IwAR13egleq5zaZ8FYSztlihB1Tv5ZUTnpH7f7C4Ghhaly5GTXTSWYBK34z-8#ref-CR1>.
Now, those physicians are eager to analyse faecal samples from their
patients in the hope of predicting who is likely to respond to anticancer
drugs. “It was an eye-opener for a lot of people who couldn’t see the
clinical relevance of gut microbes,” says Routy, who is now at the
University of Montreal Health Centre in Canada.

Cancer has been a late bloomer in the microbiome revolution that has surged
through biomedicine. Over the past few decades, scientists have linked the
gut’s composition of microbes to dozens of seemingly unrelated conditions —
from depression
<https://www.nature.com/news/the-tantalizing-links-between-gut-microbes-and-the-brain-1.18557>
to obesity
<https://www.nature.com/news/gut-microbe-may-fight-obesity-and-diabetes-1.12975>.
Cancer has some provocative connections as well: inflammation is a
contributing factor to some tumours and a few types of cancer have
infectious origins. But with the explosive growth of a new class of drug —
cancer immunotherapies — scientists have been taking a closer look at how
the gut microbiome might interact with treatment and how these interactions
might be harnessed.

After preliminary findings in mice and humans revealed that gut bacteria
can sway responses to such drugs, scientists started trying to decipher the
mechanisms involved. And researchers are launching a handful of clinical
trials that will test whether the gut microbiome can be manipulated to
improve outcomes.

Some proponents say that strategies to mould the microbiome could be
game-changing in cancer treatment. “It’s a smart place to be,” says
Jennifer Wargo, a surgeon–scientist at MD Anderson Cancer Center in
Houston, Texas. But others are worried that the move to the clinic is
premature
<https://www.nature.com/news/microbiology-microbiome-science-needs-a-healthy-dose-of-scepticism-1.15730>.
William Hanage, an epidemiologist at the Harvard T. H. Chan School of
Public Health in Boston, Massachusetts, calls the idea “phenomenally
interesting”, but adds: “I have some anxiety about the notion that only
beneficial effects are possible.”

*Intriguing link*

Although the excitement about microbes and immunotherapy has emerged only
in the past three years, some researchers have been exploring connections
between gut bacteria and cancer for much longer. Scientists first linked
the infectious bacterium *Helicobacter pylori* to gastric cancer back in
the 1990s, for example. And since then, other bacteria have been associated
with cancer initiation and progression. Some of these microbes activate
inflammatory responses and disrupt the mucus layers that protect the body
from outside invaders, creating an environment that supports tumour growth.
In other cases, they promote cancer survival by making cells resistant to
anticancer drugs.

But gut bacteria can also help fight tumours
<https://www.nature.com/news/gut-microbes-can-shape-responses-to-cancer-immunotherapy-1.22938>.
In 2013, a group led by Laurence Zitvogel2
<https://www.nature.com/articles/d41586-018-05208-8?utm_source=fbk_nnc&utm_medium=social&utm_campaign=naturenews&sf204568270=1&fbclid=IwAR13egleq5zaZ8FYSztlihB1Tv5ZUTnpH7f7C4Ghhaly5GTXTSWYBK34z-8#ref-CR2>
at Gustave Roussy and one led by immunologists Romina Goldszmid and Giorgio
Trinchieri3
<https://www.nature.com/articles/d41586-018-05208-8?utm_source=fbk_nnc&utm_medium=social&utm_campaign=naturenews&sf204568270=1&fbclid=IwAR13egleq5zaZ8FYSztlihB1Tv5ZUTnpH7f7C4Ghhaly5GTXTSWYBK34z-8#ref-CR3>
at the National Cancer Institute in Bethesda, Maryland, showed that some
cancer treatments rely on the gut microbiome activating the immune system.

Zitvogel’s team found that the chemotherapy drug cyclophosphamide damages
the mucus layer that lines the intestine, allowing some gut bacteria to
travel into the lymph nodes and spleen, where they activate specific immune
cells. For mice raised without microbes in their guts or given antibiotics,
the drug largely lost its anticancer effects.

Following this observation, Zitvogel decided to explore whether bacteria in
the gut might influence responses to a class of immunotherapy drugs called
checkpoint inhibitors. These drugs, typically antibodies to cell-surface
molecules such as CTLA4 and PD1, unleash a person’s immune system against
tumour cells, and are used to treat several types of cancer (see ‘A little
help from their friends’). But only 20–40% of people respond to treatment4
<https://www.nature.com/articles/d41586-018-05208-8?utm_source=fbk_nnc&utm_medium=social&utm_campaign=naturenews&sf204568270=1&fbclid=IwAR13egleq5zaZ8FYSztlihB1Tv5ZUTnpH7f7C4Ghhaly5GTXTSWYBK34z-8#ref-CR4>
.

In 2015, Zitvogel and her team showed that microbe-free mice failed to
respond to one such drug, and mice given a particular bacterium, *Bacteroides
fragilis*, responded better than did mice without it5
<https://www.nature.com/articles/d41586-018-05208-8?utm_source=fbk_nnc&utm_medium=social&utm_campaign=naturenews&sf204568270=1&fbclid=IwAR13egleq5zaZ8FYSztlihB1Tv5ZUTnpH7f7C4Ghhaly5GTXTSWYBK34z-8#ref-CR5>.


The idea started to spread. Thomas Gajewski, a cancer clinician at the
University of Chicago in Illinois, reported that *Bifidobacterium* microbes
increased the response to cancer immunotherapy in mice6
<https://www.nature.com/articles/d41586-018-05208-8?utm_source=fbk_nnc&utm_medium=social&utm_campaign=naturenews&sf204568270=1&fbclid=IwAR13egleq5zaZ8FYSztlihB1Tv5ZUTnpH7f7C4Ghhaly5GTXTSWYBK34z-8#ref-CR6>.
These gut-dwelling bacteria acted by boosting the ability of some immune
cells to initiate a response against tumours.

Wargo saw these results presented at a meeting in 2014, and on returning to
Texas, immediately started to collect stool samples from people with skin
cancer who were about to undergo immunotherapy at her institution. Last
November, Wargo7
<https://www.nature.com/articles/d41586-018-05208-8?utm_source=fbk_nnc&utm_medium=social&utm_campaign=naturenews&sf204568270=1&fbclid=IwAR13egleq5zaZ8FYSztlihB1Tv5ZUTnpH7f7C4Ghhaly5GTXTSWYBK34z-8#ref-CR7>,
Gajewski8
<https://www.nature.com/articles/d41586-018-05208-8?utm_source=fbk_nnc&utm_medium=social&utm_campaign=naturenews&sf204568270=1&fbclid=IwAR13egleq5zaZ8FYSztlihB1Tv5ZUTnpH7f7C4Ghhaly5GTXTSWYBK34z-8#ref-CR8>
and Zitvogel1
<https://www.nature.com/articles/d41586-018-05208-8?utm_source=fbk_nnc&utm_medium=social&utm_campaign=naturenews&sf204568270=1&fbclid=IwAR13egleq5zaZ8FYSztlihB1Tv5ZUTnpH7f7C4Ghhaly5GTXTSWYBK34z-8#ref-CR1>
all published results in *Science* linking positive immunotherapy responses
in people to specific varieties of gut bacteria. The samples that Routy had
collected in Paris helped Zitvogel’s team to also show that people who had
taken antibiotics for unrelated infections tended to respond poorly to
immunotherapy.

To solidify the relationships, the researchers transferred bacteria from
the human participants into the intestines of mice with comparable cancers.
Rodents who got ‘beneficial’ bacteria developed smaller tumours than did
mice that received microbes from people who hadn’t responded to treatment.
“All of this work has been very exciting,” says Neeraj Surana, a
microbiologist at Boston Children’s Hospital. “They’ve opened up the
possibility for a clear therapeutic application of microbiome science.”

*Heading to the clinic*

Researchers are now running with that possibility. Hassane Zarour, an
immunologist at the University of Pittsburgh in Pennsylvania, partnered
with the global pharmaceutical company Merck to collect faecal bacteria
from people who respond to treatment with a checkpoint inhibitor and
transfer them into the intestine of non-responders, a process called faecal
microbiome transplant. Merck has invested about US$900,000 into this trial,
which is set to start in the next few weeks.

Wargo is planning a similar trial. Together with the Parker Institute for
Cancer Immunotherapy in San Francisco, California, and the biotech company
Seres Therapeutics in Cambridge, Massachusetts, she expects to test whether
faecal transplants can reshape the gut microbiome of non-responders in a
beneficial way.

The tantalizing links between gut microbes and the brain
<https://www.nature.com/news/the-tantalizing-links-between-gut-microbes-and-the-brain-1.18557>

These microbiome transplants are becoming a mainstream treatment
<https://www.nature.com/news/policy-how-to-regulate-faecal-transplants-1.14720>
for some non-cancer illnesses. In February, for example, the Infectious
Diseases Society of America recommended that physicians use these
procedures to treat people with bowel infections caused by the
bacterium *Clostridium
difficile* who had failed to respond to other treatments. But the approach
has downsides. To avoid the risk of inadvertently infecting people with
pathogenic microbes, researchers must be careful in how they select donors
and screen faecal material before transferring it to recipients. That’s
why, in addition to faecal transplants, Seres Therapeutics, the Parker
Institute and Wargo will test a pill containing a set of spore-forming
bacteria that have been purified from the faeces of responding patients.

Gajewski and his partners at Evelo Biosciences, a biotech company in
Cambridge, are using a similar approach. Their trial will assess the
effects of two pills containing single bacterial strains in people with
different types of cancer, including colon and skin cancer.

Zitvogel is not planning to start clinical trials but she has co-founded
the Delaware-based start-up EverImmune, which is developing a
microbiome-based pill.

It’s still unclear exactly how microbes might interact with
immunotherapeutics. A widely accepted hypothesis is that some boost the
body’s response against tumours by regulating how easy it is to activate
the immune system. But the precise mechanisms, including which bacteria
modulate which immune cells, remain a mystery.

The researchers hope that the clinical trials will help to clarify things.
Wargo, for instance, is exploring bacterial metabolites. Her team hopes to
find specific metabolic signatures of a good outcome in the stools and
blood of people who respond to therapy, as well as to document the numbers
of immune cells in the blood and tumours of trial participants.

Gajewski suggests that microbes might be unleashing the immune response by
stimulating the gut cells to produce certain molecules. His team is testing
whether circulating immune-cell precursors change their behaviour when
specific bacteria are given to mice. At the same time, the group is trying
to pin down which species might be driving the positive outcomes.

*Too early, or just right?*

Given the uncertainties, some scientists argue that testing these
approaches in humans is risky. Some trial participants could experience
side effects, Surana says. And changing the make-up of an individual’s
microbiome might predispose them to other health problems.

Faecal transplants come with a lot of unknowns. They have proved safe and
effective in many people without cancer, Wargo says, but they have also
been associated with unexpected effects, including one case in which the
procedure led to weight gain and obesity9
<https://www.nature.com/articles/d41586-018-05208-8?utm_source=fbk_nnc&utm_medium=social&utm_campaign=naturenews&sf204568270=1&fbclid=IwAR13egleq5zaZ8FYSztlihB1Tv5ZUTnpH7f7C4Ghhaly5GTXTSWYBK34z-8#ref-CR9>.
“Should we look for safety signals on these trials? Absolutely.” Wargo
says, “But I strongly feel that we need to go into these trials. We need to
design them well. We need to really learn from these trials.”

Gajewski, who plans to test the effects of just one bifidobacterial strain
at a time, says there’s good reason to be confident. “People have eaten
bifidobacteria for a thousand years,” he says. The bacteria are present in
the gut of infants and decline in number as the people grow up, so they
should at least be safe, he adds.

But it’s unclear whether a single species can help people with cancer and,
if so, what bacterium that is. The papers published in *Science* last year
all associated different bacteria with the best outcomes, even for the same
cancer and therapy.

Microbiome science needs a healthy dose of scepticism
<https://www.nature.com/news/microbiology-microbiome-science-needs-a-healthy-dose-of-scepticism-1.15730>

The researchers looked at people with cancer from France and the United
States, so diet could account for some of the differences, Wargo says. But
variations in sample collection, data analysis and statistical methods
could also have skewed the results, says Joël Doré, a biologist at the
French National Institute for Agricultural Research in Paris who in 2011
helped to launch the International Human Microbiome Standards (IHMS)
project with the aim of improving data reproducibility in microbiome
research.

Hanage says that even the two studies7
<https://www.nature.com/articles/d41586-018-05208-8?utm_source=fbk_nnc&utm_medium=social&utm_campaign=naturenews&sf204568270=1&fbclid=IwAR13egleq5zaZ8FYSztlihB1Tv5ZUTnpH7f7C4Ghhaly5GTXTSWYBK34z-8#ref-CR7>
,8
<https://www.nature.com/articles/d41586-018-05208-8?utm_source=fbk_nnc&utm_medium=social&utm_campaign=naturenews&sf204568270=1&fbclid=IwAR13egleq5zaZ8FYSztlihB1Tv5ZUTnpH7f7C4Ghhaly5GTXTSWYBK34z-8#ref-CR8>
that analysed people in the United States with the same type of cancer
identified only a partially overlapping set of microbes associated with
positive outcomes. If researchers don’t work out the reason for these
differences, they might not be able to interpret the outcomes of the
trials, Hanage says.

Before starting clinical trials, the three groups should try to reproduce
each other’s results and converge on a set of ‘beneficial’ microorganisms,
Hanage argues. “Any of these bacteria could be a useful approach.” But
inconsistencies might mean that the results are not reproducible.

It’s a concern common to microbiome research. “A lot of findings have
proven to either not stand up or be considerably more complicated than they
first appeared,” Hanage says. Standards such as those developed by the IHMS
project should help, but scientists will be reluctant to take them on
board, says Susan Erdman, a microbiologist and cancer biologist at the
Massachusetts Institute of Technology in Cambridge. Doing so would come at
the cost of innovation, she argues — it’s by experimenting in different
settings that researchers make discoveries.

Wargo says that the community should standardize its approaches for
collecting samples and doing analyses, as well as for validating studies in
larger groups of patients. Since last year, her group has analysed stools
from more than 500 people with skin cancer who had received different
therapies. In parallel with the Paris-based team led by Zitvogel, the
researchers are analysing patients treated with two combined
immunotherapies to work out which gut bacteria mediate a response to that
combination. Wargo hopes that the gut microbiome could eventually help to
identify which patients will respond to which anticancer treatments. “Can
we use it as a biomarker? It’s a provocative question,” she says.

In the short term, there will be a whole lot more sample collection. And
this time around, it’s likely that fewer oncologists will raise an eyebrow,
says Routy, who is now investigating how the gut microbiome boosts
immunotherapy with his own group. In cancer therapy, “gut microbes have
gone from ignored to super-popular organisms”, he says. Now, they’ll just
have to live up to their reputation.

Nature *557*, 482-484 (2018)
doi: 10.1038/d41586-018-05208-8