How the Microbiome Could Be the Key to New Cancer Treatments
The effectiveness of drugs that help the immune system fight cancer cells appears to depend on bacteria in the gut
Chemical engineer Stephanie Culler was just 13 years old when both her grandmothers died of cancer within six months of each other. Confronting the cruel randomness of the disease is tough for any young teenager, but Culler was further confused by an American Cancer Society poster on her parents’ refrigerator.
“These good food choices may help protect you against certain cancers,” read the poster text accompanying 30 beautifully photographed fruits and vegetables.
But Culler’s grandmothers, one who had lung cancer and the other colon cancer, already ate most of those foods. In fact, her maternal grandmother, an immigrant from Iran, stuck to the traditional Persian cuisine of chopped salads, grilled veggies and pomegranates that would rival any American diet in sheer anti-oxidant glory. Her diet also included gut-friendly fermented foods like homemade yogurt and pickled vegetables. As far as Culler could tell at the time, her grandmothers should have been spared.
The poster on Culler’s family fridge, and the link it suggested between diet and cancer, would eventually lead her to a lab at Johnson & Johnson’s startup division JLABS where she genetically sequences fecal samples. Culler and other oncology researchers hope to answer one of the most pressing questions in current cancer research: Does the quality and diversity of human gut bacteria determine whether people will successfully respond to cancer treatment?
“When we looked at stool from breast and lung cancer patients, we discovered that important bacteria were missing from the microbiome,” Culler says. The absence of certain gut microbes, mostly Firmicutes bacteria, could explain why immune checkpoint inhibitors—drugs that block cancer-friendly proteins and help facilitate the immune system’s response to cancer cells—don’t work on some patients. “We believe that those bacteria are important for the immune system to be able to respond to those drugs,” Culler says.
Along with fellow chemical engineer Steve Van Dien, Culler cofounded Persephone Biome in the summer of 2017 to study the relationship between gut bacteria and cancer. Named for Persephone, the Greek goddess of vegetation who appears in the spring and descends back into the underworld after harvesttime, Culler’s company is gearing up for clinical trials that will test specific gut microbes to see if they improve the function of checkpoint inhibitors in breast and non-small cell lung cancer patients. (A second product will focus on CAR-T cell therapy, which uses patients’ own immune cells that have been genetically engineered to treat their cancer.)
“Our goal is to create therapeutics to convert non-responders into responders,” Culler says, referring to patients who do or do not respond to checkpoint inhibitors. Her company hopes to engineer a mix of selected gut bacteria that can be taken in pill form to heal patients’ microbiomes, which can be damaged by antibiotics and poor diet, as she discussed recently in a talk at TEDx San Diego.
“Even healthy people might be missing these gut microbes, but cancer patients and people with compromised immune systems are more likely to be missing them,” Culler says. “We want to give them back.”
Although at least 70 percent of immune cells are believed to reside in the gut—often called the “second brain”—scientists didn’t become particularly interested in the human microbiome until 2005. A groundbreaking paper published that year suggested that obese mice had different gut bacteria than thin mice. Since then, researchers have explored the idea of swapping out humans’ gut bacteria and have even used fecal microbiota transplants (often called “poop pills,” even though they are usually administered as a liquid) to successfully treat people who suffer from inflammatory bowel disease. (However, they’ve yet to develop a weight loss supplement by transferring the bacteria of enviably trim people to the guts of the fat masses.)
Over the last decade, there’s been a flurry of research exploring the microbiome’s role in everything from depression to autism to Parkinson’s disease. Studying the microbiome can help determine which patients are likely to respond to different pain and heart drugs, according to Rob Knight, founding director of the Center for Microbiome Innovation at the University of California San Diego. “We’re extremely interested in the interplay between food, drugs and the gut microbiome,” says Knight, who also cofounded the American Gut Project, a citizen science effort that has collected fecal samples from more than 11,300 participants in 42 countries.
While the connection between gut bacteria and health is becoming clearer, scientists have struggled to successfully manipulate the microbiome as a form of treatment. “We know more than ever about how the microbiome influences chronic disease,” Knight says, “but what we don’t know yet is how to change your microbiome in a particular direction.” (Researchers do agree, however, that probiotics aren’t the godsend some people think they are.)
Last year, three research papers published in Science rocked the cancer field by showing that it might be possible to manipulate the microbiome to affect treatment responses. In a series of “man-meets-mice” interspecies experiments, a French team transplanted human gut bacteria into mice from both successfully treated cancer patients and patients who did not respond to checkpoint inhibitors. Two weeks after the new bacteria had been introduced to the rodents’ guts, the researchers injected cancer cells and checkpoint inhibitors every three days for another two weeks. The drugs worked to reduce tumors in mice that had received human bacteria from successfully treated cancer patients, while the drugs were not effective in the mice that received bacteria from humans who did not respond to treatment.
Teams from the University of Chicago and University of Texas MD Anderson Cancer Center in Houston have conducted similar experiments using gut microbes from metastatic melanoma patients who responded well to checkpoint inhibitors. Those mice improved, too. “We basically put a little tube into the mouse’s esophagus and put in the poop sample. It reconstituted the mouse’s gut so that it now contained microbes from the patient,” says Deepak Gopalakrishnan, a postdoctoral research fellow and lead author of the MD Anderson study.
The next step is clinical trials with humans. The MD Anderson team is studying the possibility of giving patients the missing gut bacteria in the form of spores (which don’t have to be frozen like fecal matter) from donors with favorable microbiomes. Another arm of the trial will test poop pills made from the bacteria of cancer survivors whose tumors disappeared after taking checkpoint inhibitors. And researchers are also tracking patients’ lifestyles, including produce and fiber intake, to connect the dots between cancer drug response rates, gut diversity and diet.
“We know that diet matters, but everyone wants to know what the secret sauce is to change the microbiome to respond better to cancer treatment,” says Jennifer Wargo, a professor of surgery and genomic medicine at the University of Texas who co-authored a review of microbiome science last month. “We simply don’t know that yet.”
Neither does Culler, who still wonders why her grandmothers didn’t respond to the chemotherapy treatments that were available in the mid-1990s. Yet she hopes the same genetic sequencing tools that make it possible to peer into our poop and study bacteria strains will also provide a way to better diagnose tumors and choose the right treatments.
In the meantime, Culler joins a chorus of researchers trying to bring attention to the biggest barrier to their research: lack of stool samples. Scientists need donations from cancer patients, cancer survivors, people with a family history of cancer and everyone else. “I’m always surprised why it’s so difficult to get samples,” Culler says. “People think it’s gross and are embarrassed. But I’m grateful for the cultural acceptance of the poop emoji for destigmatizing it.”
Culler even launched “Poop for the Cure,” a research project that offers $50 Visa gift cards for samples. “Hopefully there will be a day when collecting stool will be as routine as collecting blood. Until then, we need everyone to help out.”