What Gut Bacteria Tell Us About Treating Melanoma and Other Cancers
Despite success in the use of immunotherapy to treat cancer by harnessing the body’s immune system to fight it, a major difficulty continues to be the range of responses to treatment among patients. It’s why researchers are exploring why some cancer patients, like former President Jimmy Carter — diagnosed with melanoma at 91, exhibit astounding results with little side effects while others receive no benefits to the treatment and/or experience severe side effects.
In an effort to determine whether there are drugs with the potential to help boost the body’s response to immunotherapy, researchers at MD Anderson, in a study partly funded by the Melanoma Research Alliance and led by Jennifer Wargo, MD, professor of genomic medicine and surgical oncology at MD Anderson, are exploring those possible drugs and what role genetics may play in its effectiveness. Though the team’s recent research has centered on what intrinsic properties of tumors allow them to respond or resist immune checkpoint blockades, Wargo’s team became increasingly interested in the role of factors beyond the tumor that might influence a patient’s ability to respond to treatment. Hoping to discover if there is a plausible link between how patients respond to therapy and microbes that exist in their gut, they began analyzing the role of microbiome.
But what is the microbiome? In our bodies we have around 100 trillion microorganisms that sit on our skin and within our gastrointestinal tract or gut. Long ignored, researchers recently discovered these bacteria may influence numerous diseases, from autism to depression to obesity. Because a vast number of diseases are linked to changes in the microbiome, Wargo wants to understand its role in melanoma and cancer and how it responds to therapy.
Dr. Laurence Zitvogel and Dr. Tom Gajewski, whose published studies on mouse models showed bacteria within mice intestines could influence how quickly melanoma tumors grow, further prompted Wargo’s interest in this theory. They discovered its influence on the response to therapy, specifically to immune checkpoint inhibitors targeting CTLA4 or PD1/PDL-1. Their results showed that augmenting the microbiome with specific species of bacteria, which differed depending on the checkpoint inhibitor received, could make mice more responsive to therapy.
Inspired by the study, Wargo’s team wanted to explore how effective it may be in patients. After creating a protocol to collect both oral and gut microbiome from patients with metastatic melanoma going on to systemic therapy, the team collected samples from over 300 patients over the last two years. The vast majority was treated with checkpoint blockades. Samples were collected at the start of therapy via cheek swabs and fecal sample kits. As PD1 based therapy was initiated on approximately 100 patients, they looked for treatment responses using CAT scans and imaging, followed by collecting another microbiome sample. In addition, biopsies of the tumor were done to interrogate the relationship of what is happening in the gut and what is seen in the tumor itself.
After closely examining the relationship between response and composition of both oral and gut microbiome, Wargo’s team found that though the difference between responders and non-responders to PD1 therapy for the oral microbiome showed no clear differences, differences in the gut microbiome between responders and non-responders were profound. Patients who responded to PD1 based therapy had a more diverse gut microbiome, i.e., they had a larger distribution of bacteria within the gut.
In current clinical trials, Wargo’s team is performing genome sequencing with a substantial cohort of patients who had a good response to PD1 versus a poor response. Her team hopes to utilize the information to boil down the unifying factors that differentiate the gut microbiomes of responders from non-responders. The aim is to determine the top 10-20 bacteria that are enriched in patients that respond and then fashion a cocktail of these bacteria to administer to the non-responders.
Wargo believes what should be done with this information is a matter of better understanding the mechanism behind it. “We should be sampling the gut microbiome of patients with metastatic melanoma and looking at diversity and composition; then incorporating that into clinical trials, and testing for a hypothesis that we could plausibly use it as a biomarker,” she explains.
Wargo also claims that composition matters. “It’s not just having more bacteria, but having more of the right bacteria,” she says. Responders to therapy had more bacteria in the Clostridiales order, whereas non-responders had a higher abundance of bacteria in the Bacteroidales. Wargo’s team drilled down to further examine the relationship of these particular bacteria in the gut with immune cells in the tumor and found strong correlations, including increased numbers of immune cells, like killer CD8+ T cells, infiltrating their tumors.
A significant implication of the study is that melanoma patients could increase the likelihood that checkpoint inhibitor therapy would shrink their tumors by modulating their gut microbiome either via transplant or dietary intervention such as prebiotics or probiotics. Wargo thinks testing this is possible as long as it is done in the context of a clinical trial. “We don’t want patients to be under the false impression that ingesting a probiotic will enhance the effectiveness of their checkpoint inhibitor,” Wargo explains. “In fact, a plausible modulation strategy might be first administering an antibiotic which is then followed by a probiotic to actually change the bacteria in their gut.”
Despite pragmatic optimism, Wargo claims the gut microbiome is not the total answer — only part of it. Tumor genetics still play a key role. “In terms of using the composition of a patient’s gut microbiome as biomarker, the gut microbiome helps shape the tumor environment and immunity, but it’s not the whole picture,” she says. “It won’t be like the magic biomarker that’s going to predict everything.” The range of variables Wargo believes must also be considered are host polymorphisms, including patients’ HLA type, and antigen presentation. She envisions use of the tumor genome in their research from a prognostic standpoint – while also using the microbiome to enhance patients’ responses. “Microbiome will still play a major role, as it’s changing things not only for cancer, but for overall health,” she says.
Continuing to work with partner institutes in cancer immunotherapy on microbiome studies, Wargo’s team is planning clinical trials expected to be underway by this summer to test the hypothesis that changing the microbiome can enhance response to immune checkpoint blockades. She says that the key to reaching success in this type of research is collaboration, acknowledging that a number of NIH researchers have been exploring similar questions. Wargo credits MRA with bringing together key researchers to advance such studies. “MRA has the right idea in mind by facilitating collaboration among researchers in an environment that’s highly competitive. Their strategy is not simply monetary, but in connecting people, their ideas and the research,” she says. “Banding together in a unified way is of immeasurable benefit to everyone, particularly patients.”
Wargo believes the first generation clinical trials would harness fecal transplants. Examining a profile group that has had a complete response to compare with a healthy donor that has similar composition of gut microbiome will hopefully allow them to make a formulation. Essentially, a poop pill containing the beneficial bacteria would be given to patients in the setting of treatment with checkpoint blockades, the hypothesis being that it will enhance their response to therapy. Aside from a fecal transplant trial, Wargo’s team is working with a partner institute to identify an industry partner to help formulate the perfect poop pill using the top 5-10 bacteria plus pre-biotics; then potentially a novel delivery system.
Wargo posits that her team and those of Gajewski are turning a corner with the discovery of gut bacteria’s potential relation to how patients respond to therapy for melanoma. “My team and I are building on what our colleagues have initiated. We’re essentially standing on the shoulders of giants,” she says. “We’re all in one big team for the common goal of curing cancer.”
Wargo says they likely would not have had the ability to explore the microbiome theory de novo were it not for organizations like MRA that fund such high-risk research. “MRA has been critical in enabling us to advance these studies.”
Targeted Therapy Immunotherapy microbiome CD8+ T cells Treatment