Israel: Fecal transplants may help flush tumors from body


Three terminal cancer patients treated with pills of fecal matter saw their tumors shrink, and in one case disappear completely, Israeli doctors say,

The results of the small Phase I study of fecal microbiota transplantation at Sheba Medical Center were published this month in the peer-reviewed journal Science, sparking hopes of a possible new lifeline for cancer patients.
“For the first time in the world, we have successfully fought tumors by modulating the gut microbiome,” Dr. Ben Boursi, oncologist at Sheba’s Gastrointestinal Cancer Department, told The Times of Israel.

The three patients were part of a 10-person cohort of melanoma patients treated with the pills three years ago, after doctors said they had no established treatment options remaining and had just weeks to live.

They had previously been failed by immunotherapy, but when they restarted treatment while taking pills, the three showed improvement based on imaging, gene profiles and examinations.

Two of them surprised doctors by living for a year, and one of them is still alive, leading a normal life without signs of cancer. The other seven saw little or no benefit from the pills.

While icky-sounding, the use of fecal matter as a treatment for various ailments dates back to the late 1950s. The treatment works by transplanting gut microbes of healthy donors to patients, thereby changing the composition of the gut microbiome, and was used to treat various gastrointestinal disorders.

In recent years, researchers have increasingly begun to study possible therapeutic effects of the treatment for other ailments as well. (It has also been explored as a possible weight control tool.)

Three years ago, Boursi, together with Prof. Gal Markel and other colleagues, decided to create the pills and initiate the Phase I clinical trial, prompted by oncologists’ fascination with the gut environment.

They increasingly believe that differences in the so-called gut microbiome of patients may help to determine why some respond to immunotherapy while others don’t.

“We were keen to try this method to modulate the gut microbiome because immunotherapy only works for 40 percent to 50% of patients,” Boursi said. “We want to turn as many of the others as possible from non-responders to responders.”

The study was the first time fecal microbiota transplantation was deployed to combat cancer. The pills were made by extracting small amounts of matter from the feces of melanoma patients who were thought to be cured and showed no evidence of the disease in imaging, Boursi said.

Bolstered by the results, Boursi’s team now hopes to test the pills, which are odorless and tasteless, on other malignancies that are treated with immunotherapy.

“These pills could help patients with melanoma and various other cancers treated with immunotherapy, including colon, lung and bladder,” he said. “What we have shown so far is this is feasible, safe and relatively inexpensive and what we want to do now is to run additional clinical trials and lab studies.”

“We’re now expanding to involve more melanoma patients, as well as a type of lung cancer, and the plan is to continue clinical trials.”

Nissan Yissachar, a cancer expert from Bar-Ilan University who is unconnected to the new Sheba study, described it as “serious science by serious researchers in a serious journal.”

“[It] follows several other research projects that show changes in composition of gut microbe can impact efficacy of immunotherapy,” he said.

Background and rationale for FMT in immunotherapy
The human microbiome refers to the trillions of microorganisms (and their genomes) that live on and in human bodies in a symbiotic relationship. The microbes that inhabit our gut aid in harvesting nutrients from our diet and maintaining gut mucosal integrity, among other functions.

The gut microbiome has also been shown to play a key role in shaping the development of mucosal and systemic immunity [2]. There is considerable cross-talk between the gut microbiome and our immune system, with a homeostatic balance of tolerance of beneficial commensal microbes and defense against pathogenic bacteria.

Dysbiosis, i.e., an imbalance in the gut microbe, has been implicated in the pathogenesis of multiple diseases, including autoimmune diseases, gastrointestinal disorders, and luminal malignancies [3,4,5,6]. Initial evidence that the gut microbiome could play a role in therapeutic outcomes in cancer came from work in allogeneic hematopoietic stem cell transplant (HSCT) and graft-versus-host disease (GVHD) [7, 8, 9]. In preclinical studies, it had been demonstrated that the gut microbiome can influence the immune response to chemotherapeutics such as cyclophosphamide [10].

A role for the gut microbiome in response to immunotherapy was first suggested in two preclinical studies published in Science in 2015 where it was shown that the gut microbiota influenced response to ICB in mice [11, 12]. Multiple studies in human cohorts subsequently demonstrated strong associations between the gut microbiome and response to ICB in various types of cancer [13, 14, 15, 16, 17].

Importantly, it was further shown in preclinical models that the gut microbiome could be modulated to enhance therapeutic response [11, 12, 13, 14, 15]. Thus, the gut microbiome is not only a biomarker of response to immunotherapy, but also an interventional target.

The gut microbiome can be targeted with a variety of modalities including via diet and the provision of putative beneficial organisms as either single-strain probiotics or bacterial consortia [18]. However, the most well-established method of microbiome modulation is through FMT, whereby a donor microbiome is transferred to a recipient in the form of a stool suspension given either endoscopically or in capsule format.

FMT is a guideline-recommended therapy for recurrent Clostridium difficile infection, where it has been shown to correct the dysbiotic state and result in clinical resolution of symptoms in randomized clinical trials [19,20,21], and FMT is being investigated in multiple other diseases.

FMT is the most direct method of microbiome modulation and results in the transfer of the entire donor microbial ecosystem. This approach has two distinct advantages over the introduction of single putatively pro-immunotherapy response bacteria. First, colonization of single bacteria introduced into a complex host microbiome ecosystem with an established homeostasis can be challenging [22]. Second, the transfer of an entire ecosystem includes both the putative pro-response bacteria and the many other organisms which may either support or have redundant roles with these candidate bacteria.

Lessons learned from non-cancer FMT studies
Though investigations of FMT have only recently been initiated in the context of immunotherapy, FMT has been well-studied for other indications with important lessons to be learned from these investigations in terms of approach. The most established indication for FMT is for recurrent/refractory Clostridium difficile infection (CDI).

CDI is a clear dysbiosis associated with antibiotic use disrupting the normal gut microbiome allowing outgrowth of this toxin-producing spore-forming obligate anaerobe [23]. CDI can be treated by metronidazole or oral vancomycin but recurrence is high, in part due to collateral damage to the commensal microbiota by these antibiotics [24].

Randomized clinical trials have established that FMT given as a single dose is a highly effective treatment for refractory CDI with systematic reviews demonstrating efficacy rate of 80–90%, and importantly a much lower rate of recurrence than standard-of-care, and consensus guidelines support the use of FMT for this indication [19,20,21].

Longitudinal microbiome profiling has demonstrated that in this setting, a single-dose colonoscopically delivered FMT from unselected healthy donors leads to rapid and reliable engraftment of donor stool, with normalization of community structure and diversity, and durability (at least up to 6 months which is longest time period which has been surveilled) [25].

In an effort to improve FMT accessibility and safety, more recent studies have utilized oral capsules of frozen donor stool specimens, with a randomized study demonstrating non-inferiority compared to colonoscopic FMT [26].

The success of FMT in CDI has prompted the investigation of this modality in multiple other indications, spanning from gastrointestinal to metabolic to neuropsychiatric disorders [27]. The most well-studied indication beyond CDI is inflammatory bowel disease (IBD), a disease in which the gut microbiome has also been implicated, though direct causality is less clear [28].

FMT within this context has shown significant promise, though results have been more mixed than in CDI with variability of engraftment and clinical response when single-dose unselected FMT is used in this setting [28, 29]. However, more recently, an RCT of an intensive FMT protocol in ulcerative colitis published in The Lancet demonstrated a significant improvement in steroid-free clinical remission rates for the FMT group vs placebo (26% vs 8%) [30].

In this study, patients received a single FMT by colonoscopic infusion followed by FMTs via enema, 5 times per week for 8 weeks. Interestingly, despite meeting the primary outcome of clinical response, there was no significant benefit detected in terms of quality of life which may reflect the intensity of the treatment regimen.

While single infusion healthy donor FMTs have repeatedly been shown to be effective in CDI, these data suggest that less profoundly dysbiotic disease states/hosts may be more resistant to therapeutic microbiota modulation and require more intensive/ongoing interventions [31].

Donor selection may also be important, with “superdonor” patterns emerging in some trials in IBD where clinical response is enriched by specific donors [32]. Specific donor microbiota features associated with response have been described, including taxonomic and metabolic profiles, as well as overall richness and diversity emerging as a key characteristic [32,33,34,35].

Again, this is in contrast to CDI where response does not appear to vary by donor. As the optimal donor microbial characteristics in IBD are being established, others have instead pursued a donor “pooling” approach to minimize donor-dependent effects [30]; however, how pooling effects on the overall ecology of the infused stool and associated engraftment is unclear and there are potential risks associated with donor pooling, as well as issues in understanding the contribution of specific microbes/donor profiles to potential therapeutic response.

FMT has also been studied in metabolic syndrome bolstered by preclinical studies demonstrating that obesity and metabolic syndrome are transferable by FMT in mice [36]. Two clinical studies have suggested that insulin resistance can be improved by FMT from lean donors to patients with metabolic syndrome, though these responses were variable and not durable. Of note, these studies also employed a single FMT infusion and no preceding antibiotic ablation [37, 38].

In this setting, baseline fecal microbiota composition of the recipient predicted response to FMT, with those with lower baseline diversity exhibiting better response [38]. These findings along with those from the IBD studies have important potential implications for optimizing recipient and donor selection and FMT frequency and duration to promote engraftment into less dysbiotic and potentially more resistant host states.

Studies in these other indications have shown that FMT is quite safe, with the most common adverse event being abdominal discomfort [19]. Over the many patients treated in trials and now in clinical practice with FMT, infection transmission has not been a substantial problem with only 4 cases of gram-negative bacteremia reported, three of which had alternative explanations [39]. However, recently, there were two cases (and one resulting death) reported of systemic infections with extended-spectrum beta-lactamase-producing (ESBL) Escherichia coli which was traced back to donor stool [39].

Obviously, this has placed renewed attention on the established guidelines to test donors for potential pathogens [40] and the Food and Drug Administration (FDA) issued a safety alert and has mandated additional screening following these events [41].

Overall, experience with FMT for recurrent CDI supports that FMT can be a highly effective and safe approach to modulate the microbiome, with more variable results in other indications suggesting that host and donor characteristics and timing and duration of intervention may influence therapeutic efficacy and are important considerations in the design of clinical trials in the immunotherapy space (Fig. 1)—as this patient population is more reminiscent of a highly heterogeneous group of individuals with relative dysbiosis (as opposed to the profound dysbiosis observed in CDI).

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Figure 1.
Fecal microbiota transplant to enhance immunotherapy in cancer patients: overview of the potential role of fecal microbiota transplant (FMT) as a therapeutic strategy to modulate the gut microbiome. Through FMT, donor microbiome is transferred to a recipient in the form of a stool suspension given either endoscopically or via pills. Key considerations in the design of FMT interventions include patient selection, donor profile, timing, FMT modality, and post-FMT follow-ups.

Future of FMT: Influence on tumor microbiome
As treatment with ICB is being investigated and approved in more and more malignancies, there is a growing interest in investigating the effect of microbiota (and potential for microbiome modulation via FMT) in these cancers. Provocative recent data has further suggested that modulation of the gut microbiome may impact the intratumoral microbiome in gastrointestinal malignancies. Recent studies have demonstrated that, far from being sterile, there are intratumoral bacteria in the majority of pancreatic cancers (and not in adjacent normal pancreatic tissue) [47].

Studies in murine models have further suggested that this likely represents translocation of these bacteria from the gut [5]. In a recent Cell publication, long-term survivors of pancreatic adenocarcinoma were found to have distinct tumor microbiomes compared to short-term survivors, with an intratumoral microbiome signature highly predictive of survival [48].

Interestingly, FMT from humans to mice using fecal microbiome specimens from long-term vs short-term demonstrated that FMT could modulate not just the gut microbiome in the mice but also the tumor microbiome, tumor growth, and tumor immune infiltrate. This study provides a strong rationale to study the impact of FMT on tumor microbiome in patients.

Another malignancy where this is a strong rationale to examine the role of the intestinal (and tumor) microbiome and FMT is hepatocellular carcinoma. Studies have shown that the liver is exposed to intestinal microbiota through the portal vein which delivers gut-derived bacterial products or toxins, such as lipopolysaccharide and deoxycholic acid [49].

FMT has shown some initial promise in small studies in the treatment of chronic liver disease, including alcoholic hepatitis [50], hepatic encephalopathy [51], and viral hepatitis clearance [52]. Given the recent approval of ICB in HCC, the potential of FMT in patients with hepatocellular carcinoma deserves investigation.

Next Steps:
Valuable lessons will be gained from these initial trials of FMT in immunotherapy and will be used to further optimize this modality in the effort to improve therapeutic outcomes. Intensive characterization and analysis of the host and donor features predictive of benefit will be critical to efforts to further personalize microbiota modulation efforts. Early data has suggested both healthy donors and complete responder gut microbiota profiles differ in expression of pro-response signatures identified in retrospective cohorts suggesting that donor profiling may be an important consideration [53].

In studies that utilize multiple donors, it will thus be important to examine microbiota characteristics associated with better engraftment (though studies will be too small at this point to examine associations with therapeutic response). Similarly, though no studies at this point appear to be using baseline microbiota profile as an inclusion criteria, at least one study is stratifying patients based on previously identified pro-response microbiota signature (NCT03353402), and again, these early studies may suggest microbiota features to be used as selection criteria for future studies to enrich for patients most likely to benefit from FMT.

Beyond donor and recipient microbiota characteristics, underlying genetic and immunological differences could influence both engraftment and downstream physiological and clinical outcomes. External factors may also be critical—medications can strongly influence the gut microbiota [54], and antibiotic use has been associated with impaired response to immunotherapy [15••]. Antibiotic ablation prior to FMT may be critical to allow engraftment of the donor microbiota; however, medication and antibiotic use (and relationship to microbiota profile) should be carefully tracked following FMT.

Interestingly, many of the candidate pro-immunotherapy response bacteria have well-described dietary associations and known functions in the metabolism of specific nutrients such as fiber, a key prebiotic [18]. Diet is a key determinant of the gut microbiota, with nutrients ingested by the host providing the commensal microbes with substrates required for their proliferation and survival and the microbes in turn digesting nutrients otherwise indigestible to their hosts [55, 56].

The effects of pre- or post-FMT diet on engraftment has not been well-studied to date [57], but dietary assessment at baseline and after FMT would be a useful adjunct to understand this potential interaction which could plausibly inform future patient guidance on how to best sustain a donor microbiota. However, this also begs the question of how important maintenance of the donor microbiota is in this setting.

Is an initial shift in the gut microbiota triggering an immune response sufficient or is sustainment of the transplanted gut microbiota necessary to sustain response? Longitudinal profiling of the fecal microbiota and integration with response and clinical variables from these early trials will provide rich data on these interactions.

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