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Adjunctive fecal microbiota transplantation in supportive oncologyWardill, H. R.; Secombe, K. R.; Bryant, R.; Hazenberg, M. D.; Costello, S. P.

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DOI:10.1016/j.ebiom.2019.03.070

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EBioMedicine 44 (2019) 730–740

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Review

Adjunctive fecal microbiota transplantation in supportive oncology:Emerging indications and considerations inimmunocompromised patients

Wardill H.R. a,b,⁎, Secombe K.R. a, Bryant R.V. a,c, Hazenberg M.D. d, Costello S.P. a,ca Adelaide Medical School, University of Adelaide, South Australia, Australiab Beatrix Children's Hospital, Department of Pediatric Oncology, University Medical Centre Groningen, Groningen, the Netherlandsc IBD Service, Department of Gastroenterology, The Queen Elizabeth Hospital, South Australia, Australiad Department of Hematology, Amsterdam University Medical Centre, Location AMC, Cancer Center Amsterdam, Amsterdam Infection and Immunity Institute, Amsterdam, the Netherlands

⁎ Corresponding author at: NHMRC CJMartin BiomedicE-mail address: [email protected] (H.R

https://doi.org/10.1016/j.ebiom.2019.03.0702352-3964/© 2019 Published by Elsevier B.V. This is an o

a b s t r a c t
a r t i c l e i n f o
Article history:Received 30 December 2018Received in revised form 25 March 2019Accepted 25 March 2019Available online 30 March 2019

FMThas gained enormousmomentum in the treatment of acute inflammatory and infectious diseases. Despite anencouraging safety profile, FMT has been met with caution in the oncological setting due to perceived infectiousrisks in immunocompromised patients. Theoretical risks aside, the application of FMT in oncology may stand tobenefit patients, via modulation of treatment efficacy and the mitigation of treatment complications. Here, wesummarize most recent safety data of FMT in immunocompromised cohorts, including people with cancer,highlighting that FMTmay actually provide protection against bacterial translocation via introduction of a diversemicrobiome and restoration of epithelial defenses.We alsodiscuss the emerging translational applications of FMTwithin supportive oncology, including theprevention and treatment of graft vs. host disease and sepsis, treatmentof immunotherapy-induced colitis and restoration of the gut microbiome in survivors of childhood cancer.

© 2019 Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Keywords:Fecal microbiota transplantation (FMT)Supportive oncologyImmunocompromisedSafetyEmerging applications

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7312. Proposed mechanism(s) of action of FMT in CDI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 731

2.1. FMT and the gut microbiota . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7312.2. FMT and host immunity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 731

3. General safety considerations of FMT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7314. Safety profile of FMT for CDI in immunocompromised recipients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 732

4.1. Shifting the perception of risk in immunocompromised cohorts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7325. Emerging applications of FMT in supportive oncology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 732

5.1. Gastrointestinal toxicity/mucositis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7325.2. Immunotherapy colitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7335.3. Graft versus host disease and blood stream infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7345.4. Promoting health in survivors of childhood cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 734

6. Adjunctive FMT in supportive oncology: how should it look? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7376.1. Practical considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7376.2. Regulatory considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 737

7. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7388. Search strategy and selection criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7389. Outstanding questions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 739Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 739References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 739

al Research Fellow, Dept. Pediatric Oncology, Beatrix Children's Hospital, UniversityMedical Centre, Groningen, the Netherlands.. Wardill).

pen access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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1. Introduction

Fecal microbiota transplantation (FMT) involves the administrationof a fecal suspension into the digestive tract of an individual, withthe aim of treating or preventing disease via manipulation of themicrobiome [1]. FMT was first reported as a novel treatment ofpseudomembranous enterocolitis in 1958. Since that time, the efficacyof FMT for recurrent or refractory Clostridium difficile infection (CDI)has been established in multiple randomized controlled trials and itsuse in this setting is supported by society guidelines [1–3]. FMT success-fully treats recurrent or refractory CDI in N90% of cases, compared withcure rates of 26–30% with the previous standard of care, vancomycin[4,5]. A burgeoning understanding of the gut microbiome coupledwith the success of FMT in treating CDI has garneredwidespread enthu-siasm for the use of FMT across of range of diseases, with several trialsdemonstrating the efficacy of FMT for the induction of remission of ul-cerative colitis [6]. However, a novel application of FMT resides withinoncology, with experimental FMT currently under investigation for itsability to modulate treatment efficacy and mitigate serious complica-tions of treatment including sepsis and graft versus host disease(GvHD).

Despite a growing scientific rationale and emerging clinical potentialfor FMT use in oncology, it has been met with caution due to the per-ceived risk of bacterial translocation and infection in potentially immu-nocompromised individuals. This parallels current investigation of FMTfor the treatment of CDI, with most clinical trials excluding immuno-compromised patients. These recommendations are also echoed in clin-ical practice guidelines developed for the treatment of CDI in childrenwith hematological cancers [7], and parallel recent recommendationsfrom the Food and Drug Administration/Center for Biologics Evaluationand Research cautioning against FMT in immunocompromised cohorts[8]. While these recommendations are intended to avoid harm, theyare based primarily on expert opinion without supportive evidence.The limited evidence currently available suggests that FMT holds no ad-ditional risk in immunocompromised individuals [8] and as such, coor-dinated and interdisciplinary efforts to investigate its safety and efficacyin various indications within oncology are warranted.

This review aims to provide an overview of the current mechanisticunderstanding of FMT and the emerging applications in supportive on-cology with particular emphasis on the adverse events or safety issuesregarding reported for experimental FMT in immunocompromisedindividuals.

2. Proposed mechanism(s) of action of FMT in CDI

To date, themechanisms of FMT have been primarily investigated inthe setting of CDI. Fundamental research into the underlying mecha-nism(s) for FMT in this setting identify two possible avenues by whichFMT is effective: 1) direct interaction with the gut microbiota and2) modulation of the host's intestinal physiology and immune capacity[9,10].

2.1. FMT and the gut microbiota

CDI is typically induced by exposure to antibiotics, which deplete theindigenous gut flora and leaves an ecological void into which Clostrid-ium difficile may proliferate. Disruption of the host's microbiota allowsopportunistic and resistant microbes greater access to intestinal nutri-ents. This is nicely illustrated in the biosynthesis of sialic acid, acarbon-backboned monosaccharide ubiquitously expressed within gly-coproteins and glycolipids [11]. Certain commensal bacteria, includingBacteroides thetaiotaomicron, are able to liberate sialic acid from mucinglycoproteins, but are unable to break it down completely [10]. In con-trast, Clostridium difficile possesses the ability to catabolize sialic acid,utilizing it as an energy source. Similarly, microorganisms also liberatemonomeric glucose and N-acetylglucosamine, which then become

more accessible to Clostridium difficile when indigenous microbiota areabsent or suppressed. As such, a potential factor in the efficacy of FMTfor CDI is its ability to reintroduce microbial competition, recolonizingthe microbial niches that Clostridium difficile would otherwise exploit.

Depletion of microbial diversity also reduces the host's natural de-fenses against pathogenic bacteria including antimicrobial peptidesand bile acids, both of which effectively control Clostridium difficile ex-pansion and spore formation. Bactericidal peptides such as thuricinCD, produced by Bacillus thuringiensis, and nisin, produced by Gram-positive bacteria, both have high potency against certain Gram-positive microbes including Clostridium difficile.10 Similarly, secondarybile salts, generated via bacterial-dependent deconjugation of taurineand glycine, are almost absent in people with recurrent CDI as bacteriawith this functional capacity are commonly reduced by antibiotics[12]. Of particular relevance is the loss of Clostridium scindens, a 7α-dehydroxylating gut microbe, which encodes for the bai operon and isresponsible conversion of primary bile acids into secondary bile acids[13]. Importantly, these secondary bile acids produce deoxycholic andlithocholic acids, both of which have shown to inhibit germination ofClostridium difficile spores [14]. In line with this understanding, it hasbeen recently demonstrated that successful FMT for recurrent CDI is as-sociated with increased signaling in the bile acid-farneoid X receptor-fibroblast growth factor pathway [15].

2.2. FMT and host immunity

It is well demonstrated that a bidirectional, symbiotic relationshipexists between the host and its resident microbes, with continuous sig-naling from the indigenous microbiota required to maintain a healthygut barrier function and balancedmucosal immunity. Numerous factorsincluding mucus, tight junctions and antimicrobial peptides, maintainappropriate compartmentalization of the microbiota in the intestinallumen, regulating their interaction with the underlying mucosal im-mune system. Antibiotics are well demonstrated to disrupt almost allaspects of this defense, weakening the intestinal barrier and disruptinghomeostatic control of paracellular permeability [16]. Once in contactwith the epithelia, Clostridium difficile toxins disrupt intestinal tightjunctions and promote apoptotic death of colonocytes [17], resultingin increased permeability of the epithelial barrier and interaction oftoxins and Clostridium difficile pathogen-associated molecular patterns(PAMPs) with resident mucosal immune cells via toll-like receptors(TLRs).Whilst excessive activation of certain TLRs, such as TLR4, is asso-ciatedwith aberrant immune signaling, activation of other TLR subtypesis associated with dampened immune responses. For example, stimula-tion of TLR2 via binding of cell wall components of primarily gram-positivemicrobes, increases interleukin-10 (IL-10) production and is as-sociatedwith enhanced intestinal barrier function observed in vitro andin vivo [18,19].As such, the efficacy of FMT in treating CDI is also likely toreflect its ability to restore TLR signaling, thus repairing intestinal bar-rier defenses and controlling exuberant immune responses. Comparableimmunomodulatory effects have also been proposed to underpin theemerging efficacy of FMT in IBD, equilibrating aberrant immune signal-ing towards the indigenous microbiota [20].

3. General safety considerations of FMT

FMT has demonstrated an excellent overall safety profile, with fewand primarily mild adverse events reported in the short term. However,the majority of FMT studies that have been reported in the literaturehave occurred in the last 5–10 years and as such, long-term safetydata is lacking. Despite the encouraging safety record of FMT, there isrisk of disease transmission from thedonor to recipient via stool, includ-ing infection, as well as immunological and metabolic disorders [21].Transmission of an obese phenotype has been demonstrated in animalstudies and the possible transmission of a microbiome that drives obe-sity has been reported in a single human case report [22]. However, it

732 H.R. Wardill et al. / EBioMedicine 44 (2019) 730–740

remains difficult to dissect causation in this case due to a variety of otherfactors that may have explained the weight gain seen in this patient.Rigorous and standardized donor FMT screening protocols are required,which diminish but do not entirely eliminate risk of disease transmis-sion. Although the risks associated with autologous FMT are lower(where pre-emptive collection and storage of a patient's own stool isundertaken so that it may be readministered at a time of need), appro-priate safety assessments, processing and storage is essential.

In a large systematic review of adverse events (AEs) for FMT (N =1089 patients), it was reported that the majority of AEs were gastroin-testinal in nature, including abdominal discomfort, acute diarrhea, tran-sient fever, nausea, vomiting and constipation [23]. The overallincidence of AEswas 28·5%. Authors attributed AEs to a variety of causalfactors, with only five categories of AEs definitely linked with FMT. AEsdefinitely linked to FMT were a sore throat, rhinorrhea (both followingupper GI administration), aminormucosal tear and a bowel perforation(both from colonoscopically administered FMT). Thirty-eight kinds ofAEs, probably related to FMT, were reported in 35 articles andwere con-sidered the result of temporary systemic immune responses to thetransplanted bacteria.

Authors reported that the mode of delivery was a key risk factor forFMT-related AEs, with endoscopic manipulation associated with nasalstuffiness, a sore throat, rhinorrhea and upper gastrointestinal hemor-rhage. Abdominal discomfort was reported to be more frequent withupper gastrointestinal delivery. Serious adverse events (SAEs) were re-ported in 9·2% of patients including infection, disease relapse and CDI,with a mortality rate of 3·5%. In both cases of FMT-related mortality,death resulted from aspiration pneumonia in immunocompromised in-dividuals (outlined below).

4. Safety profile of FMT for CDI in immunocompromised recipients

FMT for the treatment of immunocompromised patients has beenmet with caution due to the perceived risk of bacterial translocationand sepsis. However, systematic review data suggest that FMT for thetreatment of CDI in immunocompromised patients is feasible and safe,describing similar rates of serious adverse events to immunocompetentpatients [24,25]. A systematic review identified 44 articles in whichFMT had been performed for CDI in 303 immunosuppressed patients.A patient was defined as immunocompromised if receiving immuno-suppressive agents (including but not limited to mTOR inhibitors, cal-cineurin inhibitors, anti-TNF agents, other biologic agents, high dosesteroids N20 mg/day or ≥ 1 mg/kg for N14 days), or diagnosed withHIV infection (regardless of CD4 count), acquired immune deficiencysyndrome (AIDS), inherited or primary immunodeficiency syndromes,hematologic malignancy or solid tumor (active with treatment in past3 months or in remission for b5 years), solid organ transplant, and/orbone marrow transplant. FMT was primarily delivered via colonoscopy(76%), with the remaining delivered via ingestible capsule/nasal tube/endoscopy or retention enema. Reported efficacy for CDI was 87·7%from a single FMT, which increased to 93% after repeated FMTs,paralleling efficacy rates reported in immunocompetent cohorts.

Two deathswere reported in the immunocompromised FMT cohort,both related to aspiration pneumonia. The first patient aspirated duringsedated endoscopic FMT delivery to the duodenum [26] and the otheraspirated during the anesthetic for colonoscopic FMT [8]. Other re-ported adverse events include 2 colectomies due to worsening CDI, 5episodes of bacteremia or infection, 10 subsequent hospitalizations, 7otherwise unspecified life-threatening complications, and 7 flares ofIBD, as well as generalized abdominal discomfort. The rate of reportedcomplications, as well as the nature of AEs, were comparable to thoseof immunocompetent cohorts, suggesting that FMT confers no addi-tional risk in immunocompromised patients. However, it must benoted that limited long-term data exists for both immunocompetentand immunocompromised cohorts, and the possibility of late complica-tions remains unclear. There is an observation trial currently underway

aiming to collect long-term data for 10 years post FMT (NCT03325855),and FMT registries are planned.

4.1. Shifting the perception of risk in immunocompromised cohorts

Despite the growing body of evidence demonstrating comparablesafety profiles for FMT in immunocompetent and immunocompro-mised cohorts, there remains a perception that FMT may be unsafe inthese patients. While larger cohorts of patients are needed to establishwhether FMT is safe in immunocompromised patients, there are theo-retical reasons why FMTmay actually reduce the risk of bacterial trans-location and ensuing infection in immunocompromised individuals.

A complex and diverse microbiota is able to resist colonization bypathogenic organisms, through regulation of the intestinal barrier, pro-motion of epithelial repair and proliferation, mucus production and thegeneration of antimicrobial peptides (Fig. 1). It has been demonstratedthat disruption of themicrobiota, induced by antibiotics or othermicro-bial insults, is a key risk factor for infectious complications [27]. Admin-istration of antibiotics prior to pathogen exposure results in a markedincrease in colonization and systemic uptake of these pathogens [28];a phenomenon clearly underpinning the pathobiology of CDI. Similarly,it has been demonstrated that fluoroquinolone administration inallogeneic-stem cell transplant (allo-SCT) recipients, results in domina-tion of themicrobiota by aerobic gram-negative bacteria, which is asso-ciated with subsequent gram-negative bacteremia [29]. Most recently,dominant microbial phyla in allo-SCT recipients have been shown topredict subsequent bacteremia, suggesting that dominant bacteria aremore likely to translocate and drive infectious complications [30]. Sim-ilar associations have been demonstrated in the longitudinal analysis ofthemicrobiome in hematopoietic-SCT (HSCT) recipients, in whom a re-duction in obligate anaerobes is associatedwith expansion and domina-tion of pathogenic microbes (including viridans-group streptococci andvancomycin-resistant enterococcus) [31]. As such, delivering a diversemicrobiome to immunocompromised patients may in fact decreasethe risk of infectious complications and efforts to better characterizethe safety of FMT in these cohorts are therefore warranted, albeit withcaution.

5. Emerging applications of FMT in supportive oncology

People undergoing cancer therapy,many ofwhomare immunocom-promised, are at risk of microbiome disruption due to anti-cancer ther-apy and antibiotics. It is well demonstrated that numerous anti-canceragents significantly disrupt the intestinal microbiota with decreases inmicrobial diversity and a shift towards a gram-negative enterotype[32]. Dominance of opportunistic gram-negative microbes, combinedwith the direct cytotoxic damage to the intestinal lining (mucositis),predispose patients to secondary infections and various complications,including infection and, in the case of allo-HSCT, GvHD. As such, the po-tential applications ofmicrobial intervention in supportive oncology canbe broadly categorized into the prevention/management of 1) acutetoxicities, and 2) secondary complications (Table 1).

5.1. Gastrointestinal toxicity/mucositis

Gastrointestinal (GI) toxicity, manifesting as diarrhea, remains oneof the most common and clinically significant complications of allanti-cancer therapies. Prior to the widespread availability of genomictechnology, GI toxicity was understood to incorporate both direct cyto-toxic and indirect inflammatory-based mechanisms leading to epithe-lial injury and gut dysfunction. Bacterial colonization at the injuredsites was documented and linked with secondary complications suchas bacteremia and sepsis. Technological advances have facilitated aclearer mechanistic appreciation of the contribution of gut microbiotato GI toxicity in anti-cancer therapy [33,34], however dissecting thecausative role for the microbiome in GI toxicity remains challenging.

Fig. 1. Potential mechanisms by which FMT may be beneficial to those undergoing cancer therapy. Delivering a diverse microbiome serves to promote microbial competition, thuscontrolling pathogen expansion and reducing the risk of infectious complications. Similarly, FMT has been shown to restore short chain fatty acid profiles, thus aiding epithelial repairand intestinal homeostasis. FMT may also be used to promote a unique microbial phenotype known to induce preferable treatment responses; an approach increasingly investigatedfor immunotherapy-colitis and efficacy. Promoting microbial diversity via FMT is also likely to enhance natural barrier defenses, including anti-microbial peptides, tight junctionassembly/integrity, mucus production and epithelial proliferation. These hold great promise in promoting recovery from acute mucosal injury and preventing bacterial translocation;each of which are key initiating factors in GvHD development. FMT efficacy is also considered to occur via immunomodulating, promoting TLR equilibrium and dampening aberrantinflammatory signaling.


Current evidence suggests that microbial disruption observed in GI tox-icity exacerbates the pathobiology of GI toxicity [34] via direct effects ondrug metabolism, modulation of the host immune system and disrup-tion of the intestinal barrier. Furthermore, it is becoming increasinglyclear that an individual's unique microbiome is critical in shaping theirresponse to treatment [35]. As such, efforts to modulate an individual'spre-treatment microbiome or preserve microbial diversity after treat-ment are explored.

The identification of cancer therapy-inducedmicrobiome disruptionprompted the investigation of probiotic therapies to prevent and treatthe symptoms of GI toxicity. Despite strong preclinical support in ani-mal models [36–38], the efficacy of probiotic formulations in humanshas been underwhelming. In fact, a recent meta-analysis reported nobenefit for probiotics in GI toxicity prevention [39]. Currently availableprobiotics lack the density and complexity to compete with indigenousmicrobiota and are not rationally designed to fulfil specific therapeuticroles. Lack of probiotic efficacy is multifactorial, and reflective of vari-able probiotic formulations and doses, variations in cancer treatmentschedules and the lack of diversity in currently available probiotic prep-arations. As such, FMT represents a far more attractive alternative toprobiotics, given its ability to deliver a diversemicrobiome with greaterbacterial load, as well as the capacity to collect, bank and readministerautologous fecal samples.

The only study to investigate FMT in GI toxicity management wasperformed in mice following 5-fluorouracil (5-FU) treatment (Table 2)[40]. Le Bastard et al., (2018) reported that autologous FMT (200 μL sus-pension at 5 g feces/1 mL PBS, delivered by oral gavage for 3 days) wasable to restore microbial diversity following exposure to 5-FU and anti-biotics. However functional endpoints (e.g. diarrhea/weight loss) werenot reported and as such, the translational relevance of this study is lim-ited. These results do however illustrate some important practicalpoints regarding FMT in supportive cancer care. Firstly, this study dem-onstrates that chemotherapy exposure does not influence FMT durabil-ity in mice, with taxonomic order restored following FMT. This wasdespite FMT being delivered the day after cessation of antibiotics and

5-FU, and coinciding with the time period where cytotoxicity, mucosalinjury and diarrhea are likely to be highest. These results echo the find-ings from Suez et al., (2018) showing a single autologous FMT inhumans was sufficient to restore microbial diversity after antibioticexposure [41]. In fact, authors reported superior efficacy to probiotics,providing an excellent rationale to further investigate FMT as an adjunc-tive supportive care measure.

5.2. Immunotherapy colitis

A relatively newproblem in supportive oncology is themanagementand prevention of severe colitis induced by newly developed immuno-therapies. Treatments with immunotherapies targeting cytotoxic T-lymphocyte-associated antigen4 (CTLA-4), programmed cell death pro-tein 1 (PD-1), and programmed cell death ligand 1 (PD-L1) are associ-ated with increased T-cell activation and effective antitumor immuneresponses in a subset of ill-defined patients [42]. However, these agentscarry a risk of severe colitis. Certain bacterial signatures have beenshown to associate with differential responses to immunotherapies[42,43], both in terms of treatment efficacy and toxicity. Additionally,modulation of the gut microbiota via FMT from patients has beenshown to alter antitumor immunity and response to immunotherapyin gnotobiotic mice (Table 2) [44]. These findings have now promptedinvestigation of FMT as a therapeutic option for refractoryimmunotherapy-induced colitis [45].

In 2018, the first case series of immune checkpoint inhibitor-associated colitis successfully treated with FMT was published [45].Data, from the treatment of two individuals, highlight the ability ofdonor FMT (50 g, delivered by colonoscopy) to restore microbial diver-sity and induce complete resolution of clinical symptoms. FollowingFMT, there was a substantial reduction in CD8+ T-cell density with aconcomitant increase in mucosal CD4+ FoxP3+ in one of the partici-pants, offering a potential mechanism through which FMT could abro-gate immunotherapy-associated toxicity (Table 2). A phase 1 trial is

Table 1Potential applications for FMT in supportive oncology.

Treatment toxicity management

Indication Rationale Approach

Gastrointestinalmucositis

GI toxicity is associated with microbial disruption characterized by a lossof overall species diversity and shift towards a gram-negativeenterotype.Although causal relationship remains unclear, interventions targetingthe microbiota have proven efficacious in various preclinical models,with varying translational success.

Personalized donor or synthetic FMT to prophylactically enhanceoutcomes; requires characterization of optimal microbial phenotypesassociated with treatment outcome in unique oncological settings.Therapeutic FMT (autologous or donor) to1) manage acute diarrhea,2) promote recovery of microbiota and thus mitigate toxicity insubsequent cycles, and 3) restore/maintain microbial diversity toprevent secondary complications.

Immunotherapy-inducedcolitis

A growing evidence base shows stark differences in the microbialcomposition of patients who develop colitis compared to those that donot. Inconsistencies lie in the microbial phenotype linked with optimaloutcomes.

Prophylactic FMT to prevent colitis by modulating microbiota to acomposition associated with optimal toxicity profiles.Therapeutic FMT to treat chronic immunotherapy-induced colitis.

Cognitive impairment A growing body of data now implicates the gut-brain axis inneurocognitive function, with anecdotal evidence suggesting themicrobiome is critical in chemotherapy-induced neuroinflammation.GI complications often occur in comparable patient cohorts asneurocognitive impairment, indicating common underlyingmechanisms.Probiotics and dietary interventions aimed at modulating the microbiotahave been shown to be effective in mitigating cognitive impairment inother indications.

Assuming a ‘healthy’ microbiome at baseline, autologous FMT tomaintain individual's indigenous microbes and preventneuroinflammation via modulation of the gut-brain axis.In cases where baseline microbiome composition is compromised, donorFMT may be used prophylactically or therapeutically.

Secondary complicationprevention Infection

Pathogen dominance, bacterial translocation and blood stream infectionare more prevalent when the microbiota is compromised.Antibiotics and GI toxicity are both risk factor for blood streaminfections in oncology cohorts with the microbiome composition able topredict subsequent infections.A diverse microbiome enhances natural defenses against bacterialtranslocation and pathogen expansion.

Autologous or donor FMT to maintain microbial diversity throughouttreatment to prevent infectious complications via enhancing defenses(intestinal barrier function, mucus production, antimicrobial peptides,bile acid metabolism) and promoting colonization resistance.

Graft versus host disease Species diversity following conditioning chemotherapy predicts GvDHin allo-SCT recipients.

Prophylactic FMT to maintain or restore microbial diversity thuspreventing mucosal injury and bacterial translocation; both of which arecritical in initiation of GvHD.Therapeutic FMT for the treatment of refractory GvHD.

Pediatric oncologyLate effects (e.g.metabolic disease)

Chronic deficits are observed in the microbiota of survivors of childhoodcancer.Many of the late effect experienced by survivors have been linked withthe microbiome (e.g. metabolic syndrome).

Autologous FMT to restore individual's baseline microbiota compositionand prevent late effects associated with chronic microbial disruption.


currently underway to investigate the efficacy of donor FMT as a pro-phylactic, adjunct supportive care measure (NCT03772899).

5.3. Graft versus host disease and blood stream infections

In addition to the direct benefits FMT may yield for acute GI injury(mucositis and colitis), restoring the injured microbiota after the cessa-tion of active cancer therapy may also offer a novel method ofpreventing secondary complications (Fig. 2). It is clear that acutemicro-bial disruption during cancer therapy predisposes to a number of sec-ondary complications. Of particular importance is its potentialapplication in the prevention of blood stream infection [46] and GvHD[47]; both ofwhich remain significant causes ofmorbidity andmortalityin people undergoing cancer therapy. Whilst FMT for the preventionand management of these complications lacks rigorous and controlledclinical investigation, there is a growing body of data to support its po-tential use. For example, intraduodenal donor FMT, performed in 20 pa-tients (40% of whom were neutropenic), has been shown to be safe,whilst also aiding in the eradication of antibiotic-resistant bacteria inpeople with blood disorders (Table 2) [48]. Similarly, donor FMT (ad-ministered by rectal enema or nasogastric tube) was shown to safelyeradicate multidrug-resistant bacteria in allo-SCT recipients, with 70%of patients showing full decolonization. Whilst encouraging, conclu-sions regarding the safety and efficacy of FMT in this study must bedone so with caution due to the low sample size (N=10) and inconsis-tencies in the timing and delivery of FMT [49].

Similarly, a recent case study has shown donor FMT is able to treatacute intestinal steroid-refractory and -dependentGvHD,with 3 of 4 pa-tients showing complete resolution (Table 2) [50]. The same group hasalso reported the feasibility of delivering encapsulated FMT for GvHDtreatment in a single case report [51]. This was further supported in an-other pilot study (N=8) inwhich donor FMT (delivered via nasogastrictube) induced a reparative effect onmicrobiota composition, increasingdiversity and elevating the abundance of Bacteroidetes, Bacteroidaceae,Ruminococcaeae and Desulfovibrionaceae. This was accompanied by adecrease in stool volume, reductions in abdominal pain and clinical res-olution (termed “cure” in this study) in 50% of patients [52]. Of the re-maining 4 patients, one showed an improvement in symptoms,another was considered remissive and two relapsed. Whilst theseresults are encouraging, these studies are underpowered, aiming tosimply investigate feasibility in small patient cohorts. Randomizedcontrol trials are now warranted, and are underway (NCT02269150;NCT03359980; NCT03492502; NCT03549676; NCT03720392).

5.4. Promoting health in survivors of childhood cancer

The plausible benefits of FMT in adjunctive oncology are similar forchildren as adults and should, in cases where it permits, be investigatedin parallel. Guidelines for the management of CDI in children currentlyrecommend against the use of FMT due to perceived infection risks[7]. This largely reflects the exclusion of children from FMT trials, anda consequent paucity of data. However, data from case studies do

s-

Table 2Preclinical and clinical studies of FMT in supportive oncology.

Indication Study type anddescription

FMT source/screening Preparation/dose Route ofadministration

Timing/frequency ofdelivery

Outcome meas s) Key finding(s) Reference

Gastrointestinaltoxicity

Preclinical; N = 18

Male C57BL/6 mice;Ampicillin antibiotics(1 g/L days 1–7) and 5-FUchemotherapy (150 mg/kgday 8) used to mimiconcology setting

Pellets from untreated mice Pellets resuspended in PBS (1pellet/1 mL PBS); pellets werepooled from multiple mice

Oral gavage(200 uL/day)

Daily for 3 daysbeginning on dayafter 5-FU (day 9–11)

Microbial diver (alphaand beta)

5-FU and ampicillin caused adecrease in microbial diversity,remaining significant for 1week; mice that received FMTshowed no detectable changein diversity

Le Bastardet al. [40]

Immunotherapycolitis

Case series; N = 2

Patient 1: 50-year old,female with high grademetaststic urothelialcarcinoma (refractory tochemotherapy); treatedwith combined CTLA-4and PD-1 blockade;developedsteroid-resistant grade IIcolitisPatient 2: 78-year oldmale with prostate cancerrefractory tochemotherapy andhormonal therapy;received two doses ofipilimumab; developedsteroid-resistant grade IIcolitis

Single, healthy, unrelateddonor; stool collected at 3separate time points andpooledStringent donor screeningbased on exclusion of blood-and stool-based pathogens andrelevant medical conditions.Clear summary of exclusioncriteria can be found in thesupplementary files of theoriginal publication.

150 g stool, processed within4 h of passage; diluted 1:10 in0.85% NaCl; prepared usingStomacher80 Master andfiltered through gauze; storedat -80oC and used within 6months of storage.

Colonoscopicallyadministered(250 mL)

Patient 1: OncePatient 2: Twice

Endoscopic eva ion,CD4/CD8/FoxPimmunohistoc istry, 16Smicrobiome an is

Patient 1: complete resolution,return of solid daily bowelmovement without bleeding;steroids were graduallyremoved. Endoscopicevaluation showed markedimprovement, indicated by areduction in CD+ T cells andconcomitant increase in CD4+FOXp3+.Patient 2: Partial improvementwith persistent ulcers andrecurrent abdominal pain.Complete resolution aftersecond FMT.

In both patients, the number ofOTUs increased following FMT,with principal coordinatesanalyses of unweightedUniFrac distancesdemonstrating themicrobiome composition wassimilar to those of the donor.

Wanget al. [45]

Infection Retrospective clinicalstudy; N = 10Data was retrospectivelyanalysed from consecutiveadult patients diagnosedwith hematologicalmalignancy who receivedFMT during allo-SCT formulti-drug resistantbacteria colonization.All patients were onimmunosuppressivemedication.

Healthy related or unrelateddonors aged between 18 and65 with no digestive disorderswithin 3 months of donation,no chronic disease ortreatments, no antibiotics inthe past 3 months. Donorswere also excluded if theylived in the tropics, or had beenhospitalised abroad for N24 hin the year leading up todonation. Complete biologicaland microbiologicalassessment was alsoperformed.

Minimum of 50 g of stool wasprepared within 6 h ofcollection.50–100 g stool mixed with300 mL 0.9% glycerol/saline,filtered through gauze. Storedat -80oC.

In some cases (N = 2), freshstool was used withpreparation occurring within6 h of donation.

Enema (N = 8)or nasogastric(N = 2)delivery.

Once; N = 4 receivedbefore allo-SCT, N =6 received afterallo-SCT.

Degree of deco ation- Major: 3 cons ive negativemicrobial cultu- Persistent: on gativemicrobial cultu lastfollow-up

Major decolonization wasachieved in 7/10 patients;persistent colonization wasachieved in 6/10 patientsFailure occurred in threepatients:- Unable to cease antibiotics- Difficulties positioningnasogastroric tube, and unableto retain enema- Insufficient stool load (43 g)

N = 2 deaths reported:- Uncontrolled GvHD- Disease progression

Battipagliaet al. [49]

GvHD Case series; N = 4Adult patients with steroidresistant (N = 3) orsteroid-dependent (N =1) gastrointestinal acute

Related donor aged 20–64years; no tattoos/piercings, nosexual intercourse with a newpartner for 3 months, no bloodtransfusion for 3 months, no

Fresh, collected on day ofdonation; store day 4oCunder anaerobic conditionsuntil preparation.

Nasogastric tube Once, howeverpatients withoutnewly developedadverse events wereoffered a second FMT

Efficacy: gut Gv grade(assessed using idatedcriteria)- Complete res e:resolution of al estinal signs

FMT was effective in allpatients, with completeresponse in 3/4 patients andpartial response in 1/4patients.

Kakihanaet al.[50,69]

(continued on next page)

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Table 2 (continued)

Indication Study type anddescription

FMT source/screening Preparation/dose Route ofadministration

Timing/frequency ofdelivery

Outcome measure(s) Key finding(s) Reference

GvHD

All patients onimmunosuppressivemedication.

travel to tropical areas in 3months, no antibiotics in lastmonth, no history ofmalignancy or inflammatorybowel disease, no abdominalsymptomology on day ofdonation. All samples werescreened for transmissiblediseases.

200–300 mL sterile saline wasadded to fecal sample (weightunknown); fecal slurry wasfiltered through sterile metalsieve and leached throughgauze. Sample was preparedunder ambient conditions.

between 4 and 14days after the first atthe discretion of thephysician.

and symptoms- Partial response: decrease inseverity of gut GvHD byminimum of one stage- Progression: worsened gutGvHD symptoms- No change: no significantchange in gut GvHDFMT was considered effective ifthe patient achieved CR or PRin steroid-resistant cases, or areduction of ≥40% in the doseof steroid in steroid-dependentcases.Safety: Adverse events thatfirst occurred or progressedwithin 1 week of infusion.

Adverse events were largelymild and transient; thepossibility of an associationbetween FMT and someadverse events could not becompletely ruled out.

Case report; N = 1

21-year old female withacute, stage III, steroidrefractory gastrointestinalGvHD,

Related donor (sister); notattoos/piercings, no sexualintercourse with a new partnerfor 3 months, no bloodtransfusion for 3 months, notravel to tropical areas in 3months, no antibiotics in lastmonth, no history ofmalignancy or inflammatorybowel disease, no abdominalsymptomology on day ofdonation. All samples werescreened for transmissiblediseases.

71–144 g donated feces werehomogenised with sterilesaline; fecal suspension aspassed through a metal sieveand filtered through sterilegauze; sample wascentrifuged to isolatemicrobial pellet which wasresuspended in 10%glycerol/saline.

450 uL concentrate wasencapsulated into a #1hypomellose capsule andrapidly frozen in liquidnitrogen; stored at -80oC.

Capsules 15 capsules per dayon days 125, 130, 133and 144 aftertransplantation,followed by a secondround of FMT on days173, 181 and 189.

Colonization and uptake ofdonor microbiome determinedby 16S sequencing.

Recipients microbiomecomposition rapidly reflectedthat of the donor, increasing indiversity with a highabundance of Lactobacillus.Enterococcus re-emerged at 4weeks, and the participant wasoffered another FMT.

Second FMT resulted in partialresolution of symptoms,decreasing to grade I GvHD.

Kaito et al.[51]

Feasibility study; N = 8Adult patients with steroidrefractory gastrointestinalGvHDAll patients onimmunosuppressivemedication.

Donor FMT prepared from N =2 healthy female donors, aged23.No information regardingscreening.

40–50 mL of frozen fecalmicrobiota resuspended in200 mL of warm saline.

No further informationprovided on preparation.

Nasogastric tube Once Efficacy: severity of GvHDsymptoms (abdominal pain,diarrhea, presence of bloodypurulent stools); clinicalremission defined if diarrheaand intestinal spasms and/orbleeding disappeared, or stoolvolume decreased by 500 mLin 3 days.Safety: presentation of adverseevents during FMT procedureor at follow up.Durability: 16S sequencing ofrecipient microbiota.

All patients achievedsymptomatic remission afterthe FMT. At second follow up,4/8 patients maintained fullcure and 1/8 remained inremission. Improvements inGvHD symptoms seen in 1/8patients. 2/8 patients relapsedat follow-up.No adverse events werereported. Progression freesurvival was enhanced in FMTrecipients compared tohistorical controls (no FMT).

Qi et al.[52]

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upport the use of FMT in the treatment of refractory CDI in childrenwithIBD [1,53]. Large, randomized control trials are now required to confirmsafety and efficacy and refine FMT protocols in children.

Beyond the use of FMT in treating CDI and in an adjunctive oncolog-ical setting, there remains a clear opportunity for FMT in pediatric on-cology that is yet to be exploited. Survivors of childhood cancer are atan increased risk of developing late effects and chronic disease[54–57]. This is becoming an increasingly clear public health problem,with the large majority (N80%) of children now surviving their diagno-sis. Recent evidence now indicates that the microbiota of these survi-vors of childhood cancer (SCC) is not only disrupted acutely duringtreatment [58], but also chronically with altered microbiome composi-tions detected months to years after the cessation of treatment [59]. Ithas therefore been hypothesized that residual microbial deficienciesmay drive the heightened risk of chronic disease, and as such, effortsto restore microbial health after treatment may act to mitigate longer-term microbiome-related diseases.

6. Adjunctive FMT in supportive oncology: how should it look?

6.1. Practical considerations

As outlined, there are a number of relevant applications for FMT insupportive oncology, with several currently under investigation acrossvarious institutions. Synonymous with the FMT field is the degree ofvariation in study protocols and trial designs, begging the question ofhow should we approach FMT as a supportive adjunct to traditionalanti-cancer therapy?

When designing FMT trials in supportive oncology, there are a num-ber of important considerations. Stringent donor selection and screen-ing is important to prevent disease transmission and the FMT deliverymethods may need to be adapted to suit the patient population.These measures are of particular importance to patient groups whoare heavily immunosuppressed or have comorbidities or treatment-related complications.

Autologous FMT presents as an attractive option in the adjunctiveoncological setting, however processes around stool collection and de-livery need to be refined and optimised in the clinical trial setting(Fig. 3). Whilst autologous FMT may be preferable due to a lower riskof disease transmission, there may be risks associated with reintroduc-tion of malignancy (in the case of colorectal cancers) or transmission ofa microbiome that drives carcinogenesis. Feasibility of autologous FMTmust also be carefully considered ensuring there is sufficient time tocollect, prepare and screen the patient's stool between diagnosis andadministration of anticancer therapy. Risks associated with route of

Fig. 2. Proposed mechanistic framework for autologous FMT in the therapeutic managementherapeutically following allo-SCT may enhance microbial diversity, thus serving to enhancmicrobiome may also promote immune tolerance and dampen inflammatory signaling, thusrisk of transmissible diseases, implementation of appropriate criteria may be warranted to esuperdonor may be warranted.

administration are also important to consider in the context of support-ive oncology, with bowel preparation and colonoscopy contraindicatedin patients with a friable bowel. Upper GI delivery is also challenging inoncology patients where oral mucositis may compromise oral mobilityand the risk of upper GI injury. As such, rectal enemas or oral capsulesrepresent as sensible options, providing greater flexibility to outpa-tients. Whilst the large majority of FMT trials continue to administerfecal slurries via colonoscopy or upper GI delivery, the efficacy of oralcapsules is increasingly demonstrated. Of particular relevance was thelandmark study demonstrating that route of delivery (enema vs oralcapsule containing lyophilized fecal microbiota from 100 to 200 g) didnot influence adverse experiences from FMT and showed comparableefficacy in treating CDI in preliminary investigations [60]. Similarly,third-party FMT prepared as oral capsules was shown to be feasible,safe and associatedwith an expansion of recipientmicrobiome diversityin allo-SCT recipients (N=27) [61]. These studies highlight the theoret-ical merit of deliverying FMT via oral capsule, an approach which hasgreat potential in thefield of supportive oncologywhich is often compli-cated by numerous factors. Oral capsules provide flexibility for out-patients and overcome contraindications in many oncology cohorts.However, it must be noted that the number of capsules required toachieve an appropriate microbial load is substantial, with both studiesrequiring participants to take over 30 capsules for one FMTdose.Withinsupportive oncology where the goal may be to maintain microbial di-versity over a long time period, rather than restore or change its compo-sition, encapsulate FMT may be undermined by issues relating tocompliance and the amount of stool required to prepare the appropriatenumber of capsules per patient.

The delivery of FMTwithin supportive oncology also remains a chal-lenge given the lack of gastroenterology expertise amongst clinical careteams supporting people with cancer. FMT in the oncological settingwould be best implemented in a centre equippedwith the necessary ex-pertise and facilities [1]. FMT for oncology patients should ideally bediscussedwithin amultidisciplinary team (MDT) to guide patient selec-tion and preparation as well as appropriate monitoring and follow-up.An FMTMDT should include oncologists, gastroenterologists, and infec-tious disease physicians, along with involved nursing and allied healthstaff [62]. As suggested by Grover et al., (2016), this team would alsolikely benefit from inclusion of a specialised oncogastroenterologist,with supportive care expertise [63].

6.2. Regulatory considerations

Currently, there is no global common standpoint regarding the reg-ulatory status of FMT, with one important problem being how FMT is

t of acute gastrointestinal toxicity and paralleled prophylaxis of GvHD. FMT deliverede natural defenses to bacterial translocation and mucosal injury. Restoring an injuredmitigating GvHD development. Whilst autologous FMT is preferential due to the lowernsure suitable response. Alternatively, donor FMT prepared from a healthy relative or a


defined. The difficulty in characterising fecalmaterialmeans it has alter-natively been described as a ‘drug’, ‘biologic’ or ‘transplant’ [64]. Awork-ing group comprised via the National Institutes of Allergies andInfectious Diseases proposed the following definition for regulatorypurposes in 2017: “a microbiota transplantation is the transfer of bio-logic material containing a minimally manipulated community of mi-croorganisms from a human donor to a human recipient (includingautologous use) with the intent of affecting the microbiota of the recip-ient” [65].

Since the landmark clinical FMT trial for recurrent CDI [4], regula-tions surrounding FMT have undergone many changes worldwide(Table 3), particularly reflected in the USA. The US Food and Drug Ad-ministration (FDA), began by announcing that FMT would be classifiedas an investigational drug, requiring an Investigational New Drug(IND) application to be submitted for each FMT use [66]. The IND pro-cess is effort and resource intensive and as such, there was an immedi-ate outcry suggesting that this regulation would severely restrict accessto a highly effective treatment [64]. Additionally, there was concernabout the unintended side-effect of increasing risks from at-homeFMT procedures [66]. The FDA responded shortly after by announcingthey would exercise enforcement discretion so IND applications wouldnot be required for CDI that had not responded to standard treatments,but would still be required for any other use of FMT [67].

The current regulation of FMT as a drug or live biotherapeutic prod-uct has had a significant impact on the ability to deploy this interventionin oncological studies in the USA due to the long and difficult IND pro-cess. Additionally, the majority of regulatory frameworks in placefocus on recurrent CDI, with little consideration for other indicationsof FMT.

Finally, there is a need for any regulations to be flexible and gradedto cater for future developments in the field such as purified or livebiotherapeutic products. There are a vast range of new productscurrently in development and in clinical trials, and include selected

Fig. 3. Practical considerations for implementing autologous s

bacterial strains cultured and administered as a capsule, cryopreservedfiltered stool products and lyophilised powders that can bereconstituted [65]. These products have a different risk profile andcould be produced at industry scales. A proposed regulation frameworkrecently released is careful to be broad enough to include these products[68].

7. Conclusions

FMT is a highly effective therapy for recurrent and refractory CDI.Limited available evidence supports the notion that it is a safe therapyin immunocompetent individuals, however further studies are required.There are a number of possible applications of FMT in supportive oncol-ogy, with the potential to manage acute treatment-toxicities and pre-vent secondary complications of therapy. Efforts should now bedirected at determining the feasibility and safety of FMT as an adjunc-tive supportive care intervention in both pediatric and adult patientsundergoing cancer therapy.

8. Search strategy and selection criteria

Data for this review were identified by searches on PubMed andWeb of Science. We reviewed the current evidence for FMT in oncologycohorts with particular focus on its use in immunocompromised co-horts. (Fecal microbi* transplant*) AND (immunocompromised host[MeSH]) AND (safety OR adverse event) were used to identify key,English-language publications, with no restrictions on publicationdates. Meta-analyses and clinical guidelines were priortised. All levelsof evidence were considered, including case studies, with appropriateacknowledgement of study limitations highlighted throughout thereview.

tool banking and FMT into supportive oncology practices.

Table 3Current and potential international regulatory frameworks for the administration of FMT.

Region Current Framework Future directions Reference

USA The US Food and Drug Administration (FDA) classified FMT as aninvestigational drug, requiring an Investigational New Drug (IND)application for each FMT use. Outcry due to resource intensive INDprocess. The FDA responded shortly after by announcing they wouldexercise enforcement discretion so IND applications would not berequired for CDI that had not responded to standard treatments, butwould still be required for any other use of FMT.

Draft guidance under public consultation: stool banks would requireIND to obtain and distribute stool, but not required for physiciansperforming the procedure or for hospital laboratories. Classificationof FMT as a drug (a live biotherapeutic product) requires thoroughcharacterization and composition consistency for approval-infeasible for FMT.

Verbeke et al. [66]FDA guidancedocuments [67,70]

UK Must be manufactured in accordance with Medicines and Healthcareproducts Regulatory Agency (MHRA) guidance for human medicinesregulation. Pharmacy exemption possible for single organisation use.FMT not currently recommended for anything apart from CDI (citinginsufficient evidence).

Consensus for FMT multidisciplinary team to be formed.Recommend that FMT should be “offered with caution toimmunosuppressed patients, in whom FMT appears efficaciouswithout significant additional adverse effects”

Mullish et al. [71]

Europe Framework varies between countries. European Commission deter-mined fecal transplant does not constitute a cell/tissue transplant.Subsequently argued that individual European Union Member Statesare free to regulate fecal microbiota transplantation on a nationallevel.

Consensus document suggest Appropriate FMT registries should beimplemented, in order to collect data concerning indications,procedure, effectiveness and safety profiles., Specific national rulesfor the classification ofFMT should be followed to implement an FMT centre.

Cammarota et al. [1]

Australia FMT in local care setting can be delivered - no agreed standards. FMTmaterial meets the definition of a biological (contains humancells/tissues) - prohibits distribution unless Good ManufacturingPractice (GMP) certified.

Public consultation currently occurring. Potential transition periodto allow manufacturers and suppliers of FMT to GMP licensingrequirements. Need for unique regulatory standards to allow stoolbanks to operate.

Therapeutic GoodsAdministration briefingpaper [72]Costello and Bryant [73]

China Ten hospitals conducting FMT research and administration. Currently,no standardisation of FMT process and implementation. Consensuson standardized biobanking of samples has been recently reached.

FMT consensus expert group existing since 2016. Draft consensusfor screening and ethics to soon be published. Recommendation fora unified FMT registration system.

Shi et al. [74]


9. Outstanding questions

There is a clear scientific and clinical rationale for FMT in the preven-tion andmanagement of complications of cancer therapy, as well as themodulation of treatment efficacy. Despite the most recent data indicat-ing FMT is safe in immunocompromised individuals, there remains apaucity of data for those that are severely immunocompromised, andas such, more robust data sets are now required to draw appropriateconclusions.

Implementation of FMT within oncology requires feasible FMT pro-tocols to be integrated into the complex treatment schedules of peopleundergoing cancer therapy, particularly for applications in which autol-ogous FMT is preferential. Furthermore, the durability of FMT during cy-totoxic treatment is unclear, particularly given the widespread use ofprophylactic antibiotics in many oncological cohorts. Future researchshould focus on refining FMT protocols for applications in oncology,with particular focus on the collection, screening and preparation of pa-tient fecal material. Mode of deliverymust also be appropriately refinedin this patient population given complicating factors including oral mu-cositis (limiting oral uptake and mobility for FMT capsules), inability toperform bowel preparations for colonoscopy and the challenges sur-rounding FMT delivery in the out-patient setting. In cases where FMTmay be used tomodulate response rates to immunotherapies, future re-search should focus on defining the microbial composition that pro-motes optimal treatment response. Potential risks associated withtransfer of circulating malignant cells, or microbial phenotypes thatdrive carcinogenesis, should also be identified/eliminated.

Acknowledgements

Dr Hannah Wardill is the recipient of an NHMRC CJ Martin Biomed-ical Research Fellowship (2018-2022, APP1140992).

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Adjunctive fecal microbiota transplantation in supportive oncology: Emerging indications and considerations in immunocompro...1. Introduction2. Proposed mechanism(s) of action of FMT in CDI2.1. FMT and the gut microbiota2.2. FMT and host immunity

3. General safety considerations of FMT4. Safety profile of FMT for CDI in immunocompromised recipients4.1. Shifting the perception of risk in immunocompromised cohorts

5. Emerging applications of FMT in supportive oncology5.1. Gastrointestinal toxicity/mucositis5.2. Immunotherapy colitis5.3. Graft versus host disease and blood stream infections5.4. Promoting health in survivors of childhood cancer

6. Adjunctive FMT in supportive oncology: how should it look?6.1. Practical considerations6.2. Regulatory considerations

7. Conclusions8. Search strategy and selection criteria9. Outstanding questionsAcknowledgementsReferences

University of Groningen Adjunctive fecal microbiota ...Bacteroides thetaiotaomicron, are able to...

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