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Background The gut microbiome plays an important role in immune modulation. Specifically, presence or absence of certain gut bacterial taxa has been associated with better antitumor immune responses. Furthermore, in trials using fecal microbiota transplantation (FMT) to treat melanoma patients unresponsive to immune checkpoint inhibitors (ICI), complete responses (CR), partial responses (PR), and durable stable disease (SD) have been observed. However, the underlying mechanism determining which patients will or will not respond and what the optimal FMT composition is, has not been fully elucidated, and a discrepancy in microbial taxa associated with clinical response has been observed between studies. Furthermore, it is unknown whether a change in the microbiome itself, irrespective of its origin, or FMT from ICI responding donors, is required for reversion of ICI-unresponsiveness. To address this, we will transfer microbiota of either ICI responder or nonresponder metastatic melanoma patients via FMT. Methods In this randomized, double-blinded phase Ib/IIa trial, 24 anti-PD1-refractory patients with advanced stage cutaneous melanoma will receive an FMT from either an ICI responding or nonresponding donor, while continuing anti-PD-1 treatment. Donors will be selected from patients with metastatic melanoma treated with anti-PD-1 therapy. Two patients with a good response (≥ 30% decrease according to RECIST 1.1 within the past 24 months) and two patients with progression (≥ 20% increase according to RECIST 1.1 within the past 3 months) will be selected as ICI responding or nonresponding donors, respectively. The primary endpoint is clinical benefit (SD, PR or CR) at 12 weeks, confirmed on a CT scan at 16 weeks. The secondary endpoint is safety, defined as the occurrence of grade ≥ 3 toxicity. Exploratory endpoints are progression-free survival and changes in the gut microbiome, metabolome, and immune cells. Discussion Transplanting fecal microbiota to restore the patients’ perturbed microbiome has proven successful in several indications. However, less is known about the potential role of FMT to improve antitumor immune response. In this trial, we aim to investigate whether administration of FMT can reverse resistance to anti-PD-1 treatment in patients with advanced stage melanoma, and whether the ICI-responsiveness of the feces donor is associated with its effectiveness. Trial registration ClinicalTrials.gov: NCT05251389 (registered 22-Feb-2022). Protocol V4.0 (08–02-2022).

Background Faecal microbiota transplantation (FMT) is an efficacious treatment for patients with recurrent Clostridioides difficile infections (rCDI). Stool banks facilitate FMT by providing screened faecal suspensions from highly selected healthy donors. Due to the ongoing coronavirus disease 2019 (COVID-19) pandemic and the potential risk of SARS coronavirus-2 (SARS-CoV-2) transmission via FMT, many stool banks were forced to temporarily halt and adjust donor activities. Goal The evaluation of a strategy to effectively continue stool banking activities during the ongoing COVID-19 pandemic. Study To restart our stool banking activities after an initial halt, we implemented periodic SARS-CoV-2 screening in donor faeces and serum, and frequent donor assessment for COVID-19 related symptoms. FMT donor and recipient data obtained before (2016–2019) and during the COVID-19 pandemic (March 2020-August 2021) were compared to assess stool banking efficacy. Results Two out of ten donors developed COVID-19. No differences during versus before the COVID-19 pandemic were observed in the number of approved faeces donations (14 vs 22/month, p = 0.06), FMT requests for rCDI (3.9 vs 4.3/month, p = 0.6); rCDI patients eligible for FMT (80.6% vs 73.3%, p = 0.2); rCDI cure rate (90.3% vs 89.2%, p = 0.9); CDI-free survival (p = 0.7); the number of non-rCDI patients treated with FMT (0.5/month vs 0.4/month), and the number of possibly FMT related adverse events (9.5% vs 7.8%, p = 0.7). Two FMTs for rCDI were delayed due to COVID-19. Conclusions There is a continued need for FMT treatment of rCDI during the COVID-19 pandemic. Appropriate donor screening and SARS-CoV-2 infection prevention measures can be implemented in existing protocols without increasing the burden for donors, and allow safe, effective and efficient FMT during the ongoing COVID-19 pandemic. Stool banks should evaluate their SARS-CoV-2 donor screening protocols for long-term sustainability and efficacy, and share their experiences to help the utilisation, standardisation and improvement of stool banks worldwide.

BACKGROUND & AIMS: Patients with multiple recurrent Clostridioides difficile infection (rCDI) have a disturbed gut microbiota that can be restored by fecal microbiota trans-plantation (FMT). Despite extensive screening, healthy feces donors may carry bacteria in their intestinal tract that could have long-term health effects, such as potentially procarci-nogenic polyketide synthase-positive (pks+) Escherichia coli. Here, we aim to determine whether the pks abundance and persistence of pks+ E coli is influenced by pks status of the donor feces. METHODS: In a cohort of 49 patients with rCDI treated with FMT and matching donor samples-the largest cohort of its kind, to our knowledge-we retrospectively screened fecal metagenomes for pks+ E coli and compared the presence of pks in patients before and after treatment and to their respective donors. RESULTS: The pks island was more prevalent (P = .026) and abundant (P < .001) in patients with rCDI (pre-FMT, 27 of 49 [55%]; median, 0.46 reads per kilobase per million [RPKM] pks) than in healthy donors (3 of 8 donors [37.5%], 11 of 38 samples [29%]; median, 0.01 RPKM pks). The pks status of patients post-FMT depended on the pks status of the donor suspension with which the patient was treated (P = .046). Particularly, persistence (8 of 9 cases) or clearance (13 of 18) of pks+ E coli in pks+ patients was correlated to pks in the donor (P = .004). CONCLUSIONS: We conclude that FMT contrib-utes to pks+ E coli persistence or eradication in patients with rCDI but that donor-to-patient transmission of pks+ E coli is unlikely.

Fecal microbiota transplantation (FMT) is a well-established treatment for recurrent Clostridioides difficile infection. FMT has become a more readily available and useful new treatment option as a result of stool banks. The current state of knowledge indicates that dysbiosis of the gut microbiota is implicated in several disorders in addition to C. difficile infection. Randomized controlled studies have shown FMT to be somewhat effective in treating ulcerative colitis, irritable bowel syndrome, and hepatic encephalopathy. In addition, FMT has been beneficial in treating several other conditions, such as the eradication of multidrug-resistant organisms and graft-versus-host disease. We expect that FMT will soon be implemented as a treatment strategy for several new indications, although further studies are needed.

International audience; Fecal microbiota transplantation (FMT) or donor feces infusion is a therapy that aims to restore a perturbed gut microbiota composition and function. FMT is effective for treatment of patients with (multiple) recurrent Clostridioides difficile infections1–3 and recommended by current guidelines.4–6 In the near future, FMT may also become an accepted treatment option for other intestinal or extra-intestinal diseases.7FMT is performed using suspensions made of donor stool from carefully selected and screened healthy individuals.1,7 Donor screening is time consuming and costly. Before the establishment of stool banks, physicians and patients had to find their own donors. This resulted in uncontrolled application of FMT, and the logistical challenge made physicians reluctant to offer FMT to their patients. To overcome these problems, stool banks have been established.8,9 The mission of those stool banks is :to produce ready-to-use donor feces suspensions for treatment of patients,to improve the quality and safety of FMT by centralization and standardization,to increase the cost effectiveness of FMT, andto facilitate research.Stool banks are built in concordance with the model of blood banks and should follow quality standards applied to other transplantation products. Most stool banks are non-profit institutions, operating at a local (institution-based), national or international level. Recently, a UEG-funded working group was initiated to define quality standards for stool banking and FMT, which will result in further standardization of this new treatment approach. The current costs to deliver a ready-to-use stool suspension are €1050–1700 in Europe.9,10 There are also commercial initiatives,11 which may aim for much higher prices.Driven by the needs of patients, stool banks have emerged as new entities in a landscape without existing regulatory boundaries. This lack of guidance and National or European legislation may become a serious threat to providing the treatment for severely ill patients. This is also illustrated by the recent safety alert in the US about the transmission of multi-drug resistant organisms through FMT,12 which underlines the need for standardization, quality assurance, and a regulatory framework supporting the activities of stool banks. Legislation requires classification of stool as a product to treat patients. We strongly believe that stool should be considered a transplant product, or be regarded equivalent in status to blood products used for transplantation or transfusion purposes. The EU Tissue and Cells Directive (2004/23/EC) is best suited to guide FMT. Currently, this Directive does not cover FMT because the mechanism of action is not mediated by human cells. An adjustment to align this directive with the new reality of fecal transplantation is thus urgently needed. Only in the case of modification to the donated feces, other than those necessary for the conservation of the microbial community, does the product made of the donated feces become comparable to a drug and is best covered within the European directive for medicinal products intended for human use (2001/83/EC).Unfortunately, the misclassification of donor feces suspensions as a drug or pharmaceutical product, although difficult to imagine, is still one of the possible outcomes of the current discussion about classification. Currently, stool has already been classified as a drug in countries such as France, Germany, and the United Kingdom. Recently, companies have formed the “Pharmabiotic Research Institute” in Europe and the “Microbiome Therapeutics Innovation Group (MTIG)” in the US. The mission of those groups is “to improve market access,” and to “enhance the regulatory, investment, and commercial environment for microbiome therapeutic drug product development.” Both groups have published statements about the classification of FMT as a drug.13,14 MTIG actively collaborates with the Food and Drug Administration for the evaluation of safety parameters related to microbiota-based therapeutic products. Concern has been raised by the MTIG that the existence and accessibility of material from stool banks limits enrollment into clinical trials for microbiome therapeutics. This illustrates how companies are active to influence the current discussion about classification and regulation of FMT. In fact, this discussion has already been troubled by commercial interest in the US some years ago.15In this regard, it is important to mention the overall major disadvantages of classification as a drug, which will result in time-consuming and costly registration processes, and a sharp and unjustified rise in costs. Most importantly, this will negatively impact availability and innovation, obstructing, for example, the future development of single-donor individualized solutions due to the requirements for standardization of active substances. We postulate that stool treatment defined as drug treatment is counterproductive. Stool is not a standardized product that is produced in a factory, but a highly diverse and donor-specific substance of human origin (SoHO) delivered by healthy, usually unpaid, volunteer donors. Therefore, stool suspensions require suitable guidance of quality and safety measures comparable to guidance of other SoHO (blood, tissues, cells and organs) within the EU.If government authorities seek affordable and quality-assured FMT, a supportive regulatory framework, in combination with appropriate funding or reimbursement, is required for stool banks. This will not only guarantee broad access and safety of FMT, but also enable the future innovation of this new treatment strategy targeting the gut microbiota. If eventually future research results in the replacement of FMT by standardized mixtures of bacteria (or another yet undiscovered stool extract that could theoretically underly the clinical effects of FMT), these should indeed be regulated as a drug or pharmaceutical product.