exclude: true --- background-image: url(img/cdiff_flip_dark.png) background-size: cover class: middle left hide-count .fade-in[ # <span style='color:white'>Fecal Microbiota Transplantation</span> ] .fade-in[ .callout-url-leftcorner[ <span style='font-size:0.75em;font-weight:bold;color:white'> Brendan J. Kelly, MD, MS Infectious Diseases & Epidemiology University of Pennsylvania </span> <span style='font-size:0.5em;font-weight:bold;color:white;'> 25 March 2021 </span> ] ] --- # Disclosures .pad-left[ - None ] --- class: full-screen hide-count <div class="grid-3-1"> <div class="extension-tile gridset-a animated flipInY"><div>What & Why?</div></div> </div> --- layout: false class: full-screen hide-count <div class="grid-3-1"> <div class="extension-tile gridset-a"><div>What & Why?</div></div> <div class="extension-tile gridset-b animated flipInX"><div>FMT @Penn</div></div> </div> --- layout: false class: full-screen hide-count <div class="grid-3-1"> <div class="extension-tile gridset-a"><div>What & Why?</div></div> <div class="extension-tile gridset-b"><div>FMT @Penn</div></div> <div class="extension-tile gridset-c animated bounceInDown"><div>Applications<br>in Oncology</div></div> </div> --- layout: false class: full-screen hide-count <div class="grid-3-1"> <div class="extension-tile gridset-a"><div>What & Why?</div></div> <div class="extension-tile gridset-grey"><div>FMT @Penn</div></div> <div class="extension-tile gridset-grey"><div>Applications<br>in Oncology</div></div> </div> --- # Fecal Microbiota Transplantation (FMT) .pad-left[ - Transplant fecal microbiota from healthy donor to colon of recipient - <u>Methods</u>: frozen oral capsules, solution via enteric tube, enema, colonoscopy - <u>Indications</u>: - _C. difficile_ infection (CDI) = driving force behind development - MDRO colonization - inflammatory bowel disease (IBD) - oncology: auto-FMT post allo-SCT; immune checkpoint inhibitors; GVHD ] --- # _Clostridioides difficile_ Infection .pad-left[ - Infectious colitis that occurs after antibiotic treatment ("antibiotic-associated") - Depletion of protective taxa (abx & PPI) ⇾ altered bile acid metabolism ⇾ germination of resident or recently ingested _C. difficile_ spores ⇾ expansion of vegetative _C. difficile_ ⇾ toxin production ⇾ colonic inflammation ⇾ CDI - Treatment with anti-CDI antibiotics (vancomycin, fidaxomicin) contributes to persistent depletion of protective taxa ⇾ risk for recurrent CDI - **FMT restores colonization resistance by restoring protective taxa** - <u>Note</u>: treatment with anti-CDI antibiotics is prerequisite ] --- background-image: url(img/tariq_2fmt_forest_plot.png) background-size: 900px background-position: 50% 35% .footnote[Tariq R et al _Clin Inf Dis_ 2019] --- background-image: url(img/cdiff_idsa_guideline_2017_fmt.png) background-size: 900px background-position: 50% 35% .footnote[IDSA/SHEA Guidelines: McDonald LC et al _Clin Inf Dis_ 2018] --- # Efficacy Despite Product Heterogeneity? .pad-left[ - FMT contains multitudes: - bacteria, fungi, archaea... bacteriophage, eukaryotic viruses (e.g., TTVs) ... ... human colonocytes, metabolites - Causal models for efficacy versus _C. difficile_ infection: - Direct bacterial interaction? Bile acid metabolism-mediated interaction? - Bile acid metabolism & Th17 regulatory cells? - **We do it because it works, but we don't know why!** ] .footnote[Bojanova & Bordenstein _PLoS Biology_ 2016; Ott et al _Gastroenterology_ 2017; Hang et al _Nature_ 2019] --- # FMT Regulation & Commercial Alternatives .pad-left[ - **Guideline-recommended for CDI but no FDA-approved product**: - IND required for non-CDI indications - for CDI, FDA exercises "enforcement discretion" - concern that product availability (e.g., OpenBiome) limiting RCT enrollment - Multiple companies with "ecobiotic" FMT alternatives in phase 2/3 trials: - Finch, Rebiotix, Seres, Vedanta - May 2020: "Rebiotix and Ferring are the first to announce positive preliminary results on primary efficacy endpoint from ongoing pivotal Phase 3 clinical trial" ] --- layout: false class: full-screen hide-count <div class="grid-3-1"> <div class="extension-tile gridset-grey"><div>What & Why?</div></div> <div class="extension-tile gridset-b animated flipInY"><div>FMT @Penn</div></div> <div class="extension-tile gridset-grey"><div>Applications<br>in Oncology</div></div> </div> --- # FMT Program Development at Penn .pad-left[ - <u>2014-2016</u>: ID Division Stool Bank - FDA enforcement discretion (no IND) - 67 FMTs: 82% aggregate cure rate - <u>2016-2018</u>: OpenBiome partnership - <u>2019-present</u>: "Penn Microbiome Therapy (PMT)" - IND for 3 products: capsule, upper GI liquid, enema - 3 protocols: R-CDI, SC-CDI, postpartum incontinence (OB-GYN: Uduak Andy, PI) (compassionate use for MDRO colonization) ] --- # Impact of COVID-19 on FMT at Penn .pad-left[ - **FDA partial hold**: all doses manufactured after December 1, 2019 - Adequate donor/dose screening: - challenges with stool testing for SARS-CoV-2 (high LOD) - donor screening with serology? NP NAAT? - Ongoing COVID-19 activity slows (already slow) clinical trial enrollment - **Recent resumption of enrollment for all protocols** ] --- layout: false class: full-screen hide-count <div class="grid-3-1"> <div class="extension-tile gridset-grey animated"><div>What & Why?</div></div> <div class="extension-tile gridset-grey animated"><div>FMT @Penn</div></div> <div class="extension-tile gridset-c animated flipInX"><div>Applications<br>in Oncology</div></div> </div> --- background-image: url(img/peled_nejm_2020.png) background-size: 1000px background-position: 50% 60% # Dysbiosis & Death .footnote[Peled et al _NEJM_ 2020] --- background-image: url(img/taur_diversity_vs_engraftment.png) background-size: 800px background-position: 50% 50% # Auto-FMT Post Allo-SCT .footnote[Taur et al _Sci Trans Med_ 2018] --- background-image: url(img/taur_fmt_taxa.png) background-size: 600px background-position: 50% 60% .footnote[Taur et al _Sci Trans Med_ 2018] --- # FMT & Immune Checkpoint Inhibitors .pad-left[ - Differential bacterial signatures of ICI responders versus non-responders - Modulation of the gut microbiome via FMT from patients alters antitumor immunity and response to ICI therapy in gnotobiotic mice - FMT also applied to & resolves ICI-related colitis: - variable (donor-dependent) effects on microbiome - increase proportion of regulatory T-cells in colonic mucosa ] .footnote[Routy et al _Science_ 2018; Gopalakrishnan et al _Science_ 2018; Matson et al _Science_ 2018; Wang et al _Nat Med_ 2018] --- # FMT & GVHD .pad-left[ - Disruption of intestinal microbiota associated with GVHD - Recent prospective single-arm study: - 15 post-allo-HCT with steroid-dependent, acute or late-onset acute intestinal GvHD - effect of donor FMT on GVHD symptoms and biomarkers - 10 of 15 study participants with complete clinical response observed within 1 month after FMT, without additional interventions to alleviate GVHD symptoms - associated increase in gut microbial alpha-diversity, a partial engraftment of donor bacterial species, and increased abundance of butyrate-producing bacteria, including _Clostridiales_ and _Blautia_ species ] .footnote[van Lier et al _Sci Trans Med_ 2020] --- # Risks of FMT in Oncology Patients .pad-left[ - Disseminated bacterial infection: - ESBL _E. coli_ sepsis and death* - CMV & EBV: - CMV colitis post-FMT has been reported - risk of CMV listed on informed consent for our PMT prooducts (donors are screened for CMV/EBV but not restricted) - GVHD: given heterogeneity of FMT, potential for exacerbation? ] .footnote[*DeFilipp et al _NEJM_ 2019] --- class: middle center hide-count background-image: url(img/cdiff_flip_dark.png) background-size: cover # <span style='color:white'>Questions?</span> <!-- .callout-url-bottom[ .fade-in[<span style="font-size:0.5em; color:white">slides ↓ </span>] <span style="link-color:white">[bjklab.org](http://www.bjklab.org)</span> ] -->