Study Title: A Phase 1b Study to Evaluate Safety, Tolerability, PK, and Efficacy of SER-155 in Adults Undergoing HSCT
ClinicalTrials.gov Identifier: NCT04995653
Sponsor: Seres Therapeutics, Inc.
Accrual Goal: Approximately 70 adult participants undergoing allogeneic hematopoietic stem cell transplantation (HSCT)
Participating Centers: Memorial Sloan Kettering Cancer Center, New York; University of Chicago Medical Center, Chicago; Mayo Clinic, Scottsdale, AZ; Massachusetts General Cancer Center, Boston.
Study Design: Participants in this study are divided into two cohorts. Cohort 1 is open-label, and patients will receive microbiome “conditioning” with oral vancomycin followed by treatment with the SER-155 bacterial consortium. Cohort 2 patients will participate in a randomized, double-blind placebo-controlled study of vancomycin/SER-155 or placebo/placebo. The primary end points for the study are safety and tolerability, in addition to engraftment of SER-155 strains compared to placebo through day 100. Secondary end points include incidence of bloodstream infections, gastrointestinal infections, acute graft-versus-host disease, and febrile neutropenia.1
SER-155 is a cultivated microbial community, administered orally (in pill form) during the pretransplant phase and then again after neutrophil engraftment. A third course will be administered without microbiome conditioning to patients who require at least three days of systemic antibiotics following HSCT.
Rationale: Loss of alpha-diversity within the intestinal microbiome during both the pretransplant and perineutrophil engraftment periods have been linked with poor outcomes for recipients of HSCT.2 In addition to overall microbial diversity, microbial taxa have been linked with desirable clinical outcomes (including reduced graft-versus-host disease, relapse, and infectious complications).3-6 While the precise mechanism for these associations remains unclear, a diverse microbiome has also been linked with more robust immune reconstitution7, 8 and lower rates of chronic graft-versus-host disease, which are both linked with increased transplant-related mortality.9
There are numerous hypotheses as to why a highly diverse microbiome is likely to be important for optimal recovery after allo-HSCT: 1) the intestinal microbiome is thought to promote intestinal integrity via preservation of the mucous layer10 ; 2) immunomodulatory metabolites (e.g., short-chain fatty acids) may promote regulatory T cell populations within the gut11, 12 ; and 3) it may reduce the risk of alloreactivity and facilitate immunologic tolerance.9
Possible direct, investigational microbiome-targeted interventions include the administration of defined cultivated consortia (e.g., SER-155 as in this trial), or the administration of purified bacterial products (postbiotics). Previous studies have largely focused on fecal microbiota transplantation, where healthy donor stool has been transferred into the intestinal tract of allo-HSCT patients with severe, treatment-refractory graft-versus-host disease,13 or early after transplantation for the restoration of diversity following antibiotics.14 This approach has had some success in single-arm studies but remains somewhat difficult to provide on a large scale, given the reliance on healthy screened stool donors and absence of scientific rationale for optimal donor selection.15 In addition, transmission of drug-resistant bacteria via fecal microbiota transplantation has led to serious adverse outcomes including hospitalizations and death in immunocompromised patients.16
Indirect approaches to prevent the onset of a low diversity microbiome such as minimizing exposure to broad spectrum antibiotics, or dietary supplements to support a broad microbial community, are the subject of ongoing trials.
Comment: The SER-155 study will generate important data using a novel, highly precise approach to restructuring the microbiome early after transplantation. Since SER-155 is a cultivated bacterial product, this represents a scalable approach that could subsequently be easily tested in larger cohorts or administered as part of standard transplant protocols. Ideally, approaches that restore microbial diversity and provide beneficial taxa will result in clinically meaningful improvement of outcomes for patients undergoing allo-HSCT.
Dr Markey holds equity in and is on the advisory board of PostBiotics Plus.