Purpose

Gastrointestinal (GI) microbiome modulators, such as fecal microbiome transplants (FMTs), are being considered as supplements to standard immune checkpoint inhibitor (ICI) treatment to improve efficacy. This systematic review aims to assess the study design and outcomes of clinical trials that use FMTs to enhance ICI treatment.

Methods

Systematic literature searches were conducted on PubMed and Embase using search terms that included names of ICIs and gastrointestinal microbiome. A first search identified interventional trials, and the second search identified interventional, retrospective, and observational studies.

Results

The search for interventional trials produced 205 articles, 3 of which met the inclusion criteria. All studies had sample sizes ranging between 10 and 30 participants. 2 of the studies were single-arm studies with no control arm. One study reported an overall response rate (ORR) of 3 out of 15 (20%), a median progression-free survival (PFS) of 3 months, and a median overall survival (OS) of 7 months. The second study reported 1 complete response out of 10 (10%) and 2 partial responses out of 10 (20%). The third study reported an ORR of 58% vs. 20%, a median PFS of 12.7 months vs. 2.5 months in patients receiving nivolumab-ipilimumab plus CBM588 compared with patients receiving nivolumab-ipilimumab alone respectively, and an undefined median OS.

Conclusion

Current studies on the microbiome modulators with ICI use are limited in study design. Future clinical trials should be randomized, use larger sample sizes, and use an appropriate control arm to better ascertain the clinical effect of the GI microbiome on ICI treatment.

The AGILE trial compared ivosidenib and azacitidine versus azacitidine for IDH1-mutant acute myeloid leukemia (AML) in elderly patients who were ineligible to receive intensive chemotherapy. While the results of this trial appear encouraging, various concerns become evident from the study design and methodology. First, the AGILE trial did not use post-protocol therapy that met the current standard of care. Second, researchers continued patient enrollment despite knowledge of the survival benefit of azacitidine plus venetoclax shown in the VIALE-A trial, resulting in an inferior control arm. Third, the primary endpoint of AGILE was changed from overall survival (OS) to event-free survival (EFS), and the sample size was reduced to expedite the results. Finally, the trial was halted early based on a non-primary endpoint, which likely led to exaggerated effect size or misleading results. We discuss these limitations and continue to advocate for careful analysis of study design to ensure that appropriate and accurate outcomes are implemented in future studies.

When the social boundaries between groups are breached, the tendency for people to erect and maintain symbolic boundaries intensifies. Drawing on extant perspectives on boundary maintenance, we distinguish between two strategies that people pursue in maintaining symbolic boundaries: boundary retention—entrenching themselves in pre-existing symbolic distinctions—and boundary reformation—innovating new forms of symbolic distinction. Traditional approaches to measuring symbolic boundaries—interviews, participant-observation, and self-reports are ill-suited to detecting fine-grained variation in boundary maintenance. To overcome this limitation, we use the tools of computational linguistics and machine learning to develop a novel approach to measuring symbolic boundaries based on interactional language use between group members before and after they encounter one another. We construct measures of boundary retention and reformation using random forest classifiers that quantify group differences based on pre- and post-contact linguistic styles. We demonstrate this method's utility by applying it to a corpus of email communications from a mid-sized financial services firm that acquired and integrated two smaller firms. We find that: (a) the persistence of symbolic boundaries can be detected for up to 18 months after a merger; (b) acquired employees exhibit more boundary reformation and less boundary retention than their counterparts from the acquiring firm; and (c) individuals engage in more boundary retention, but not reformation, when their local work environment is more densely populated by ingroup members. We discuss implications of these findings for the study of culture in a wide range of intergroup contexts and for computational approaches to measuring culture.