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Upfront fecal microbiota transplantation for the management of immune checkpoint inhibitor mediated diarrhea and colitis

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  • January 13, 2025
  • Yinghong Wang, et al.,  MD Anderson Cancer Center
Topic/Product:
Inflammation, Inflammation Panel 250
Disease Area:
Colitis
Sample Type:
Plasma

Abstract

Introduction: Immune checkpoint inhibitors have revolutionized cancer therapy; however, adverse events from an unchecked immune system such as immune checkpoint inhibitor mediated diarrhea and colitis (IMDC) can develop. Fecal microbiota transplantation (FMT) remains an option for patients with refractory colitis, but has not been tested in an upfront setting. 

Methods: From an open-label, phase I/II clinical trial (NCT0403861) starting June 2021, we report an analysis of adult patients with IMDC treated with upfront FMT. We performed fecal shotgun metagenomic sequencing, metabolomic, transcriptomic and immunofluorescence profiling pre-FMT and post-FMT and and plasma biomarkers of inflamamtion and immune response pre-FMT to predict response. 

Results: 13 patients were treated with FMT, of which 11 (84.6%) achieved clinical response with a median time to clinical improvement of 1(1-5) days. Among responders sequenced with baseline and follow-up (n = 8), 6 patients (75%) had an increase in alpha diversity post-FMT. Notably, in responders Lacrimispora amygdalina and Alistipes shahii increased independently at both 2 and 4 weeks post FMT. Interestingly, aspartic and propionic acid decreased post-FMT (p < 0.05). Using multiplex immunohistochemical immunofluorescence staining of samples obtained at presentation, we determined that total CK+ and CK+Ki67+ cell populations were reduced in non-responder patients. Additionally, there was a trend toward lower pre- and post-FMT CD20+, CD20+Ki67+, CD4+FOXP3+, and CD8+FOXP3+ cell populations in non-responder patients. Immune cell-type abundance scores showed increased plasma cells, neutrophils, (M1 and M2) macrophages, memory activated and resting memory CD4+ T cells , CD8+ T cells,T follicular helper (Tfh) cells, regulatory T cells (Treg), in pre-FMT samples which all decreased dramatically in post-FMT samples, likely related to response to FMT. Non-responders had lower baseline plasma GDF2, TLR3, CCL22, and FGF21 and higher baseline plasma CXCL14, OSM, IL-1β and IFNG. 

Conclusion: FMT is a promising front-line therapeutic option for patients who develop IMDC with high efficacy and favorable safety profile. Additional microbiome, blood and tissue analysis provides insights in future directions of potential mechanisms and targets for development of novel therapeutic intervention.

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Authors & Affiliations

Yinghong Wang, University of Texas MD Anderson Cancer Center Christopher Fan, Houston Methodist Krishnavathana Varatharajalu, MD Anderson Cancer CenterMalek Shatila, MD AndersonCarolina Cruz, MD AndersonBaohua Sun, University of Texas MD Anderson Cancer CenterNejla Ozirmak Lermi, MD Anderson Tomo Hayase, MD AndersonAnusha Thomas, MD AndersonKlaudia Szymonowicz, MD AndersonBeatriz Sanchez-Espiridion, The University of Texas MD Anderson Cancer CenterDzifa Duose, MD Anderson Cancer CenerEiko Hayase, MD AndersonLin Tan, University of Texas MD Anderson Cancer CenterYiwei Liu, MD Anderson
Chia-Chi Chang, Department of Genomic Medicine, The University of Texas MD Anderson Cancer CenterCesar Arias, Houston Methodist Kristin Junek, MD AndersonHerbert DuPont, University of Texas Health Science centerZhi-Dong Jiang, University of Texas Health Science Center at HoustonSang Kim, Yale UniversityRoza Nurieva, MD Anderson Cancer Center Matthew Campbell, The University of Texas MD Anderson Cancer CenterNizar Tannir, UT MD Anderson Cancer CenterJianjun Gao, The University of Texas MD Anderson Cancer Center Stephanie Watowich, UT MD Anderson Cancer Center Xin Wang, MD Anderson Ken Chen, The University of Texas MD Anderson Cancer CenterPhilip Lorenzi, The University of Texas MD Anderson Cancer Center Cara Haymaker, The University of Texas MD Anderson Cancer Center Edwin Parra, The University of Texas MD Anderson Cancer Center Robert Jenq, MD Anderson
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Steve Williams, MD, PhD

CSO

Dr. Willams serves as the company’s Chief Scientific Officer. He was previously Chief Medical Officer at Standard Biotools and at SomaLogic where he pioneered the discipline for discovery and validation of predictive, diagnostic and prognostic models using machine-learning applied to large-plex proteomics. 20 such tests were used for drug characterization, safety and efficacy when incorporated in clinical drug trials at Pharma/Biotech and 17 different multivariate tests were validated and translated into regulated healthcare uses. Prior to SomaLogic, Dr. Williams was at Pfizer in the UK and the USA as a clinical triallist in Translational Medicine, and subsequently as VP, Global Clinical Technology. He sat on the National Advisory Council for the National Institute of Biomedical Imaging and Bioengineering, the Executive Committee for the FNIH Biomarkers Consortium, and worked with FDA and PhRMA on developing evidentiary standards for biomarker qualification. Dr. William’s medical training was in London, at Charing Cross and Westminster Medical School, followed by a PhD in medicine/physiology at the same institution and training in Radiology at the University of Newcastle Upon Tyne. Steve is co-inventor on 26 proteomics patents and author/coauthor on multiple foundational proteomics manuscripts.

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Justin McAnear

CFO

Mr. McAnear serves as the company’s Chief Financial Officer. He brings over 25 years of operational and financial leadership experience across various sectors and was instrumental in taking 10x Genomics public in 2019, serving as its CFO for over five years. Mr. McAnear served for over 3 years as Tesla’s VP of Worldwide Finance and Operations, supporting landmark initiatives such as the Model X and Model 3 launches and Solar City acquisition.  He also held various roles at Apple and J&J earlier in his career and served as a naval officer and aviator for over 9 years.