This blog was collaboratively written by Haider Hassan, PhD, Data Scientist at Bridge Informatics, and Saman Maleki, PhD, Assistant Professor in the Departments of Oncology, Pathology and Laboratory Medicine, and Medical Biophysics at Western University.
Summary
The human gut microbiome is essential for maintaining good health, and dysregulation in the microbiome is often associated with diseases such as cancer. In a phase 1 clinical trial published in Nature Medicine, Routy et al. (2023) provide evidence that re-establishing a healthy gut microbiome, in combination with immune checkpoint inhibitors, is safe and potentially enhances the activity of immunotherapy in the first-line setting in patients with advanced melanoma.
What is the human microbiome?
The human microbiome consists of a complex ecosystem of microorganisms that are found within various organs in our body, such as the skin, mucosa, gastrointestinal tract, respiratory tract, urogenital tract, and the mammary gland. The microbiome plays a critical role in maintaining our health and promoting normal bodily functions, such as digestion, protection from potentially pathogenic bacteria, nutrient digestion, and vitamin metabolism.
The human microbiome and immunotherapy
Recent advances in microbiome research have identified the involvement of gut microbiota in modulating immune responses, including responses to immunotherapies in cancers such as melanoma. Melanoma, which is a deadly type of skin cancer, has long been a challenging disease to treat, especially in advanced stages. Conventional therapies like surgery and radiation often come with significant side effects and are only applied in early stages of the disease. In late stage melanoma, immune checkpoint inhibitors (ICI) represent the primary treatment option. However, recent developments in cancer research have opened new possibilities for innovative treatments. One such treatment involves fecal microbiota transplantation (FMT), which involves transplantation of fecal bacteria from healthy donors into diseased patients to restore their gut microbiota. In combination with ICI, FMT represents a promising new step forward in cancer treatment.
In a recent Nature Medicine publication led by Dr. Saman Maleki, Routy et al. present the results of a phase 1 clinical trial on combining healthy donor FMT with ICI for the treatment of advanced melanoma in the first-line setting, yes that’s right, melanoma!
Studying Changes in Gut Microbiome After FMT
In this study, 20 patients with advanced cutaneous melanoma, with no previous anti-PD1 treatment, were administered a single FMT from healthy donors. The FMT was given via oral capsules a week before starting first-line anti-PD-1 therapy. Most patients had stage IV disease, with some having brain metastases or elevated serum lactate dehydrogenase levels. The median follow-up time was approximately 20.7 months, with six patients remaining on anti-PD-1 therapy at the end of study.
To study changes in gut microbiome after FMT, fecal matter from patients was collected at staggered timepoints post transplantation and analyzed by 16S rRNA gene sequencing and metagenomics shotgun sequencing. MetaPhlAn4, a computational tool, was used to classify bacteria into their respective taxonomies and relative abundance estimation, whereas StrainPhlAN4, another computational tool, was used to determine the species and strain. Additionally, to determine metabolic alterations in plasma and changes to metabolic pathways after FMT treatment, ultra high performance liquid chromatography – mass spec/mass spec and the HUMAnN pipeline, were used, respectively.
Strain Differences Between Responders and Non-Responders
It was demonstrated that healthy donor FMT administration significantly increased microbiome diversity in diseased patients. Interestingly, the microbiome composition of all patients evolved closer to their respective donors; however, the microbiome content of non-responders regressed towards baseline between 1 – 3 months following FMT. It was observed that responders were enriched in Ruminococcaceae, Alistipes communis, and Blautia, whereas non-responders had overrepresentation of the Enterocloster asparagiformis and Catabacter hongkongensis bacteria. Differential abundance and diversity analysis was performed using the ALDEx2 algorithm, which demonstrated an increase in bacterial diversity in both responders and non-responders.
Metabolic profiling of responding patient’s plasma demonstrated a sustained increase in histidine levels, which has been linked to increased CD8+ T cell activation and response to ICI in other cancers. Immune profiling of patients corroborated these findings by demonstrating that the FMT-ICI combination therapy resulted in an increase in activated ICOS+CD8+ and MAIT-cells in patients whose tumors responded to treatment, which interestingly was reproduced in murine models.
FMT in combination with immune checkpoint inhibitors is a promising first-line treatment for advanced melanoma
Overall, the study suggests that dysregulation in the gut microbiome is associated with disease pathology and that modifying the microbiome may create a more favorable immune environment for anti-cancer therapies to work effectively, which is also indicated previously by other landmark publications (Lee et al, 2022; Halsey et al., 2022; Derosa et al, 2021; Sepich-Poore et. al., 2021; Matson et al, 2018; Baruch et al, 2020; Gopalakrishnan et al, 2017). While the current study requires further validation in larger trials, the initial results are encouraging and provide hope for improving treatment outcomes and quality of life for patients with advanced melanoma.
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Haider M. Hassan, Data Scientist, Bridge Informatics
Haider is one of our premier data scientists. He provides bioinformatic services to clients, including high throughput sequencing, data pre-processing, analysis, and custom pipeline development. Drawing on his rich experience with a variety of high-throughput sequencing technologies, Haider analyzes transcriptional (spatial and single-cell), epigenetic, and genetic landscapes.
Before joining Bridge Informatics, Haider was a Postdoctoral Associate at the London Regional Cancer Centre in Ontario, Canada. During his postdoc, he investigated the epigenetics of late-onset liver cancer using murine and human models. Haider holds a Ph.D. in biochemistry from Western University, where he studied the molecular mechanisms behind oncogenesis. Haider still lives in Ontario and enjoys spending his spare time visiting local parks. If you’re interested in reaching out, please email [email protected] or [email protected]
