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First-in-class Microbial Ecosystem Therapeutic 4 (MET4) in combination with immune checkpoint inhibitors in patients
A Spreafico1, A A Heirali2, D V Araujo3
1Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto; Tumor Immunotherapy Program, Princess Margaret Cancer Centre, University Health Network, Toronto.
Background:
The intestinal microbiome has been associated with response to immune checkpoint inhibitors (ICIs) in humans and causally implicated in ICI responsiveness in animal models. Two recent human trials demonstrated that fecal microbiota transplant (FMT) from ICI responders can rescue ICI responses in refractory melanoma, but FMT has specific limitations to scaled use.
Patients And Methods:
We conducted an early-phase clinical trial of a cultivated, orally delivered 30-species microbial consortium (Microbial Ecosystem Therapeutic 4, MET4) designed for co-administration with ICIs as an alternative to FMT and assessed safety, tolerability and ecological responses in patients with advanced solid tumors.
Results:
The trial achieved its primary safety and tolerability outcomes. There were no statistically significant differences in the primary ecological outcomes; however, differences in MET4 species relative abundance were evident after randomization that varied by patient and species. Increases in the relative abundance of several MET4 taxa, including Enterococcus and Bifidobacterium, taxa previously associated with ICI responsiveness, were observed and MET4 engraftment was associated with decreases in plasma and stool primary bile acids.
Conclusions:
This trial is the first report of the use of a microbial consortium as an alternative to FMT in advanced cancer patients receiving ICI and the results justify the further development of microbial consortia as a therapeutic co-intervention for ICI treatment in cancer.
Insights
A novel oral microbial consortium (MET4) showed safety and tolerability in advanced cancer patients receiving immune checkpoint inhibitors (ICIs). MET4 engraftment was linked to beneficial microbial and metabolic changes, supporting its development as an alternative to fecal microbiota transplant (FMT).
Area of Science:
- Oncology
- Microbiome Research
- Immunotherapy
Background:
- The gut microbiome influences immune checkpoint inhibitor (ICI) efficacy in cancer patients.
- Fecal microbiota transplant (FMT) from ICI responders can restore treatment response but has scalability issues.
- Microbial consortia offer a potential alternative to FMT for enhancing ICI therapy.
Purpose of the Study:
- To evaluate the safety, tolerability, and ecological effects of an orally administered 30-species microbial consortium (MET4) co-administered with ICIs.
- To establish MET4 as a viable, scalable alternative to FMT for cancer patients undergoing ICI treatment.
Main Methods:
- An early-phase clinical trial involving patients with advanced solid tumors receiving ICIs and MET4.
- Assessment of safety, tolerability, and changes in gut microbial composition and function.
- Analysis of MET4 engraftment and its association with host biological markers.
Main Results:
- The trial met its primary safety and tolerability endpoints.
- While primary ecological outcomes showed no significant differences, MET4 species abundance varied by patient and species post-randomization.
- Increased abundance of specific MET4 taxa (e.g., Enterococcus, Bifidobacterium) and decreased primary bile acids were observed with MET4 engraftment.
Conclusions:
- This study is the first to report on a microbial consortium (MET4) as an alternative to FMT in advanced cancer patients on ICIs.
- The findings support the further development of microbial consortia as therapeutic co-interventions to improve ICI treatment outcomes.
- MET4 demonstrates potential as a safe and tolerable option for modulating the microbiome to enhance cancer immunotherapy.
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