1150 MaaT034, a new co-cultured microbiome ecosystem therapy candidate, potentiates anti-PD1 mediated antitumoral activity in germ-free mice
Bibliographic record
Abstract
Background Increasing evidence suggests that gut microbiome composition modulates tumor response to therapies, including immune checkpoint inhibitors (ICI). Clinical proofs of concept were obtained in pilot studies using healthy or ICI-responder donor-derived fecal matter transfers to modulate the gut microbiome of non-responding cancer patients and improve their response to ICI. 1–3 We have developed Microbiome Ecosystem TherapiesTM (MET) replicating at large industrial scale the effects of ICI-responders gut microbiome. MaaT034, the first-in-class co-cultured microbiome product, has been selected through artificial intelligence and in vitro screening assays for optimizing intestinal homeostasis and to activate immune functions alone and in combination with an ICI treatment.Methods We used germ-free mice to evaluate MaaT034 engraftment and safety, as well as its impact on metabolite production, immunity, gut morphology as well as tumor growth inhibition in combination with anti-PD1 treatment.Results Metagenomic analysis demonstrates that MaaT034 replicates the richness, diversity and functions of native-based microbiome ecosystems. Metagenomic analysis demonstrates that MaaT034 engrafts in the gut of germ-free mice, as evidenced by the presence of the four major phyla of the human product in mice. KEGG (Kyoto Encyclopedia of Genes and Genomes) analysis revealed the presence of genes involved in the synthesis of key metabolites such as short chain fatty acids, indoles, as well as secondary biliary acids. In line, metabolite quantification in the feces of mice further confirmed the capability of MaaT034 microbes to produce these metabolites. MaaT034-treated mice displayed a reduction of the size of cecum, which translates in decreased cecal content, suggesting that MaaT034 improves food digestion. MaaT034-treated mice displayed an increase in the depth of intestinal crypts, highlighting an improvement of gut physiology compared to control germ-free mice. All mice remained healthy throughout the experiment and no adverse event was observed. MaaT034 was able to potentiate anti-PD1 mediated antitumoral activity in germ-free mice bearing MC38 tumors. RNAseq analysis of the tumors revealed key pathways modulated in response to MaaT034 as well as changes in the proportions of tumor-infiltrating immune cells.Conclusions Altogether, these findings underscore MaaT034’s potential to safely colonize the gastro-intestinal tract of mice and to produce key metabolites allowing to restore a healthy gut physiology and to stimulate immunity. MaaT034 was able to potentiate anti-PD1 mediated antitumoral activity in tumor-bearing germ-free mice. MaaT034 could offer a promising therapeutic benefit for the treatment of solid tumors in combination with ICI therapy.References Davar D, Dzutsev AK, McCulloch JA, Rodrigues RR, Chauvin JM, Morrison RM, et al. Fecal microbiota transplant overcomes resistance to anti-PD-1 therapy in melanoma patients. Science. 2021 Feb 5 2021;371(6529):595–602.Baruch EN, Youngster I, Ben-Betzalel G, Ortenberg R, Lahat A, Katz L, et al. Fecal microbiota transplant promotes response in immunotherapy-refractory melanoma patients. Science. 2021 Feb 5;371(6529):602–9.Routy B, Lenehan JG, Miller WH, Jamal R, Messaoudene M, Daisley BA, et al. Fecal microbiota transplantation plus anti-PD-1 immunotherapy in advanced melanoma: a phase I trial. Nature medicine. 2023 Aug;29(8):2121–2132.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".