The human gut microbiome has emerged as a critical determinant of cancer treatment success, with mounting evidence showing that bacterial composition can make the difference between therapeutic response and resistance. This revelation is driving a new wave of biotechnology innovation aimed at harnessing the power of gut bacteria to enhance cancer immunotherapy outcomes.
Microbiome's Role in Treatment Response
Research published in the British Medical Journal reveals that altered gut microbiota are associated with resistance to both chemotherapy and immune checkpoint inhibitors, while supplementation with distinct bacterial species can restore responses to anticancer drugs. The gut microbiome, containing 10 to 100 trillion symbiotic microbial cells per person, influences cancer treatment through multiple mechanisms including modulating inflammation, causing DNA damage, and producing metabolites involved in tumor formation or suppression.
Studies demonstrate that certain gut bacteria can enhance or suppress immune responses to cancer treatments by producing metabolites that influence drug metabolism and affect immune cell function. The microbiome stimulates anti-tumor responses by modulating CD8+ T cells, T helper 1, and tumor-associated myeloid cells, making it a powerful ally in the fight against cancer.
Clinical Evidence and Breakthrough Results
The therapeutic potential of microbiome modulation is being validated in clinical trials with remarkable results. In the phase 2 TACITO trial, fecal microbiota transplantation (FMT) achieved 66.7% progression-free survival at one year in patients with renal cell carcinoma. Similarly, the FMT-LUMINATE study in lung cancer patients met its primary endpoint with an impressive 80% overall response rate.
Dr. Arielle Elkrief from the University of Montreal explained the significance: "We learned that dysbiosis is a key biomarker of response and resistance to immunotherapy. As a result, multiple microbiocent interventions and clinical trials are being developed with the goal of transforming an unfavorable microbiome associated with resistance to immunotherapy to that of a favorable microbiome associated with a robust immune response."
Innovative Therapeutic Approaches
Several biotechnology companies are pioneering novel approaches to leverage the gut microbiome for cancer treatment. Enterome, a clinical-stage company, has developed "OncoMimics" - synthetically manufactured, bacteria-derived peptides that mimic tumor-associated antigens. The company has four drug candidates in Phase 2 trials, with EO2401 being tested in combination with checkpoint inhibitor nivolumab and bevacizumab.
According to Enterome's spokesperson, "EO2401 in combination with nivolumab generated strong systemic immune responses through activation of specific effector memory CD8+ T cells, correlating with clinical efficacy." This approach allows the company to "overcome the immune tolerance to TAAs, which are recognised as self-antigens, and that severely limits the effectiveness of existing immunotherapies."
MaaT Pharma is advancing its lead asset MaaT013, a donor-derived microbiome ecosystem therapy containing butycore, through Phase 2a trials in immuno-oncology and Phase 3 onco-hematology trials. The treatment contains bacterial species known to produce anti-inflammatory, short-chain fatty acids and is being explored in combination with nivolumab and ipilimumab.
The Antibiotic Challenge
A critical concern emerging from this research is the detrimental impact of antibiotics on cancer treatment outcomes. Studies show that antibiotic use in cancer patients leads to lower overall survival rates and reduced responses to immunotherapy, with a hazard ratio of 1.7 across studies for increased risk of death.
Dr. Laurence Zitvogel from Institut Gustave Roussy emphasized the need for careful antibiotic management: "Pharmacovigilance in the use of antibiotics should be approached judiciously, such as narrowing the antibiotic spectrum, minimizing polypharmacy, limiting conservative prescribing tendencies, and reducing the duration of therapy."
Antibiotics significantly reduce microbiome diversity and suppress immune system effectiveness crucial for immunotherapy success. They impair immunosurveillance, increase T-cell exhaustion, and disrupt the complex ecosystem of microbial species that stimulate immune responses.
Addressing Gut Dysbiosis
Gut dysbiosis, characterized by reduced microbiome diversity and depletion of beneficial bacteria, affects approximately 50% to 60% of cancer patients compared to 20% of healthy individuals. This imbalance serves as both a risk factor for treatment resistance and a predictive biomarker for immunotherapy response.
Treatment approaches vary based on dysbiosis severity. Mild cases can be addressed through discontinuing inappropriate medications and increasing fiber intake. Moderate dysbiosis may benefit from prebiotics, live bacterial products, and potentially FMT. Severe cases typically require FMT as the preferred intervention.
FMT is administered as an odorless, tasteless oral capsule containing approximately 200 grams of healthy donor stool, with patients often receiving bowel preparation 24 hours before transplant to clear the native microbiome.
Industry Collaboration and Future Prospects
The potential of microbiome-based cancer treatments has attracted major pharmaceutical companies. AstraZeneca has established a collaboration with Seres Therapeutics to explore SER-401, an investigational microbiome therapeutic, alongside AstraZeneca's anticancer portfolio including checkpoint inhibitor Imfinzi.
As MaaT Pharma's spokesperson noted, "Recent studies have shown the key role it plays in educating, regulating, and influencing our immune system, in turn influencing our response to cancer and cancer treatment." The company emphasizes that correcting dysbiosis is essential not only for improving patient health conditions but also for enhancing the efficacy of established treatments.
The convergence of microbiome science and cancer immunotherapy represents a paradigm shift toward personalized medicine, where understanding each patient's unique bacterial ecosystem could determine the most effective treatment approach and significantly improve outcomes for cancer patients worldwide.
