Could bacteria function as tissue agnostic cofactors for checkpoint blockade immunotherapy?
Immune checkpoint inhibitors (ICI) have provided a disruptive breakthrough treatment strategy for some tumours by reversing the immune privileged status that allows them to survive and grow. Unfortunately, objective response rate is low, not exceeding 30%. This low success rate has prompted the search for biomarkers indicative of an improved outcome. The key biomarker discovered to date is the correlation between high mutational burden, and effectiveness of the ICI therapy. Conversely, antibiotic treatment prior to ICI treatment is known to worsen clinical outcomes in patients receiving this therapy.
The human microbiome is considered a de facto organ with functions in digestion and metabolism, including drug metabolism and immune system regulation among many others. This makes it a logical starting point, especially given the effect of antibiotics.
A potential relationship between the microbiome and ICI treatment outcome was confirmed when it was showed that increased microbial diversity in the gastrointestinal tract corresponded with increased success of immune therapy treatment. These findings have been expanded upon again to show that responders and non-responders to ICI can be stratified based on their gut microbiome, with a panel of bacterial taxa associated with the specific outcome being identified in both groups. It must be said that the underlying mechanism for this remains unclear, and that there is yet to be a consensus on these panels of outcome associated bacteria between studies.
Relationships between bacteria and response to ICI targeting cytotoxic T lymphocyte associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) have been identified in multiple tumours to date including:
- Non small cell lung carcinoma
- Renal Cell Carcinoma
- Urothelial Carcinoma
- Small Cell Carcinoma of the Head and Neck
Faecal Microbiota Transplants (FMT) from human responders into mouse models has been shown to improve response to ICIs, which confirms the key role played by the gut microbiome. As such, progress must be made to identify the underlying mechanisms modulating ICI efficacy before this information can be translated into a therapeutic strategy.
The current cutting-edge research into this potential therapeutic avenue shows that not only FMT (containing billions of diverse bacteria), but also specific bacterial taxa cultured and administered to mice have a significant impact on their response rate. The prime example is B. pseudolongum, a key metabolite of which is the nucleoside inosine, found to enhance the effect of anti-PD1 treatment through enhanced activation of anti tumour T-cells. This process is accelerated by the degradation of gut barrier function which is a side effect of immunotherapy. This was observed across a spectrum of tumour types such as colorectal cancer, bladder cancer and melanoma.
It is premature to state whether such effects could be repeated in humans, and considerable research is still required, but results in preclinical models raise the prospect for the following precision medicine treatment strategies:
- At a minimum, point of care sequencing using rapid turnaround tabletop sequencing technology to rapidly stratify patients into appropriate treatment group prior to therapeutic intervention.
- The ideal endpoint would be personalized treatment based on the results of (i) where targeted antibiotics are used to remove antagonists of ICI function, and create a niche if necessary, to be colonized by known agonists of ICI function.
Author: Dr. Sidney Walker, POI Postdoctoral researcher
Sidney completed a PhD in Bioinformatics investigating the tumour microbiome in 2019, and now works as a post-doctoral researcher in the Dr Mark Tangney's lab in UCC.