Decoding the microbiome for clinical success – Can we increase cancer immunotherapy response rate by exploring metagenomes?

The overlap between the gut microbiome and tumor progression, metastasis and treatment sensitivity is one of the fastest growing areas of cancer research1. Recent studies have demonstrated that the microbiome plays important roles in oncogenesis processes, especially in the context of the so-called hallmarks of cancer. It also regulates the inpatient response to immune checkpoint inhibitors (ICIs), e.g. PD-1 inhibitors and CTLA-4 blockade, or even treatment-associated toxicity2-6. These findings have recognized microbiome signatures as a promising solution for the challenges of cancer drug development7.

Figure 1. Challenges in the development of cancer drugs that are addressed by microbiome signatures.

“How to modulate the human gut microbiome to improve response rates in cancer therapy?” currently seems to be the question that is driving research in a number of laboratories all over the world. The most advanced teams led by Jennifer Wargo, Laurence Zitvogel and Thomas Gajewski are exploring various paths to answer this question. This challenge consists of many aspects that can be addressed by microbiome signatures, including low objective response rates in phase II of clinical trials, poor translation from animal models to human studies, immunologically unresponsive ‘cold’ tumors, or treatment-related adverse effects such as colitis (Figure 1)8-11.

While all the aforementioned groups discovered a similar association between increased response rate and a beneficial gut microbiome composition, the definition of ‘beneficial’ in immuno-oncology remains unclear.

The published results define specific bacteria that distinguish immune checkpoint therapy responders, including Faecalibacterium prausnitzii, Gemmiger formicilis (Chaput et al.)12, Bacteroides thetaiotaomicron, Dorea formicogenerans (Frankel et al.)13Bifidobacterium longum, Collinsella aerofaciens, Enterococcus faecium (Matson et al., 2018)3, and Akkermansia muciniphila (Routy et al.)14. Nevertheless, the specific bacterial taxa identified across different studies were not the same and so it was difficult to draw conclusions in relation to strains associated with responder groups5. This suggests that microbiota ‘signatures’ are a result not of taxonomy but of functional features (such as enhanced systemic immunity or intratumoral immune infiltration).

The limit of research in the taxonomic approach has been reached; this has resulted in researchers adopting slightly different ways of explaining the association between bacteria and cancer treatment. In the group led by Jennifer Wargo at MD Anderson (Houston, TX), the key focus was on the role of dietary factors and associated metabolic processes that lead to the production of effector agents by gut bacteria. On the other hand, researchers led by Thomas Gajewski at the University of Chicago (Chicago, IL) are investigating the role of non-bacterial members of the microbial community, namely viruses and phages. Another hypothesis drives the research of Laurence Zitvogel’s group at Gustave Roussy in Paris, which relies on analysis of the immunostimulatory agents produced by gut bacteria that may directly activate the immune system by mimicking tumor antigens.

Figure 2. Ardigen’s approach to translational microbiomics: from human cohort to biological findings.

As such a variety of potential links between microbiota and the immune system’s activity in cancer treatment have been observed, it is also worth utilizing modern computational approaches such as Big Data and Artificial Intelligence. Such unconstrained application of metagenomic sequencing data is not limited by any a priori developed hypothesis, therefore it may lead to the discovery of novel traits that will explain the ‘beneficial microbiome’.

One of the first implementations of such an approach is Ardigen’s Microbiome Translational Platform. Ardigen addresses the aforementioned drug development challenges by starting with patients’ microbial and clinical data. We provide insight into the therapy-modulating interplay between host and microbiome by exploring the functional potential of commensal microbiota. In the process of revealing microbial signatures, we decode biological findings to clinical benefit.

Scientists have provided strong evidence that the microbiome has a mechanistic impact on anticancer processes in the human body. This has opened a new segment of digital microbiome-based diagnostics and therapeutics, such as microbial safety or response biomarkers, Next Generation Biotherapeutics (therapeutic probiotics, microbiome-derived small molecules or peptides), Live Biotherapeutic Products (single strain or bacterial consortia) and bacterial cancer vaccines (bacterial antigens stimulating immune system against cancer cells) (Figure 2)15. Ardigen has already applied this approach to data obtained from metastatic melanoma patients treated with anti-PD-1 therapy. We discovered, among others, that upregulation of the arginine synthesis pathway may play a role in the treatment response. These findings are in agreement with previous studies which reported that arginine enhances T-cell antitumor activity16, 17. On one hand, our approach expands the search space by exploring the full potential of the gut microbiome. On the other hand, this approach allows the costs of the necessary biological validation to be reduced and shows the great potential that will be available in the future design of innovative diagnostic and therapeutic solutions.


References:

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Kaja Milanowska-Zabel, Ph.D.
Head of Immunology and Microbiome Research at
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Product Strategy Scientist, Immunology and Microbiome R&D at