The Official Blog of the Annual Translational Microbiome Conference

The official blog of the Annual Translational Microbiome Conference provides readers with information, insight and analysis regarding the microbiome.

New Tools are Needed to Drive Microbiome Research to the Next Level

These microbiome insights are brought to you by Dr. Peter Christey of GALT, Inc., and Arrowhead Publishers. Dr. Christey will be presenting "Driving the Tidal Wave of Microbiome Discovery - a Next Generation Platform for Exploring the Microbiome" at Arrowhead's 4th Annual Translational Microbiome Conference, 18th-20th April, 2018.

I so much enjoy microbiome meetings and continue to be blown away by the speed at which the field is developing and the innovative work being presented. However, there is a sense of frustration with many of the presentations and publications we see in the literature. You would have seen them - studies where samples are taken from healthy patients, samples are taken from diseased patients, next generation sequencing of the microbiome is performed and the results are compared. We get shown lots of charts showing that population x goes up, population y goes down. Then of course PCoA and other statistical charts are presented to demonstrate some point or other. All during the presentation I'm waiting for the punch-line, the insight that helps me understand what is going on. What is the microbiome doing? Who are the key actors? How are they impacting the disease state? What is the underlying biology, chemistry here? Data and insights that quench my curiosity. But no, the presentation ends once the sequencing data analysis is complete - we are left with that empty feeling that something is going on, but it is beyond our ability to understand.

Sequencing is an incredibly powerful tool that has helped illuminate the wonderful complexity and richness of the microbiome. It's one of the few, if not the only, research tools we currently have that scales to the complexity of the microbial systems we are studying. But is it enough? I feel we are doing the equivalent of trying to cure cancer solely by sequencing a million tumor samples. Cancer is being defeated by insights derived from multiple avenues of investigation, including clinical trials, epidemiological data, analysis of the underlying genetics and, critically, wet lab work dissecting the core biological mechanisms and pathways. Wet lab work is critical to test hypotheses and new ideas under controlled conditions - the path to getting from correlation to mechanism. Then we can seriously develop informed interventions to improve the human condition.

Microbiome wet lab work is constrained by the current toolset. Mainstream microbiology technologies were invented over 100 years ago. Core tasks, such as isolating target microbes, creating comprehensive strain collections or studying model ecosystems, are often difficult or impractical. We need new tools to drive microbiome research to the next level.

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Gut Bugs May Modulate the Efficacy of Anti-PD1 Immunotherapy

These microbiome insights are brought to you by Dr. Vancheswaran Gopalakrishnan and Dr. Jennifer Wargo of The University of Texas MD Anderson Cancer Center, and Arrowhead Publishers. Dr. Gopalakrishnan will be presenting MD Anderson’s work at Arrowhead’s 4th Annual Translational Microbiome Conference, 18th-20th April, 2018.

Pioneering research performed at the MD Anderson Cancer Center1 suggests that the gut microbiome influences how cancer responds to immunotherapy; potentially creating new opportunities to improve treatment.

Cancer patients who saw no benefit from anti-PD1 checkpoint blockade immunotherapy lacked certain beneficial gut bacteria. On the other hand, cancer patients who responded to anti -PD1 immunotherapy possessed gut bacteria whose abundance in the gut correlated with the presence of cancer-killing T-cells. When the researchers transferred gut bacteria from human cancer patients into germ-free mice using fecal matter transplantation (FMT), the rodents mirrored the patient’s fates.

Anti-PD1 immunotherapy “unleashes the brakes on the immune system” by preventing programmed-death-1 (PD-1) binding to programmed-death ligand-1 (PD-L1) on cancer cells, allowing T-cells to attack. However, anti-PD1 immunotherapy is not effective for all cancer patients and responses are not always durable.

The Answer’s in the Poop!

To assess the impact of the microbiome, the MD Anderson team analysed oral and fecal samples of 112 metastatic melanoma patients undergoing anti-PD1 immunotherapy1. 16rRNA and whole genome sequencing was performed to determine diversity, composition and functional potential of the oral and fecal microbiomes. Baseline tumor and blood samples were also analysed.

While no differences in response or progression were found in connection with the oral samples; the 43 fecal samples told another story. Analysis of the fecal microbiome samples (30 of which were responders and 13 non-responders) found that patients with a greater diversity of bacteria in their gut microbiome at baseline had a longer median progression-free survival (PFS). While the high diversity group had not reached median PFS, intermediate and low diversity groups had median PFS of 232 and 188 days, respectively. 

Additional analysis showed that responding patients with high levels of beneficial Clostridiales/Ruminococcaceae had greater presence of anti-tumor T-cells in their tumors, and higher levels of circulating T cells that kill abnormal cells. On the other hand, patients abundant with Bacteriodales had higher levels of circulating regulatory T cells, myeloid derived suppressor cells and a blunted cytokine response, resulting in diminished anti-tumor immunity.

To investigate causal mechanisms, the team transplanted fecal microbiomes from responding patients and non-responding patients into germ-free mice. Those receiving transplants from responding patients had significantly reduced tumor growth as well as higher densities of beneficial T cells in their gut and tumor sites and lower levels of immune suppressive cells. They also had better outcomes when treated with PD-1 axis blockade

Antibiotics May also Affect Anti-PD1 Immunotherapy  

Interestingly, the MD Anderson’s findings complement those of the Gustave Roussy Cancer Campus, France2. Lung, kidney or bladder cancer patients who received antibiotics to treat infection shortly before or after starting anti-PD1 immunotherapy, did not respond as well to treatment. The presence of Akkermansia muciniphila bacteria in both humans and mice was linked to improved responses to anti- PD1 immunotherapy.

Modulation of the Gut Microbiome Could Improve Cancer Prognosis

Although these findings are early, they suggest the connection between the gut microbiome and immune system could have major implications for cancer treatment and prognosis. Further work is needed to analyse the diversity and composition of the gut microbiome to predict response to anti-PD1 immunotherapy; and to modulate the gut microbiome to enhance treatment.

Research has shown that the human microbiome may be modulated by diet, exercise, probiotic or antibiotic use or FMT – however these need to be carefully studied in clinical trials. 

On that note, the MD Anderson team is now planning a clinical trial using strategies to modulate the gut microbiome in patients with metastatic melanoma going onto anti-PD1 (in collaboration with the Parker Institute for Cancer Immunotherapy and Seres Therapeutics). The primary hypothesis of this trial will be that we can safely modulate the gut microbiome in metastatic melanoma patients going on to anti-PD1 therapy.

Tremendous promise but challenges ahead

These findings have important potential implications, though challenges are also evident.  Several issues have been raised by Dr Jennifer Wargo and Dr Vancehswaran Gopalakrishnan given these results.  “These findings have important implications, but we don’t know all the answers yet. Should we be profiling the gut microbiome of patients going onto immunotherapy? And should we tightly monitor antibiotic use in these patients? Furthermore, what other factors – including diet – may be influencing the microbiome? Should we also be profiling the gut microbiome in pre-clinical models where we are testing therapeutic strategies to fight cancer and other diseases? And finally, can we manipulate the microbiome to improve overall health and to facilitate cancer immunosurveillance?”

In addition to this, strategies such as FMT have their own inherent challenges. Although first documented in 4th century China as ‘yellow soup’; FMT has slowly gained popularity over the past years in the US for the treatment of inflammatory gastrointestinal disorders

FMT as a novel adjuvant cancer therapy could bring many rewards, though poses tough challenges. As a cutting-edge forefront therapy, FMT follows unique regulatory oversight. In May 2013, the FDA announced it would regulate FMT as an Investigational New Drug (IND) and Biologics. This classification restricted physicians to file an IND application to use FMT in a clinical trial. However, both patients and physicians raised concerns this would restrict patient access to FMT.

In June 2013, the FDA responded to these concerns and issued its Guidance for Industry: Enforcement Policy Regarding Investigational New Drug Requirements for Use of Fecal Microbiota for Transplantation to Treat Clostridium difficile Infection Not Responsive to Standard Therapies (http://fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Vaccines/ucm361379.htm).

Under this ruling, qualified physicians can perform FMT for recurrent C. dfficile not responding to standard treatment outside clinical trials without filing for an IND application.

FMT also has other challenges, given variation between preparations. Ultimately, the MD Anderson team and their collaborators hope to identify a live bacterial product incorporating consortia of bacteria implicated in enhancing immunity and therapeutic responses. Though challenges exist, given the potential far-reaching rewards, these efforts are clearly worth pursuing.

References:

  • Gopalakrishnan V. et al., Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science, 2017 Nov http://dx.doi.org/10.1126/science.aan4236
  • Routy B. et al., Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science, 2017 Nov http://dx.doi.org/10.1126/science.aan3706
  • Matson V. et al., The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science, 2018 Jan http://doi1126/science.aao3290

#microbiome #Arrowhead #cancer #melanoma   #PD-1 inhibitors #Gopalakrishnan #Wargo #MD Anderson Cancer Center #FMT #FDA #Seres Therapeutics #Parker Institute for Cancer Immunotherapy

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Key Innovations in Microbiome Therapeutics: Translating the Science into the Clinic

These microbiome insights brought to you by Dana Barberio, Principal at Edge BioScience Communications and Arrowhead Publishers and Conferences.

These are glamourous times for the microbiome space. The microbiome has captured the heart of the media, and this red hot scientific area has spawned intense attention from researchers, courtship by investors and a myriad of unique business opportunities and partnerships among companies ranging in size from small start-ups to global pharmaceutical companies. Multiple companies with therapeutics in clinical trials are jockeying for position in a heated race to market, many with their lead candidate targeting Clostridium difficile (C. diff), and with a wide variety of other applications in the queue. Key players in both the scientific and business side of the microbiome space will be gathered together at Arrowhead Publishers’ 3rd Annual Translational Microbiome Conference, taking place in Boston, Massachusetts April 11th-13th 2017. Let’s capture an eagle eye view of that conference by looking at recent advances in the microbiome space, and some of the key topics represented at the conference.


Scientists are rapidly discovering the microbiome’s sophisticated and widespread network of interactions that affect human metabolism, neurology, the immune system and skin. The microbiome plays a role in radically different areas of health, such as nutrition, early childhood, hygiene, infectious disease and chronic health conditions. There is evidence that dysbiosis in the gut is a factor in an astounding array of conditions and diseases: inflammatory bowel disease (IBD), atopy, asthma, cancer, obesity, Type 2 Diabetes, fatty liver disease, and neurological disorders.

Hot Areas of Scientific Research
While investors, companies and the media are currently having a love affair with the microbiome (I decline to call it ‘hype’), arguably the science has yet to live up to the expectations. But the scientific foundation is gradually being constructed and is forthcoming with many recent studies. A January 2017 small scale clinical study of Autism Spectrum Disorder provided evidence of improved ASD symptoms resulting from Microbiota Transfer Therapy. A Dec 2016 Caltech study in a mouse model of Parkinson’s disease established that gut bacteria not only contribute to the disease, but apparently play a causal role. There are future market opportunities for treatment of anxiety, depression, and autism that may evolve from an understanding of the science behind gut-brain interactions. Emeran Meyer, MD and professor at UCLA, discusses these topics in his book “The Mind-Gut Connection: How the Hidden Conversation Within Our Bodies Impacts Our Mood, Our Choices, and Our Overall Health.”


IBD has been linked for decades with dysbiosis in the gut microbiome, and more recently scientists have been gaining a deeper understanding. Laying a foundation for defining the mechanisms for this was a March 2014 study by Dirk Gevers of Janssen Human Microbiome Institute with a multi-cohort study comprehensively defining the microbiome diversity landscape of Crohn’s Disease and identification of potential biomarkers. A February 2017 study provided evidence that IBD can be distinguished as two subtypes with distinct microbial signatures, as Crohn’s Disease and Ulcerative Colitis. These microbiome signatures are critical in the development of therapeutic targets.


Another hot area is in the immunotherapy space: predicting patient response and modulating gut bacteria to optimize treatment. Research at MD Anderson Cancer Center in February of 2017 implicated gut bacteria in melanoma patients’ response to PD1 checkpoint inhibitor immunotherapy. Patients that responded to the immunotherapy had a greater diversity of gut bacteria and larger numbers of a specific bacteria than those who did not respond.


With a partnership that will translate microbiome research in immunotherapy into the commercial space, Bristol Myers-Squibb and Enterome entered into an immuno-oncology focused partnership in November of 2016 for the discovery and development of microbiome-derived drug targets and biomarkers to be used in cancer therapeutics and companion diagnostics.


We’ll hear more about these topics at the conference.

Areas with Great Market Potential
From a January 2017 review article by University of Chicago’s Jack Gilbert (conference keynote speaker) and Thomas Kuntz, a hot area in need of more research is in drug response and interaction, as there are already more than 60 drugs known to interact with the microbiome. Enhancement of personalized treatment in a clinical setting will involve a deeper understanding of bacteria’s role in drug metabolism and host variation to drug response, in particular as it corresponds to an individual’s microbiome (and host ‘omes’). For example, a March 2014 study found genes in the gut bacteria Eggerthella lenta that can be used as predictive microbial biomarkers for inactivation of the cardiac drug digoxin, with potential application in studying drug pharmacokinetics and clinical interventions.


Another area with large market potential according to Gilbert and Kuntz is in addressing alternatives to the widespread overuse of broad-spectrum antibiotics and the resulting health-endangering spread of bacterial resistance. One alternative involves targeting specific bacterial pathogens or enzymes with precision antibiotics and therapies. Multiple companies are focused in this area, including Eligo BioscienceSecond GenomeAvidBioticsC3J Therapeutics, and EpiBiome, all of whom have platforms which selectively kill off harmful bacteria while protecting commensal bacteria.


Of course, precision prebiotics and probiotics are another hot focus area, which may involve a systems biology/bioinformatics approach such as used by Seres TherapeuticsEvelo BioSciencesMetabiomics and others.

Empowering Deep Level Understanding with Big Data
If you consider the complexity of genomic and environmental factors such as lifestyle, diet, toxins, polypharmacy, metabolomics, and the gut microbiome, it’s clear that we need some high level bioinformatics to interpret the enormous amount of data for translation into the clinic.
Microbiome-based precision medicine will stem from a deep level understanding of the mechanisms involved in the complexities of host-microbiome interactions. The ultimate level of analysis may come through a systems biology paradigm, which uses mathematical/computational models to analyze large datasets and simulate system behavior with network-based analyses of the interactions between different types of ‘omics’ data (such as genomics, transcriptomics, proteomics and metabolomics), providing novel insight into complex biological systems, new biomarkers and enhanced drug discovery and development. For example, a March 2017 article proposes an ‘omics’-based precision medicine approach for elucidating genomic and metabolic interactions in the microbiome-gut-liver axis. These Big Data practices are expected to transform clinical practice.


Jack Gilbert, one of the keynote speakers at the conference, has a brand-new startup, Gusto, which produces formulations of probiotics. They use a computational modeling platform, GUST+, which predicts bacterial interactions and their effect on the immune system and human health by compiling data from human studies and running thousands of simulations.


One technical hurdle faced in the microbiome therapeutics space is in securing precise taxonomic assignments for bacteria based on sequence alignments, which is a computational challenge for both 16S and shotgun libraries, due to the short Next Gen Sequencing read lengths. This creates an obstacle for identification of reliable clinical biomarkers and hinders follow-up experiments. James White of Resphera BioSciences, at the conference, will discuss a novel approach for high-resolution microbiome profiling of 16S sequence data, which provides accurate species-level characterization.

Databases and Specimen Collection
In the case of Fecal Microbiota Transplantation, the rapid entry into clinical practice preceded the science. The FMT National Registry, a public-private collaboration, was established as a database of clinical and patient-reported outcomes intended to establish the short- and long-term safety and efficacy of FMT.
Another organization, The BioCollective, provides a resource for obtaining human fecal specimens paired with data for use in microbiome research and development, eliminating the need for researchers to recruit individuals for studies.

Frontrunners in Clinical Trials
As leaders in the field rapidly uncover the mechanisms driving the microbiome’s role in disease, the foundation is being established for capitalizing on the science in order to decrease disease and improve health. Farthest along in clinical trials is Rebiotix, with a drug candidate, RBX2660, for recurrent Clostridium difficile in Phase 3 trials. Their Microbiota Restoration Therapy (MRT) platform, which targets other diseases as well, delivers a broad spectrum of live microbes into a patient’s intestinal tract for rehabilitation of the microbiome.


At the conference, we will hear first-hand from a few of the companies in the trenches of clinical trials - Rebiotix, Seres Therapeutics and Vedanta Biosciences - on regulatory considerations, customer expectations, messaging implications, and other critical factors involved in developing and launching microbiome therapeutics.


Partnerships and Regulation
While the scientific and technical resources are critical, we will also hear about the equally critical business side - the role of partnerships as well as regulatory and patent issues.

Since probiotics have widespread acceptance by clinicians and the general population, microbiome therapeutics is at an enviable jumping off point for some microbiome companies. However, the FDA is of course involved in prescription products. The criteria for FDA approval involve defining bacterial colonization, what effect colonization has and how fast it occurs, and the pharmacokinetics/ pharmacodynamics, among other factors. This is for live bacteria. The addition of genetic manipulation adds another level of complexity in gaining approval.


Big Pharma has taken a huge interest in the microbiome space, with numerous partnerships. Among those leading the way was a partnership in 2014 between Second Genome and Pfizer, in which the two companies engaged in a large observational study with the goal of gaining a better understanding of the connection between obesity, metabolic disorders and the microbiome. Three major pharma investment funds have invested in Second Genome. Second Genome is partnering with Monsanto in applying big data science, bioinformatics and machine learning to drive discovery of microbiome-based solutions that can help farmers better manage on-farm challenges.


In 2015, Janssen and Vedanta Biosciences struck a deal involving Vedanta’s out-license of its most advanced clinical candidate VE202: a mix of bacteria from the Clostridia subspecies that are a potential treatment for several IBD disorders: Crohn’s disease and ulcerative colitis.


Most recently, in November of 2016, the aforementioned Bristol Meyers-Squibb and Enterome established an immuno-oncology focused partnership.


Join us to hear more on all of these topics and the many exciting opportunities and challenges in the microbiome space at Arrowhead Publishers’ 3rd Annual Translational Microbiome Conference. We will see you there!

 

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The Mike Rowe of the Microbiome Space

By Martha Carlin, Chief Executive Revolutionary, The BioCollective

In every industry there are dirty jobs that must be done to fuel the business.  Business Insider recently published “Small World: 20+ Startups Targeting the Microbiome” a review of just some of the exciting new microbiome ventures that are primarily focused in four key areas - diagnostics, genomics, dietary supplements, and intestinal health/disease targeted therapies.[1] These ventures use convenient and available samples for their initial R&D obtained from relationships with universities, hospitals and friends and family. When a promising discovery is made from that initial research, it may be necessary to test it on a larger and more representative population and this is where the The BioCollective comes in. 

Everybody poops.[2] But nobody wants to have to “deal with it.” One of the biggest barriers to accelerating microbiome research is getting a sample from everyone doing their duty! (or dooty depending on the age of your audience!) So we approached the problem from the Pooper’s perspective. We created a kit that is easy to use in the comfort of your home, ick-free and even a little bit fun. There is no scooping, probing, dipping or mixing needed. There are no messy plastic “hats,” bowls or containers to be disposed of. The process is seamless with nothing left behind, so to speak. Our BioCollector patent-pending design collects the entire sample, keeping it viable and ready to leverage into any number of research pipelines. Once the live sample reaches our lab, it is divided into smaller portions and cryopreserved enabling many types of research on the same sample. One sample can generate data from phage to fungi and culture. We are much more than DNA! 

Subject recruitment and sample collection is one of the top five cost drivers in research, but when we do the “dirty job” of providing samples to support microbiome research we can save thousands of dollars from the process. The BioCollective has made pooping a fun and profitable way to participate in microbiome research. We use engaging and innovative ways to get people of all ages and walks of life to become members of The BioCollective with the goal of building a microbiome resource full of samples that are actually representative of the US population. We go beyond the narrow and limited population of WEIRD (white, educated, industrialized, rich and democrat)!

In exchange for providing a sample to aid in research members receive a share of revenue from sample sales and feedback on where their sample is being used. We also provide the member with options for learning what’s in their gut from a basic 16S analysis to whole genome sequencing.  For the super curious, we can provide specialty analysis such as metabolomics, 18S and transcriptomics through our sequencing partners.  

Learn more about what we do and how you can become an active participant in the field of microbiome research at Arrowhead’s 3rd Annual Translational Microbiome Conference, being held April 12-13, 2017 in Boston, MA.

 

[1] https://www.cbinsights.com/blog/microbiome-startups-market-map-company-list/

[2] This is fact, and for an excellent read on this subject, may we suggest “Everyone Poops,” by Taro Gomi, https://www.amazon.com/Everyone-Turtleback-School-Library-Binding/dp/0613685725

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