Microbes as Medicine: How our Microbiome Could Help Cure Cancer
The Human Microbiome: Part 3
Key Takeaways:
- Microbiome-based therapeutics (drugs) hold real promise for treating life-threatening conditions like cancer and neurological diseases.
- Specifically, researchers have found strong evidence indicating that the microbes in our guts determine whether cancer drugs called checkpoint will work. Currently, only 20–40% of cancer patients respond to these drugs. Several microbiome companies have started clinical trials in humans to improve outcomes for non-responding patients.
- The effectiveness of microbiome-based drugs in humans is still being established — to date, no microbiome-based therapeutics have received FDA approval. The path from exciting research results to an FDA-approved drug often takes 10+ years and many drug candidates fail along the way. (Note for investors: many startups are acquired or IPO after exciting early results from clinical trials, years before FDA approval.)
- The first microbiome-based therapeutics were developed to treat gastrointestinal diseases like irritable bowel disease (IBD), Chrohn’s disease, and C. Difficile Infections (CDIs). Some of these therapeutics have nearly completed clinical trials, and are expected to publish significant results this year.
- The growing amount of solid microbiome science, ever-expanding list of connected medical conditions, and opportunities to reduce human suffering with an entirely new medical toolset make this a promising area for investors (and everyone else!) to watch.
In our first post on the Human Microbiome, we explored how our health is intertwined with the trillions of microbes which also inhabit our bodies. Next we looked at how the falling cost of DNA sequencing and other technical advances spawned a massive wave of microbiome startups, many in the medical sector. What are these startups working on, and what has led investors to pour over $4.5B into microbiome-based diagnostics and therapeutics companies?
The short answer: curing disease. Recent findings suggest that microbiome-based therapies could significantly improve outcomes for cancer and other life-threatening diseases. Evidence also continues to mount that the microbiome can help correct chronic conditions spanning Crohn’s disease, infertility, autoimmune diseases and allergies. The potential benefits of using the microbiome to improve human health are staggering.
Here, we’ll focus on one specific example of how microbiome-based therapeutics could save lives: by making new cancer therapies called checkpoint inhibitors effective for more patients. This is just one example of how scientists, doctors and entrepreneurs are using our growing knowledge of the microbiome to create amazing new medical solutions.
Fighting Cancer with the Microbiome
One of the fastest-growing areas of microbiome research today is oncology — how can we beat cancer? In the past five years, scientific evidence suggests that our gut microbes both a) affect our susceptibility to certain cancers and b) can predict whether certain cancer treatments will work. The latter is specifically true for Immune Checkpoint Inhibitors (ICIs) [1], a relatively new type of immunotherapy drug for cancer. [2] Checkpoint inhibitor drugs (such as ipilimumab and Keytruda) are approved to treat lung cancer, melanoma, lymphoma and other common cancers; their approval and use has expanded rapidly since 2011.
Here’s how checkpoint inhibitors work: our immune system’s T-cells (the ones that attack bad guys) don’t attack healthy cells because “checkpoint” proteins on the healthy cells’ surface signal the T-cells to turn off. Some cancers can display their own checkpoint proteins to protect themselves from attack. The checkpoint inhibitor drugs work by blocking the checkpoint proteins on the tumor cell, allowing the T cells to kill cancer cells. (Short video here) Sadly, checkpoint inhibitor treatments only work for 20–40% of cancer patients. [3]
Between 2017 and 2018, multiple medical research groups reported strong evidence that the gut microbiome is connected to the effectiveness of checkpoint inhibitor treatments. [4] Patients who responded to checkpoint inhibitor immunotherapy had different distributions of microbes in their guts than patients for whom the treatment was ineffective. Moreover, when fecal matter from human responders was transplanted into mice with cancer, they also responded better to checkpoint inhibitor treatment (as judged by their tumors shrinking). [5]
These results have led perhaps a dozen microbiome companies to search for microbes (or molecules that the microbes make) that boost checkpoint inhibitor effectiveness. These companies are taking different approaches based on their areas of expertise and treatment platforms (see Table below). Seres Therapeutics is in clinical trials with processed stool from patients who responded to treatment. Vedanta and Persephone are using consortia (defined sets) of bacteria. Second Genome and Enterome are using small molecules identified from studying the microbiome rather than living bacteria.
Why these different approaches? What are the microbes in the responder’s guts doing that make checkpoint inhibitor drugs more or less effective? This question has yet to be definitively answered (at least publicly), but there are many possibilities. A gut bacteria might modify or consume the checkpoint inhibitor drug, either changing its effectiveness or removing it. Possibly, a group of bacteria work together or signal each other to interact with the drug. Or, some of the microbes may make other substances that interact with the drug in a negative or positive way. Our microbiomes are basically little bioreactors, making their own drugs all the time. There are 10–20 small molecules that our microbiome produces at drug-like concentrations in our guts. I may naturally have a much higher concentration of a chemical made by bacteria in my gut than a pill delivers.
From the Research Lab to Blockbuster Drug
The process of developing a new drug and bringing it through clinical trials to FDA-approval is notoriously long and expensive. Companies spend years performing preclinical studies in animals to identify the most promising drug candidate and build a case for the drug’s effectiveness. Then they submit an IND (“Investigational New Drug”) application to the Food and Drug Administration (FDA), describing their plan for human clinical trials. Once the FDA approves the IND application, enrolling the right patients can also be a significant challenge. In the best case scenario, experiments to prove the drug’s safety (Phase 1), effectiveness in humans (Phase 2), and improvement over existing therapies (Phase 3) generally take on the order of 6–7 years to complete. [6]
As expected in drug development, there have been (and will continue to be) failed clinical trials. Seres Therapeutics had a major clinical trial failure in summer 2016 for its first fecal transplant-based therapy for recurrent CDIs (and its stock price tanked as a result). Seres is currently completing a re-designed Phase 2 clinical trial.
Underscoring these long development timelines, no microbiome therapeutics have received FDA-approval yet. The first microbiome-based therapeutics to enter clinical trials targeted gastrointestinal diseases like C. difficile infections (CDIs), Irritable Bowel Disease (IBD) and Ulcerative Colitis (UC). Several microbiome startups developed drugs for these indications in the early 2010s and are still in clinical trials. As an example, Rebiotix began Phase 1 clinical trials of its lead drug for CDI in 2013 — this drug is now in Phase 3.
There is a light at the end of the tunnel however. The results of the Rebiotix study, and key clinical trials of microbiome-based drugs from Seres Therapeutics and Finch Therapeutics, are expected to be announced later this year. Moreover, startups don’t have to wait for FDA approval for an IPO or acquisition — as just one of many examples, Seres Therapeutics raised almost $140mm through an IPO back in 2015. More on this subject in our next microbiome post.
Applying similar learning curves and timelines to microbiome-based therapeutics for cancer, the first drug in this space is likely to receive FDA-approval in the 2026 to 2030 timeframe. Since there is no certainty that the handful of microbiome-based therapeutics currently in clinical trials will be successful, new candidates will continue to enter the pipeline.
Zooming Out: What This Means for Medicine
In this post, we dove into one example of how research on our microbiome is driving the development of new therapeutics. The international medical community identified a connection between the effectiveness of checkpoint inhibitor cancer drugs and the composition of the patient’s microbiome. Companies, including startups, began developing candidate drugs based on these results. The startups collaborate with medical centers and large pharma companies collaborate to bring candidate drugs through clinical trials.
Similar stories have been playing out across the medical landscape with microbiome-based therapies for other conditions. The “gut-brain axis” has become a hot topic in medicine — Researchers have found links between the composition of our microbiomes and autism, Parkinson’s Disease, and schizophrenia. [7] Microbiome therapies targeting neurodegenerative diseases are generally at an even earlier stage than those targeting cancer, and most of this development work is still done in mice. However, it is clear that innovations in microbiome research are creating a totally new field of potential tools to correct some of humanity’s toughest and least understood diseases.
While there is a justifiable amount of excitement that a microbiome based therapy could be the “next big thing” to treat scary diseases, we also have to acknowledge that we are still early in this process. We have a deeper understanding of the relationships between our different internal systems than ever before, but do we understand these relationships well enough to safely manipulate the guts of sick people? Or are we at a false summit?
Regardless, the field of microbiome-inspired medicine to only grow as we explore further. While conclusive evidence that a new microbiome-based cancer drug works in the clinic may be a few years down the road, microbes to treat C. difficile infections and other GI diseases may be just around the corner. As knowledge, experience and funding accumulates, we can expect growth to accelerate.
As many of us are probably dreaming of travel these days, let’s end with these words of wisdom from gastroenterologist Dr. Alessio Fasano:
“Your gut is not Las Vegas. What happens in the gut does not stay in the gut.”
… it might activate an immune system response that kills tumor cells in somewhere else in the body.
Notes
- The inventors of Immune Checkpoint Inhibitor therapy, James P. Allison and Tasuku Honjo, were awarded the Nobel Prize in Physiology and Medicine in 2018.
- Broadly, immunotherapy is a class of cancer treatment that engages your body’s own immune system to fight the cancer, vs methods that kill the cancer directly (chemotherapy, radiation, surgery). The two main types of immunotherapy cancer treatments used are immune checkpoint inhibitors and CAR-T (Chimeric Antigen Receptor T-cell) therapies — both were developed over the past ten years and are increasingly used to treat many types of cancer, though they are not yet as widely used as surgery, chemotherapy, or radiation therapy.
- A more comprehensive description of checkpoint inhibitor eligibility and effectiveness in US cancer patients can be found here.
- In 2018, research groups at MD Anderson, Gustave Roussy in France, and others published findings that checkpoint inhibitor effectiveness was correlated by certain bacteria in the gut. Here is a great review in Cell.
- A detailed summary on the studies showing the relationship between the microbiome and checkpoint inhibitor effectiveness in mice in humans can be found here: The Relationship Between Checkpoint Inhibitors and the Gut Microbiome and Its Application in Prostate Cancer
- A great article by Raphael Rottgen has more on drug development timelines and biotechnology company valuations.
- The microbiota-gut-brain is an incredibly interesting area of both science and early stage investment. For more information, it has its own Wikipedia page, or see this less technical review article in Nature.
Prime Movers Lab invests in breakthrough scientific startups founded by Prime Movers, the inventors who transform billions of lives. We invest in seed-stage companies reinventing energy, transportation, infrastructure, manufacturing, human augmentation and computing.
Sign up here if you are not already subscribed to our blog.
