The trillions of bacteria that live in our guts, and on our skin, also hide out in a strange place – the microenvironment around tumors. One of biotech’s daring early-stage venture capital outfits, well aware of the surge in microbiome research, is committing $35 million to get some answers to a basic question.
Can microbes be made into cancer drugs?
Cambridge, Mass.-based Flagship Ventures, which raised $537 million for a new fund in March, said it has committed $35 million to a new cancer drug developer called Evelo Therapeutics. Flagship, as some will recall, is quite familiar with the microbiome. It was the biggest investor in Cambridge, Mass.-based Seres Therapeutics, a company seeking to turn microbiome research learnings into useful new drugs for infectious diseases.
No other company in biotech really hangs its hat on the “microbiome-meets-cancer” concept, but the idea isn’t new. More than 100 years ago, New York physician William Coley famously injected live bacterial strains directly into tumors of live patients, and was excited to see a few anecdotal success stories. Unfortunately, the results couldn’t be consistently applied, and Coley’s dream of provoking an immune reaction against tumors never materialized in his lifetime.
Today, scientists can learn more in a day about the microbiome than they could imagine in Coley’s era. Cheap, fast DNA sequencing machines have enabled all kinds of new questions to be answered, and led to emerging insights about the microbiome’s interplay with the immune system, the endocrine system, and even our central nervous system. Recent research has shown links between our microbial state and our moods.
Simba Gill, a veteran biotech entrepreneur who’s worked before on big-idea applications for gene therapy and stem cells, said he was drawn to Evelo because of the considerable work that Flagship did in-house the past couple of years to apply microbiome learnings to cancer. None of the work has been published in peer-reviewed literature.
The first key observation that caught the imagination, Gill said, is that microbes are present in the microenvironments of all tumors—solid tumors and blood cancers. Second, he said, there’s reason to believe that the microbes can be activated in a way that complements some of the exciting immunotherapies on the market, and ones still in R&D.
Whenever you’re talking about trillions of bugs, you’re dealing with a complex system, which means a drug that seeks to interact here could be working many different ways – some imagined, some not. Scientists at Evelo believe that microbial-based drugs, injected into tumors, could work by further stimulating the immune system to direct its firepower against the tumor—much like Coley thought a century ago. The bugs, by their nature, are also high-metabolism creatures, and they compete for sugars and nutrients. That may alter the hyperactive metabolic pathways that allow tumors to mobilize excessive energy and nutrients for their cause. Another idea is that the microbes could help break down the stroma—the rugged lattice of connective tissues that act like physical barricades around tumors, keeping powerful killer immune cells at bay. Certain types of bacteria might even have direct tumor-killing capability, or might be used to deliver tumor-killing payloads, Gill said.
Like Seres, Evelo imagines a way of putting purified, highly-selected bacterial strains into a consistent pharmaceutical-grade package. The microbe-based drug could be injected straight into the tumor, or delivered systemically, through the bloodstream, Gill said.
While cheap, effective DNA sequencing makes it possible to identify ideal bacterial strains for such a task, doing the work isn’t going to be easy. Evelo is setting up careful processes for getting tumor samples to study them for their microbial properties. Tumor samples tend to come in small quantities, and they are a scarce and precious resource, especially as many research teams have different ideas on how to study them. Standard DNA sequencing protocols of tumors also call for getting rid of bacteria, not preserving it, before a sequencing run. Plus, tumor samples don’t exactly arrive in the lab teeming with the exact live bacteria that act in real-time inside the cancer patient. Isolating the bacteria, as Gill says, is “non-trivial.” They evolve quickly. Bacteria that are present at one stage of cancer may not be there at a later stage, or may be replaced by something else. Handling of the samples is critical, as any technician who touches a sample along the way could be introducing some different and unwanted bugs. Partly because of the sheer difficulty of studying microbes in tumors, academic research on the role of the microbiome in cancer hasn’t shed much light.
“There’s confusing and conflicting data from many groups,” Gill said.
Evelo, a Latin derivation of “disrupt,” isn’t saying much about its technology, but it depends on building consistent processes around sample collection and sequencing. The company has academic collaborations, but isn’t ready to identify them, Gill said. There is no broad venture syndicate to share the risk and reward. The board is a very tightly interlocked crew—Noubar Afeyan and David Berry of Flagship; Seres Therapeutics CEO Roger Pomerantz; and Gill. Evelo plans to spend its money on advancing multiple drug candidates in preclinical development, while simultaneously building and refining its technology platform—the thing that could yield more products in the future. When asked how far the Evelo research advanced in house at Flagship, and how close it is to clinical trials, Gill wouldn’t give a firm timeline, other than to say “as soon as possible.”
Cancer drugmakers just a few years ago didn’t embark on strategies like this. Mostly, they imagined developing their drugs for single genetic abnormalities, and usually as single new targeted agents. From the start, Evelo wants to develop its drugs in combination therapies. The notion is that a microbial therapy could be given alongside a checkpoint inhibitor antibody like
Interestingly, while decades of biology have been devoted to a reductionist quest to drill ever deeper into mechanics of genes and cells, with a focus on minimizing variables and zeroing in on a single thing that might be awry, Evelo is taking an opposite tack. A microbial community introduced in the form of a pill introduces many variables, rather than limits them. Essentially, the scientists need to embrace the fact that they won’t immediately understand the complexity of what’s going on if a drug of this nature is failing, or why it’s working if it’s working. “We’re looking for a different type of biological response,” Gill said.
