Immunotherapy is unquestionably one of the great hopes for the cancer community. The Nobel Prize–winning breakthrough is based on the premise that the immune system can be leveraged to attack cancer cells. But despite this immense promise, immunotherapy has faced a persistent stumbling block. Immunotherapy treatments fail many patients—sometimes up to 80%.
Although a decade has passed since the first immunotherapy for cancer was approved, the reason for such mixed responses is still not well understood. Now that a variety of efforts are underway to account for the disappointing response rates, some scientists and several new companies are hoping that harnessing the microbiome will push the rates upward.
Roughly five years ago, scientists started presenting data on a connection between the microbiome and immunotherapy. At the National Cancer Research Institute (NCRI) Cancer Conference in 2016, Jennifer A. Wargo, MD, a researcher at the MD Anderson Cancer Center, presented a talk entitled, “Understanding responses to cancer therapy: The tissue is the issue, but the scoop is in the poop.” Her findings showed that patients whose cancer responded to immunotherapy treatment had greater diversity in the types of bacteria found in their gut.
Combining microbiome adjustment and immunotherapy has generated results that are sometimes met with skepticism, despite the approach’s logical premise. Immunotherapy activates the immune system to attack cancer cells. Bacteria also activate the immune system. So, if a particular subset of bacteria, or their byproducts, can be harnessed to augment the work done by the immunotherapy, the signal could be increased and the tumor reduced.
Research in this area has continued over the past five years, and a recent spate of high-profile academic papers has helped dispel doubts over some of the original findings. For example, in January 2018, Science published back-to-back papers presenting results on how gut bacteria affect patient responses to cancer immunotherapy.
Early this year, another set of back-to-back papers, which also appeared in Science, presented data from the first-in-human clinical trials to test whether fecal microbiome transplantation (FMT) affects how metastatic melanoma patients respond to anti–PD-1 immunotherapy. Indeed, the papers indicated that 20% of patients derived some benefit from treatment with microbes.
“We needed this clinical proof of concept in our space,” asserts Stephanie Culler, PhD, CEO of Persephone Biosciences, who was not involved with the study, “to drive the development of these therapeutics.” Restoring health to the microbiome had a clear impact on converting nonresponders, who had run out of therapeutic options, to responders.
The result of the FMT study is a “big black box,” says Bernat Olle, PhD, CEO of Vedanta Biosciences, “because we have no idea how it happened.” However, the fact that there is a signal in such a recalcitrant population, he maintains, indicates that there “may be something in there [that is] worth exploring.” There is, he continues, “reason for hope.”
The microbiome field has gone through multiple phases, notes Aoife Brennan, MB, MRCPI, CEO of Synlogic. In the first phase, we began to find associations between patient conditions and microbiome compositions. In the second phase, we began to find cause-and-effect relationships. (FMT studies helped illustrate the microbiome’s ability to cause particular disease stages or outcomes.) In the third phase, we began to find mechanisms.
The papers being published now are mechanistically based and deconvolute what various bacterial strains, and their byproducts, are doing. It is this work, Brennan emphasizes, that Synlogic is using to build its drugs.
Straight to the source
The scientists at Synlogic were not the first to have the idea of injecting bacteria directly into tumors. In fact, a young physician named William Coley had tried this previously—in 1891. Coley, whose work marked the beginning of immunotherapeutics, made important observations while injecting live bacteria into patients’ tumors. The continued loss of patients to sepsis—long before the advent of antibiotics—pushed him to create a toxin (known as Coley’s toxin) composed of a heat-killed mixture of bacteria. It turns out that Coley achieved a 30% response rate in the patients he injected—a percentage that would excite many in the field of cancer treatment today.
Synthetic biology has allowed a more modern version of attenuation. Synlogic’s drugs are all based on an Escherichia coli chassis which can be engineered to contain (or lose) genes of the company’s choosing.
In the case of Synlogic’s immunotherapy drug, named SYNB1891 (in honor of William Coley), a dacA (diadenylate cyclase) gene from Listeria monocytogenes was imported into Synlogic’s nonpathogenic E. coli chassis. The engineered strain produces cyclic di-AMP (CDA), which activates the STimulator of INterferon Genes (STING) pathway. The bacteria initiate an antitumor immune response via activation of antigen-presenting cells and presentation of tumor antigens.
Having shown effectiveness in mice, SYNB1891 is currently in a clinical trial (NCT04167137, announced in January 2020) in patients with advanced solid tumors or lymphoma. The drug is being tested both as a monotherapy and in combination with a checkpoint inhibitor, atezolizumab (Tecentriq), in collaboration with Roche.
Why did Synlogic decide to inject bacteria straight into the tumor, rather than administer an oral drug that would colonize the gut? Brennan says that both Coley and the work done in the field of viral oncolytics, which injects intratumorally, had set a precedent. She adds that if Synlogic chose the oral route, the company would have needed to understand the mechanism underlying the association between the microbiome profile and sensitivity to checkpoint inhibitors. Without knowing what the bacteria are doing and how they are having an impact, going straight into the tumor was Synlogic’s best bet.
Interestingly, tumors have a microbiome of their own. Until a few years ago, the presence of bacteria in tumors was not widely accepted. Bacteria were thought to be contaminants. In the past year or two, Brennan says, “the space has matured,” in large part due to definitive studies that carefully control for contamination.
Although the presence of bacteria in tumors is becoming less controversial, the question remains: What are they doing there? A hint came from a Nature paper published in March 2021 showing that peptides derived from bacteria in the tumor are not only presented by the tumor cells, but also elicit an immune response, clarifying the connection between immunotherapy and the gut microbiome.
It’s never as simple as it looks
If you were to ask a large enough group of people about the prospect of using bacteria as a cancer treatment, you would, Olle asserts, “find some believers like me and … people that have some healthy skepticism.” Both groups have reasonable cases, he adds, because “it’s early days.” The microbiome is a new field, and cancer is an unrelenting opponent.
Vedanta and Synlogic are pursuing the same goal—using bacteria to harness the immune system to fight cancer—by different means. Synlogic’s bacteria are engineered whereas Vedanta’s are in their natural form. Synlogic uses a single bacterium whereas Vedanta relies on a group approach. Synlogic goes straight into the tumor whereas Vedanta wants its bacteria to colonize the gut for as long as possible.
Vedanta’s approach is to make drugs that are based on a defined consortium of bacteria. The drugs start from pure cell lines that the scientists grow by monoculture, synthetically via fermentation, to obtain a product that always has the exact same composition, eliminating sources of variability.
The bacteria that make up Vedanta’s immunotherapy drug VE800 are selected, Olle explains, to do “what we think will be important to combat the disease.” That last sentence, he emphasizes, is very important. “If the selection criteria we’ve created are correct, then you may have a good drug,” he continues. “But if you don’t choose the right selection criteria, then you may need to start over and try again.”
Vedanta’s hypothesis is based largely on the discovery of Kenya Honda, MD, PhD, team leader at the RIKEN Center for Integrative Medical Sciences in Tokyo and one of the company’s scientific co-founders. Honda showed that the accumulation of cytotoxic CD8+ T cells in the intestine is dependent on the microbiota.
In January 2019, Vedanta scientists and their colleagues published an article in
Nature (“A defined commensal consortium elicits CD8+ T cells and anti-cancer immunity”) that described how the company generates VE800. A consortium of 11 bacterial strains capable of inducing interferon-γ-producing CD8+ T cells in the intestine is assembled, strains that were selected from those found in human donor feces. The article also reported that the 11-strain mixture enhances the therapeutic efficacy of immune checkpoint inhibitors in tumor mouse models.
Vedanta’s trial, which has enrolled 54 patients since December 2019, includes patients with cancers that have not previously responded to other drugs. The patients take Vedanta’s VE800 every day on top of the typical monthly infusion of the checkpoint inhibitor nivolumab from Bristol-Myers Squibb.
Why develop a drug that incorporates 11 strains of bacteria when other companies are focusing on metabolites? What Vedanta has seen, Olle notes, is that it’s very difficult to capture the pleiotropic effects that result from microbiome changes if you try to “boil the ocean down to just a few metabolites.”
“There are, of course, people who would disagree with our decision to use the bacteria as a drug versus giving the metabolites,” Olle says. “But I think they’re wrong.”
Band of heroes
Persephone Biosciences CEO Stephanie Culler, PhD, may be one of Olle’s skeptics. Persephone’s goal is much the same—to enhance responses to immunotherapy using the microbiome. But the company’s approach is to restore the functions, or metabolic pathways, of the bacteria that are commonly missing in nonresponders—not the bacteria themselves. To determine which pathways to restore, Persephone initiated the ARGONAUT study, the largest study ever conducted in the United States to map the cancer gut microbiome–immune axis.
Launched five months ago, the study will enroll 4,000 advanced-stage cancer patients of diverse racial backgrounds (with a patient population of 50% ethnic and racial minorities) and 1,000 healthy controls, and it will profile four types of solid tumor cancers. The goal of the multiyear, longitudinal study is to create a large-scale, real-world database that will be used to determine mechanisms underlying the microbiome connections to immunotherapy. By feeding these diverse microbiomes into machine learning models, Culler hopes that the models will hone the information into a small solution space that will allow for the development of one therapeutic for multiple cancers that will be applicable for different patient demographics.
Early data suggest that the microbial damage in the patients who do not respond to treatment is both treatment and indication agnostic. These data encourage Culler to think that one therapeutic may work for different indications or people. She hopes that by early 2023, Persephone will have created the “Keytruda of the microbiome”—a microbiome-based therapeutic that incorporates a few engineered, microbes that can benefit many cancer patients.
The ARGONAUT study takes stool from patients to map their gut microbiomes, and blood to map their immune systems. Culler tells GEN that Persephone is trying to understand not only which bacteria are there, but what they are doing. In addition to sequencing the stool samples, Persephone gathers information on metabolites to begin uncovering function. It is the suite of multiomics analyses, notes Culler, that will yield mechanistic information.
When Culler started Persephone in the summer of 2017, she was met with considerable skepticism. But over the past two years, the tone has become more optimistic. She attributes this to the growing academic literature and the support of pharma companies that are investing in and/or collaborating with microbiome companies. She declares that the tide is changing.
The name of the trial, ARGONAUT, was chosen by Culler and her colleagues at Persephone to evoke the exploits of Jason and the Argonauts. Like Jason’s quest for the Golden Fleece, the quest for microbiome-augmented cancer immunotherapy has its heroes. As far as the team at Persephone is concerned, ARGONAUT’s heroes include every trial participant—every patient, clinician, caregiver, patient advocate, and scientist.