By Deborah Borfitz 

February 11, 2020 | At least three different types of phage products currently exist, and all of them are being explored as potential therapeutic remedies for people with drug-resistant bacterial infections. These include natural phages that have not been modified at all, as well as genetically engineered phages where one or more of their genes get modified to optimize their killing potential against a pathogen, says Steffanie Strathdee, Ph.D., associate dean of global health sciences and professor of medicine at the University of California, San Diego (UCSD) as well as co-director of its Center for Innovative Phage Applications and Therapeutics (IPATH). 

A few biotechs are also developing synthetic phage that is entirely manmade, for example using metagenomics to piece together little bits of DNA, Strathdee adds. This could be a solution for patients without any other phage options. 

Yale University is home to a large library of natural phages that target antibiotic-resistant bacteria, notably Pseudomonas aeruginosa—a frequent cause of nosocomial infections such as pneumonia, urinary tract infections and bacteremia. “I am not a very good engineer and feel nature can do better than I could do,” says Benjamin Chan, Ph.D., associate research scientist in the department of ecology and evolutionary biology, who maintains the library. 

An enlarging natural phage library at the University of Pittsburgh (17,630 phages, at last count, most active against the Mycobacterium genus) was only recently tapped for the first time to successfully treat a 15-year-old cystic fibrosis (CF) patient infected with M. abscessus, as reported (DOI: 10.1038/s41591-019-0437-z) in Nature Medicine. Since then, the library has been utilized for another half dozen patients—none of which have exhibited as dramatic of an improvement as the first case, reports Graham Hatfull, Howard Hughes Medical Institute professor whose students crowdsourced the viruses as part of an undergraduate research course. 

“It’s important to understand that patients who meet the criteria for doing this are really sick,” says Hatfull. “In some instances, we’ve had indications that the treatment was... killing the bacteria, but the patients died anyway because they had a lot of other [clinical issues] going on."

At least two biotechs are working on synthetic phages—U.S.-based Armata Pharmaceuticals, created by the merger of AmpliPhi Biosciences and C3J Therapeutics, and Canada-based Cytophage Technologies that traditionally worked on phage products for agricultural uses but is now interested in their human health applications. 

IPATH, the world leader when it comes to clinical experience with intravenous phage applications, has worked with almost solely with natural phages, the exception being the engineered page product that Hatfull’s lab developed to treat the CF patient in the UK, says Strathdee. Her counterpart at IPATH, Robert “Chip” Schooley, M.D., is also about to launch a phage therapy clinical trial, funded by the National Institutes of Health, in collaboration with the Antibiotic Resistance Leadership Group to treat antibiotic-resistant P. aeruginosa infections among people with CF who are exposed to a lot of antibiotics because of their inability to clear mucus from their lungs. 

The trial will look at the pharmacokinetics and pharmacodynamics of phages and provide direction on the best dosing for individual patients, says Schooley. Strathdee's husband, Tom Patterson, Ph.D., as well as the 15-year-old CF patient from the UK, were both successfully treated via an injection of about a billion phages per dose.  

Overdosing with phage is thought to be safe, since about 30 billion phages move in and out of the human body every day, Strathdee explains. But the practice isn’t sustainable from a cost-efficiency standpoint and, although IPATH has yet to see any adverse events, it is theoretically possible. 

“We want to be able to tailor [phage] dosing… and also the route of administration,” she says, noting that phage can cross into organs and reach the lungs or the brain. For some people with CF, for instance, it may make more sense to administer phage through a nebulizer than intravenously. 

“We don’t believe that phage will ever entirely replace antibiotics,” says Strathdee, “and we will likely continue to co-administer them. In some cases, our team and Yale’s has found that phage-antibiotic synergy can re-sensitize bacteria to an antibiotic it was previously resistant to. “More studies are needed to figure out which combination of phage and antibiotics will optimize the synergy.” In some cases, phage can be antagonistic and render the antibiotic less effective. 

“At IPATH, we feel this is the kind of translational research we need to do before we embark on large clinical trials,” she says. “If we don’t answer some of these basic questions first… we could end up hurting the field, which has had a lot of setbacks from the beginning.” 

Microscopic Arms Race 

Strathdee is likewise encouraged by research underway at the lab of Joseph Bondy-Denomy, Ph.D., assistant professor in the department of microbiology and immunology at UCSF. As was recently published (DOI: 10.1038/s41586-019-1786-y) in Nature, researchers discovered two jumbo phages that construct a “safe room” inside their host to protect themselves from CRISPR-fortified bacteria. The next step is finding a way to break in. 

Phages and bacteria have been in an “invisible arms race” for four billion years, she says. “If we can stay ahead of the game and anticipate how resistance occurs, then we can develop smarter therapeutics.” 

In another recent study, published in PLOS Computational Biology, researchers discovered phages can induce “regime shifts” within microbial communities, which a machine learning model could possibly simulate before introducing a phage with its benign host to suppress or eliminate the detrimental bacteria. It was a good reminder that microbial ecosystems are comprised of more than just bacteria and that removing the bad actors will require an understanding of population dynamics among all the resident organisms, including phage, archaea and fungi, says Strathdee. 

“If we can model and predict how these communities will change in the presence of a new type of phage, a new bacterium or antibiotic, or a combination, then machine learning could play a role in choosing which phages go best together in a cocktail,” she says. “That’s something Adaptive Phage Therapeutics [APT] is banking on as well.” 

As published elsewhere, researchers have been investigating the possibility of enhancing the antibacterial activity of phages to fight late-stage sepsis (DOI: 10.1038/s41565-019-0600-1) and supercharging them to stave off pneumonia by deleting a clock gene. It may be possible to trigger phage production, and a healthy gut microbiota, simply by eating the right combination of foods and herbs. Gold nanorods have also been used to turn phage into a guided missile of targeted therapy against pathogens. 

An article recently published in Nature (DOT: 10.1038/s41586-019-1742-x) describes how researchers precisely edited the gut microbiota of mice with phages to eliminate a bacterial toxin secreted by Enterococcus faecalis that worsens clinical outcomes in patients with alcoholic liver disease. The next step is to “find as many toxin-producing strains from as many patients as possible to create a biobank for these phages,” says co-author and IPATH researcher Bernd Schnabl, M.D., professor of medicine and gastroenterology at the UCSD School of Medicine and director of the San Diego Digestive Diseases Research Center. 

Once about 100 have been identified, Schnabl and his colleagues hope to proceed with a phase I safety trial to match the bacterial isolates of patients infected with cytolytic E. faecalis to phages in the library that will selectively kill them. 

Initial Trials 

In the first clinical trial cleared by the U.S. Food and Drug Administration (FDA), biotech company Intralytix is looking at the potential of phages to treat inflammatory bowel disease by editing the microbiome of bad bacteria. The investigation is being led by researchers at Mt. Sinai and focuses on phages that target Escherichia coli, a strain of bacteria regularly found in the mucosa of patients with Crohn's disease. 

The discovery and popularity of phage therapy in the former Soviet Union has created a “geopolitical bias” against its use here in the U.S., Strathdee says, but the FDA has been a positive, countering influence. She credits the agency for putting Schooley in touch with the Navy when Patterson was undergoing his last-ditch treatment, as well as holding an on-the-fly emergency meeting where an Emergency Investigational New Drug (EIND) application was approved for a single phage cocktail rather than multiple ones for each of the individual phages. 

Companies like APT are now trying to get FDA approval for their entire phage bank so any combination of the phages within a library could be used therapeutically without having to pause treatment to apply for a new EIND, says Strathdee. 

“EIND cases will not be necessary after regular approval,” confirms Greg Merril, CEO and co-founder of APT. Its enlarging PhageBank is comprised of “polymicrobial broad spectrum therapeutics… personalized based on each patient’s infection.” 

As it is, the FDA can generally approve an EIND application within a day or two, says Strathdee. But some patients only have hours. 

IPATH has provided guidance to phage therapy centers in multiple other countries—including Canada, South Korea, Germany and Brussels—all with different regulatory pathways, Strathdee says. Acceptance of the treatment approach in some countries has been notably tepid because the treating physician is held responsible if anything goes wrong.