Fighting TB with phage therapy

Treatment for TB is not trivial. Because the bacteria often adopt a dormant state in the body for at least some of the time, they are only periodically susceptible to antibiotics, which means that the drugs need to be given over an extended period of time; in some cases over more than 6 months.We also give a cocktail of drugs to gain rapid control over the infection, and reduce the risk of the patient developing an antibiotic-resistant infection. Nevertheless, we are seeing a significant increase in the prevalence of drug-resistant forms of TB, including those dubbed “extensively drug resistant”, which, unsurprisingly, can seriously limit therapeutic options.One glimmer of hope on the horizon is a technology that is actually older than antibiotics but enjoying a renaissance in recent years: phage therapy. This uses viruses that selectively attack bacteria but don’t touch human cells as a form of living antibiotic.Graham Hatfull, at the University of Pittsburgh, has been developing this line of treatment for bacteria that are in the same family (known as the mycobacteria) as human TB. He’s optimistic that phage therapy might give us a new weapon to fight TB too, as he explains to Chris Smith…

Graham - We were contacted first at the very end of 2017 by physicians treating a couple of patients in London that had infections with an organism called Mycobacterium abscessus. They had both had lung transplants and were taking immunosuppressive drugs in order to support the new lungs and got these disseminated infections. We were sent the strains to screen to see if we had any phages which would specifically infect those bacteria and after much screening we assembled a cocktail of three phages that were then administered intravenously with some evident clinical benefits, which we were pleased to see. Since then, we've had many, many inquiries as to whether we could do something similar for other patients because this is a fairly common scenario and I think that we've now treated or provided phages for treatment of about 40 patients in total.

Chris - And are they all doing well? Does it reliably work?

Graham - It's mixed. So we've published a report where we summarised the first 20 cases. Of those 20, 5 I can't really tell because other events happened. We can't really tell one way or the other. In 4 cases, patients did not obviously benefit, but in 11 we saw favourable clinical or microbiological outcomes, which we took as being promising, especially given that this was a cohort of patients who were extremely sick and literally have no other options.

Chris - And the infections that these patients had, were they what we would all call human TB or were they all members of the same family, but not specifically human TB organisms?

Graham - None of these cases are specifically human tuberculosis, but they do span a variety of closely related pathogens. Mycobacterium abscessus was the most common. There was one case of mycobacterium avian, and there was one case, which is the most closely related or relevant to tuberculosis, which was in an infection with actually a vaccine strain known as BCG.

Chris - And would you argue then that what you take away from the 40 people or so that you've managed so far with this approach, that that could now be applied to human TB?

Graham - For tuberculosis itself we're encouraged that there's very little variation amongst clinical isolates. And by doing extensive screening, we think we essentially have three to five phages that could be used as a cocktail and could be used essentially for all patients that have tuberculosis infection with mycobacterium tuberculosis.

Chris - And in practical terms then, how is this actually going to work and is it scalable?

Graham - The first decision that has to be made is what the root of administration is. For most of the cases that we've provided phages for treatment to date, they've all been by IV injection typically twice a day, but for extended periods of times - weeks or many months. So the idea with the intravenous administration is that the phages will get into the bloodstream, will find their way to the site of the infection and replicate on the bacteria killing the bacteria as they do.

克里斯-这是一个长时间,不是吗,give these infusions if it does take months. Presumably this would be for a subset of patients, those that we can't manage with antibiotics.

Graham - So first of all, I think that at least early on, we would not want to rely on a long term therapeutic application with phages as a substitute for antibiotics. I would envisage them more likely being used in conjunction with antibiotics, which would at least have the prospects of shortening treatment and maybe helping to reduce the incidence of resistance to the antibiotics, which is clearly a major concern.

Chris - And what about resistance against the phage?

Graham - Great question. And we would anticipate resistance against the phages just as you see resistance against antibiotics. Our experience, however, with the treatment of these other types of infections that I mentioned, where we do have expertise is in treating some of these other infections and 11 patients, we've administered just a single phage. In those 11 cases, we've never seen any incidents of resistance. And in fact, if we look in the laboratory and we just challenge the bacteria with the phage and we ask, "How often does resistance occur?" it appears to occur at a very low frequency. So although resistance is a concern, our experiences suggest it may not be as big an impediment as we thought it might. However, we always are wary of it and try to adopt a strategy that if we have more than one phage that we can use in a cocktail, then that's going to greatly lower the occurrence of any resistance.

Chris - Do you have any feel for what happens with respect to dormant bacteria, which is ostensibly a big problem with TB; people catch it and may wall it off in their bodies in a viable but dormant state for an extended period of time. Can your phages get at those? Are they like the Heineken equivalent that refreshes parts that other beers can't reach? Can they get to these dormant bacteria and wipe them out?

Graham - Yeah, that's a great question. And of course, we don't know, but we would love to learn and find out about that. Our view would be that although we don't have good data on that, we are really optimistic about what the possibilities and the options are. Just imagine if you could take your bacteria phages and genetically modify them so that they are decorated with signalling molecules or small peptides that would target the phages very specifically to where the sites of those bacteria are. And so maybe we could actually design phages so they would specifically go after those guys that hide away in those parts that other beers cannot reach.