The fall and rise of phage therapy in modern medicine

KEYWORDS:

• Clinical trial
• inflammation
• immunomodulation
• phage
• phage therapy

1. Introduction: current developments in phage therapy

Recent reports of successful application of phage in the treatment of antibiotic-resistant bacterial infections have ignited the interest and hope in phage therapy. Unfortunately, promising data from experimental phage therapy in animals and encouraging data from observational studies performed in patients have not so far been followed by a successful clinical trial confirming the therapeutic value of phage therapy in accordance with the current standards of evidence-based medicine. Interestingly, data have been accumulating suggesting that phage have anti-inflammatory and immunomodulatory activity which could probably be translated into the development of novel therapies unrelated to anti-bacterial effects of phage.

In the past 5 years, the number of PubMed-covered articles on phage therapy (PT) has increased from 161 (years 2007–2011) to more than 600, while at the turn of our century (1997–2001) only 15 such articles have been published [1]. It seems that the last century was the century of phage discovery as well as the rise and fall of hopes for successful introduction of PT into the treatment of drug-resistant bacterial infections, while the chances are that the present century will finally allow for determination of how phage therapy can be applied in clinical medicine. Previously published reports of therapy safety also suggesting its efficacy in human clinical practice, many reports showing its efficacy in animal models of acute bacterial infections and especially recent reports of dramatic results achieved in patients with serious infections using intravenous (IV) phage therapy [2,3] seem to mitigate skepticism and contribute to the recent rise of interest in the therapy. The safety of phage therapy has also been suggested in patients up to 7 years after completion of PT [4]. We proposed that ‘our model of phage therapy applied as experimental treatment should continue to be implemented by other medical centers’ and suggested that ‘IV PT using purified phage preparations should be seriously considered’ [5]. The recent advances in the field of phage therapy follow this route. Moreover, the first use of genetically engineered phage converted from a temperate form to its lytic variety also indicates a significant step forward [3].

The pathway leading to eventual introduction of phage to human medicine is a very long story initiated more than a hundred years ago, yet thus far ‘not one therapeutic phage product has made it to the European market’ [1]. In contrast, other treatments whose therapeutic value had been confirmed in experimental animals found their human application much faster. For example, the first allogeneic human stem cell transplant was pioneered by E. Donall Thomas in 1957, then in 1969 a full clinical treatment program was initiated and he received a Nobel prize in 1990. One could therefore wonder why the pathway of phage therapy towards its clinical application is so protracted?

Some causes of this failure have been analyzed by many earlier reviews and include lack of adequate funding and inadequate regulations at the level of regulatory agencies addressing the specificity of phage as a medicine, uncertainty about intellectual property rights, poor knowledge of phage pharmacokinetics in humans, etc [6,7]. The situation is not improved by the fact that thus far almost no clinical trials have been completed according to the current requirements of evidence-based medicine to show the efficacy of PT.

2. ‘Phages cross the border to eukaryotes’

Recently, Nguyen et al. described a phenomenon of phage transcytosis used by phage to cross epithelial cell layers [8]. As many as 10^9 phages are transcytosed daily from the gut into other tissues forming the intrabody phageome contributing to human health and immunity. That indeed phages ‘can cross the border to eukaryotes’ was demonstrated earlier by Lehti et al. [9] Those data confirm and extend our hypothesis on the protective role of ‘endogenous’ phages (those present within the body – mainly in the gut – and migrating to blood, lymph and internal organs helping to protect the mammalian organism, not only from bacteria but also against immunopathological attack) [10]. Interestingly, phages isolated from the human gut can protect from an invasive bacteria-exacerbated colorectal cancer in mice [11]. On the other hand, it has been reported that some phages can induce IFN-gamma and thereby aggravate experimental colitis in mice [11]. In addition, some filamentous phages can exacerbate chronic lung infection by sequestering antibiotics and by triggering anti-viral immunity at the expense of anti-bacterial defenses [12]. Thus, it may well be that phages differ not only with regard to their specificity towards different strains of bacteria but also with regard to their effect on the immune system.

3. Phages and the immune system

As can be expected when administered in mammals, phages can induce humoral responses whose strength depends on the immune status of a recipient, phage type and route of phage administration. Interestingly, no clear association between neutralizing phage antibody production and clinical outcome of phage therapy has been found [13]. What is more, strong responses could be a good prognostic sign. Phage interactions with the immune system are bidirectional: phage activities (e.g. the circulation in the body and antibacterial activity) can be influenced by the immune system; on the other hand, the functions of the immune system can be affected by phages. At the termination of clinical phage therapy, modifications of immune functions in treated patients do not appear to be relevant for their clinical outcome. However, improvement in phagocytosis may also be a good prognostic sign [13]. Notably, the therapy may induce a significant drop in inflammatory markers (e.g. C reactive protein (CRP)). Interestingly, a marked decrease in CRP can also be noted in patients in whom eradication of infection had not been achieved, which suggests that anti-inflammatory and anti-bacterial activities of phages can be dissociated [5]. As bacterial titers decreased in at least some patients, CRP reduction could also be associated with reduction of bacterial burden.

Our data suggest that phages may modulate the function of the immune system contributing to the maintenance of immune homeostasis [14]. Those observations have been confirmed by other authors who also noted that various phages may mediate different effects [15,16]. Furthermore, while the prevailing phage effects seem to be anti-inflammatory and immunoprotective, some phages (e.g. filamentous phages) may also exacerbate an existing disease [12].

4. Expert opinion

As mentioned, the key dilemma in further advancement of clinical phage therapy is a widening gap between its results achieved in model organisms and humans. Therefore, the need for clinical trials resolving the issue of confirmed therapy effectiveness is increasingly apparent and urgent. In this regard, data derived from experimental therapy of human bacterial infections may be of significant value for conducting a successful trial [4]. Since funding for such trials is not readily available, governments should consider their involvement to help allocate funds to achieve that goal and supranational organizations (e.g. WHO, UN) could also be of help.

Of special interest are recent data from our and other groups pointing to the anti-inflammatory and immunomodulatory activities of phage as well as their potential in the treatment of non-bacterial infections [17]. While these data require further studies and elucidation of mechanisms used by phages to mediate such effects, those studies seem to open an entirely new pathway for phage therapy application in human medicine in the potential treatment of immune-mediated disorders. Thus, an approach of ‘drug repurposing’ which proved to be so useful in a variety of drugs (e.g. metformin) may also be applicable to phage therapy, which in the future may find also uses unrelated to its well-known antibacterial action [5].

Declaration of interest

A Gorski, R Międzybrodzki, J Borysowski, S Letkiewicz and B Weber-Dąbrowska are co-inventors of patents owned by the Institute and covering phage preparations. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This work was supported by statutory funds from the L. Hirszfeld Institute.