Clin Appl Immunol Rev, 2001, 1, 131

THERAPY OF INFECTIONS IN CANCER PATIENTS WITH BACTERIOPHAGES

B. Weber-Dąbrowska, M. Mulczyk, A. Górski.

L. Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences

53-114 Wrocław, Poland

Correspondence should be addressed to B.W.D.,
e-mail: secret@immuno.iitd.pan.wroc.pl

Abbreviations: BP - bacteriophage, cancer, infections.

ABSTRACT

Cancer patients are known to be immunocompromised and susceptible to infections. We have used bacteriophages matched for specific bacterial isolates to treat antibiotic-resistant infections in those patients. Cure of infection was achived in all cases indicating very highefficacy of BP therapy.

Bacteriophages (BP) belong to a group of viruses whose life cycle is connected exclusively with bacterial cells. So far over 4,000 phages affecting a large majority of bacteria have been described [1-3].

After a bacterial cell sensitive to a particular kind of phage is infected, the phage replicates, bringing about the total destruction (lysis) of the cell, and the new phage particles which are released attack and destroy other live bacterial cells. The process takes place both in vitro and in vivo. One of the very important features of phages is the high specificity of their lytic action. Phages affect one or several related species of bacteria; they do not affect antigenically unrelated bacteria.

BP therapy was initiated with some success in the second and third decade of this century, however, since the advent and widespread acceptance of antibiotics it has been little used in the West. In the recent years, however, bacterial resistance to antibiotics has becomea serious medical problem and a major threat to human wealth. Therefore, there is a renewed interest in using BP therapy as a possible alternative tor the treatment of bacterial infections[2, 4, 5, 6].

Since 1987 the specific BP have been used in our Institute for the treatmentof more than 1400 patients. The results obtained indicate that in cases of long persistent bacterial infections caused by drug-resistant bacteria of the genera Staphylococcus, Escherichia, Klebsiella, Enterobacter, Proteus and Pseudomonas that do not respond to antibiotics, BP therapy is highly effective and in large majority of cases the only successful and safe treatment. The overall cure rate across the spectrum of pathogens and side of infections is approximately85 %. BP therapy has proved to be most effective in purulent otitis media, purulent cerebro- spinal meningitis and furunculosis. BP have also proved highly effective in septicemia, infectionsofrespiratorytractandpurulentpostoperativeinfections [7]. Furthermore,our recent data suggest that aside from the well-known antibacterial activity BP can upregulate depressed immune responses when administered in patients with infections [8]. Interestingly, short incubation of human lymphocytes and monocytes with BP in vitro may induce intracytoplasmatic cytokine synthesis in lymphocytes and monocytes (Górski et al., unpublished observations). This phenomenon may explain our earlier observations indicating that patients who had undergone BP treatment may acquire increased resistance to subsequent bacterial and viral infections [7]. For those reasons, bacterial infections in immunocompromised cancer patients should be a special target for BP treatment. Our initial observations in that group seem tosubstantiate this hypothesis.

Crude BP preparation was obtained as described in details elsewhere [7]. Briefly, BP derived from our Institute’s BP banking facility were examined for their lytic activity against respective bacteria isolated and cultivated from infected patients. Selected BP were propagated in broth and subsequently used for treatment. The mean activity of the BP lysates used was 10⁸plaque forming units/ml. Purifications of BP was performed according to the method for purification of biological preparates using sepharose4B column. The final purification of BP, which allows to remove bacterial debris and medium components was performed by different ultracentrifugation steps.

BPtreatmentwasappliedin 20 cancer patients (age: 1 - 66 years,17 with solid tumors, 3 with hematological malignanciess, all with concurrent bacterial infections (Staphylococcus aureus (8 patients), Pseudomonas aeruginosa (9), Klebsiella pneumoniae (6), Klebsiella oxytoca (2), Escherichia coli (6). Those infections were homogenous (12 patients) and mixed (8 patients). All patients had previously been treated with antibiotics without apparenteffects.In allpatients, BP wereadministeredorally 3 timesdaily.Inaddition,in

8 patients local BP treatment was added to an oral protocol. The duration of the treatment varied between 2 and 9 weeks (median: 32 days). No side effects of the therapy were observed.

The results of BP therapy are depicted in Table 1. As may be seen, the cure of infection was achieved in all cases (cessation of suppuration, closure of wounds, eradication of pneumonia etc.).

Although our results are preliminary, they appear to be very promising, since BP therapy was found to be highly efficient in all patients in whom antibiotic therapy failed. Further studies are currently underway involving placebo-controlled designs to delineate optimal conditions and efficacy of the BP therapy.

In summary, we have demonstrated that BP can cure bacterial infections in cancer patients and probably upregulate immune response in those patients.

Centers porticipating in the BP therapy:

The Medical University of Wrocław (Departments of Dermatology (Dr Kaniowska), Maxillo-Facial Surgery (Dr H. Kaczkowski), Pediatrics (Dr Wróbel), Child Surgery (Dr Sawicz), Neurosurgery (Dr Gieroń), Low Silesian Oncology Center (Dr Hirowska), Marciniak Hospital (Dr Szewczak), County Hospital (Dr Wierzbowski), Babiński Hospital (Dr Kowalska), City Hospital, Brzeg Dolny (Dr Nowak), City Hospital, Pszczyna (Dr Bodnar), County Hospital, Jelenia Góra (Dr Dworski).

The BP treatment has been approved by Wrocław Medical University Ethical Commission for Studies Involving Human Subject.

This work was supported by grant4PO5B 012 18 from KBN (State Committee for Research).

REFERENCES

Bacteriophage Therapy in Cancer Patients
Number of cancer patients		20
Type of cancer	Solid tumors Hematological malignancy	17 3
Type of Infection	Post-operative Septicemia Skin Pneumonia Decubitus Post-X Meningitis	13 7 4 6 1 1 1
Route of BP administration	Oral Local	20 8
Result of Treatment	Good / ++ Very good / +++	17* 3**
*complete healing of the local lesions and termination of the suppurative process ** as above + general improvement

Figure 1. Shigella K II bacteriophage. Virions adsorbed on a fragment of a bacterial cell; a - cell fragment, d - collar,b - capsid without nucleic acid, e - contracted sheath, c - capsid filled with nucleic acid, f- core;(magn.: 290 000).