Project of Study:


September 1997

Vladimir Mouraviev, M.D.
Senior urologist&research fellow of clinical hospital of Russian Academy of Sciences in Saint Petersburg, Russia

Introduction. Cryoablation of prostate cancer is not a new technique- it was introduced
over 30 years ago (1). It has now been reintroduced in the 1990's and is currently being
performed at approximately 100 centres in the USA (2). Future evaluations should help to
determine the most efficient methods for cryoablation of the prostate, and should also allow
appraisal of its long-term efficacy, in comparison with other therapeutic approaches (3).
Remarkable recent advances in our understanding of the immune system and the advent of
new immunostimulants, especially recombinant cytokines, now permit direct activation and
regulation (direction) of immune responses as well as ways of obtaining more long-lasting
immunity (4).
IL-1 is as main cytokine vital to the proliferation and maturation of whole immune cascade
Recent advances in the biology of cancer cell death might allow us to propose more adequate
explanations for the interactions of recombinant IL-1 with cryosurgery.
Methods. Many investigators (6,7) on the basis of the wide range of tissue effects that can
be attained by cryonecrosis, expressed great expectations for the cryoimmunologic (both a
specific humoral and a cellular immune response) augmentation of tumor destruction.
Moreover, in advanced-stage disease- where tumor heterogeneity confounds treatment by
conventional therapy and patients succumb to the direct effects of metastasis and
complications associated with treatment- cryoimmune response may additionally be
tumoricidal to metastases (4).
Cryoimmunisation may result in a response that may be tumoricidal as well as tumor
enhancing -
bidirectional (Figure 1). Primary tumor-antigen liberation lies not merely in augmentating
an antitumor response but in directing (modulating) the response toward that will be
tumoricidal. However further antigenic stimulation actually attenuates the immune response
by an intrictic biochemical feedback mechanism. This one decreases the T cell activity,
thereby self-regulating the production of interleukin-1 and other cytokines. This idea further
explains a prolongation of immune response. This a "booster" response was successfully
achieved by multiple freezing of the prostate at intervals of 30 days or more (8).
+ + + + + + + -
ice crystal formation microcirculation occlusion bidirectional immunological
- -
concomitant destruction
of immunocompetent cells
+ -
primary tumor-antigens liberation
+ + + + + + - -
+ + + +
Tumor destruction Local immunity Inflamation
- - - + injection of IL-
+ -
Secondary tumor-antigens absorption
+ + - + - + - + - + -
+ + + + + +
Augmentation of immune response
+ +
Tumoricidal effect
Intravenous injection of IL-1b + +
Fig.1. Pathways of stimulation (+) and suppression (-) of immune-mediated cryoablation,
modulating by local and systemic action of rec.IL-1b.
But these considerations may be prevented by precryosurgical intravenous using of rec. IL-1
with pleiotropic action. Our preliminary results of immunotherapy have shown the efficacy of
this modality in advanced prostate cancer (9). We have confirmed the preventive action of IL-1
to the whole cascade of humoral and cellular immunity to possible side-effects of
The regime of proposed immunotherapy may be as follow: IL-1-b (betaleukin), produced by
St.Petersburg Scientific-Investigative Institute of Special Biotechnological Agents, - in dose
5ng/kg intravenously daily during 5 days with 1-2 days interval of resting before
cryoablation . Based upon the changing immunostatus, may be repeating of this course at 1
month (minimum) after cryoablation.
Moreover, in an inflammatory response, such as that initiated by cryonecrosis, the target
tissue will be subjected to the action of not just only IL-1 but several cytokines as a result of
chain-reaction, that may act synergistically to promote one arm of the immune response
while inhibiting the other. Cytokines are pleiotropic and may function in autocrine, paracrine
and endocrine manner. Developing data suggest that locally produced cytokines may arouse
immunogenicity and facilitate cell-to-cell interactions and antigen presentation by inducing
or enhancing expression of select membrane proteins.
According to this hypothesa, we are proposing to inject IL-1b (up to 10 ng) into tumor also
followed 24 hours later by cryosurgery (Fig.1).
Expected results. Finally, from the bidirectional nature of the cryoimmune response exhibited,
evaluation and elucidation of the role of local and systemic cytokinotherapy before and after
cryosurgery and their possible regulation should prove most enlightening. This approach
permits us to improve the cryoablation efficiacy and inhibit the metastases growth in the
combinative treatment of advanced prostate cancer.
1. Gonder M.J., Soanes W.H., Schulmann S. Cryosurgical treatment of the prostate.
Invest.Urol.1966; 3:372.
2. Onik G.M. et al. Percutaneous transperineal prostate cryosurgery using transrectal
ultrasound guidance: animal model. Urology 1991; 37(3): 277-251.
3. Torp-Pedersen S. Cryoablation of the prostate. Internat.Conference on prostatic
carcinoma. Copenhagen 1995; 31-34.
4. Ablin R.J. An appreciation and realization of the concept of cryoimmunology.In:
Percutaneous prostate cryoablation.Quality Medical Publishing Inc. 1995, 136-154.
5. Kelso A. The enigma of cytokine redundancy. Immunol.Cell Biol. 1994;72:97-101.
6. Cooper I.S. Foreword. In Ablin R.J. Handbook of Cryosurgery. New York:Marcel Dekker,
7. Bradley P.F. Thermal surgery in the management of maxillofacial malignancy. Oral
Maxillofac Surg.Clin. N.Am. 5:331-346,1993.
8. Ablin R.J., Witebsky E., Jagodzinski R.V., Soanes W.A. Secondary immunologic response
as a consequence of the in situ freezing of rabbit male adnexal glands tissues of reproduction.
Exp.Med. Surg. 29:72-88,1971.
9. Symbircev A.S., Mouraviev V.B., Karelin M.I., Sygnaevsky M.A., Popovitch A.M.
Immunotherapy perspective in the treatment of advanced prostate cancer. In: Prostate Cancer
Symposium, St.Petersburg, 1-2 Nov.1996, p.21.