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Basic Concepts and Future Use of Cryoimmunology:
A Brief Commentary

Richard J. Ablin.

Innapharma, Inc., Park Ridge, NJ 07656 USA.
In addition to the physical and vascular effects of cryodestruction, a major, but little recognized property of cryosurgery is that, as a consequence of freezing, a cryoimmune response may occur. Characterized by local and systemic immunity and associated cytokines, the immunogenicity of the cryolesion and, therefore, the intensity of the immune response is related to the freezing regimen, manner of cell death, i.e., apoptosis vs. necrosis, and balance between pro- and anti-inflammatory cytokines. Likened in many respects to an autoimmune response and associated immunopathology, the systemic immunity is critical to the destruction of tumour cells beyond the freezing site, i.e., metastases. This property and the specificity of the initial immune response to destroy malignant vs. normal cells, which may leave behind a long-term memory serving to protect the patient from subsequent disease, distinguishes cryosurgery from other conventional therapeutic modalities for cancer. The ability to cryogenically ablate tumour and also induce antitumour immunity forms the basis of the concept of cryoimmunotherapy, which adds a "double-edged sword" to our armamentarium. Within the course of the recognition of the potential therapeutic application of the principles of cryoimmunology, several concerns have arisen. Well beyond the limits of this brief commentary, several of these concerns have been considered in depth elsewhere (Ablin. In: Onik et al. Percutaneous Prostate Cryoablation. QMP, Inc., St. Louis, 1995, p. 136).

For the present, a major step toward the long overdue acceptance of cryoimmunotherapy in man, for which evidence has been referred to by some in recent years as anecdotal and even "mythical," has been the increasing realization that the absence or low level of an immune response in the majority of patients following cryosurgery has been due to their generally poor, if not anergic state, of immunological competence. Fundamental as this observation is, it has been virtually ignored even though the author has explained it on numerous occasions over the past 30+ years.
Age and/or disease-related reduced immunocompetence, as well as that induced by prior therapies, has important implications for the application of immunotherapeutic strategies, inclusive of cryoimmunotherapy. Therefore, as with traditional staging and grading of a patient's malignancy, it is critical to evaluate their level or stage, hence, "immunostage," of immunological competence. Immunostaging provides the necessary criteria for determining a patient's suitability for cryoimmunotherapy and for monitoring their postoperative responsiveness. Monitoring the cryoimmune response has shown it may be biphasic (bidirectional), exerting temporally favourable (tumouricidal) vs. unfavorable (tumour enhancing) effects. Therefore, successful implementation of cryoimmunotherapy lies not merely in inducing an antitumour response, but in directing (modulating) the response toward that which will be tumouricidal.

Further related to immunocompetence is the effect of cryoablation on immunologically competent cells (immunocytes) within the target tissue and its microenvironment. Just as the immunocompetence of the systemic immune system is critical to the development of an immune response following freezing, it is axiomatic that the thermotolerance (cryoprotection) of the immunological integrity of the host and its modulation are paramount. A candidate to protect this integrity is molecular chaperones, also known as heat shock or stress proteins (HSPs). A highly conserved, constitutively expressed and stress-induced family of proteins, HSPs possess the ability to suppress the aggregation of nascent and altered cellular proteins under normal and stress conditions. Central to immune responsiveness, HSPs are involved in signal transduction pathways, wherein they may provide cryoprotection to immunocytes within the microenvironment of the cryolesion and be involved in the translocation and presentation of antigens. In looking at ways in which to increase the tumouricidal effectiveness of the cryoimmune response, re-attention to earlier observations of changes in the microcirculation following freezing have provided a means to maximize the synergistic effect of cryosurgery and selective cytotoxic agents via cryoimunochemotherapy. By way of example of this approach, recent observations in a small group of prostate cancer patients with advanced disease disclosed increases in select parameters of immune responsiveness in association with regression of metastases in some (Mouraviev et al. Int. J. Molec. Med., 6(Suppl. 1): S30, 2000). An increased understanding and appreciation of the uniqueness of cryosurgery has witnessed its increased application from the prostate to a variety of tissues, which include breast, kidney, liver and lung. There from, in this author's opinion, it is only a matter of time, before the immunotherapeutic aspects of cryosurgery are fully realized. In fact, presentations at the recent XIth World Congress of Cryosurgery (Lisbon, 5-7 October, 2001) attest to the beginnings of this realization. Given this interest, it may be useful to consider reorganization of an earlier international collaborative Cryoimmunotherapeutic Study Group (Ablin et al. J. Nat'l. Cancer Inst., 67:1173, 1981) to reassess guidelines for the implementation of cryoimmunotherapy.

 

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