|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.