Coherence 2/98



A. Shoutko, MD, PhD and N. Shatinina, MD, PhD


* Reported at the 6 Annual Conference of MSAIMA, November 25, 1998, Tel-Aviv

From the Department of Clinical Radiobiology and WHO Collaborating Center of Radiation Pathology, Central Research Institute of Roentgenology and Radiology, St.Petersburg, Russia


The history of medicine records many examples of the persistence of forms of therapy that owed more to the attractiveness of the tenuous theories underlying them than to any unequivocal demonstration of their effectiveness. In 1977, the distinguished tumor immunologists described Burnet's theory of immunosurveillance as a central fallacy of tumor immunology (1). Inspite of this, inordinate promotion of this topic was performed during the following decades. It has been attributed, by some experts, to unfortunate sociological influences encouraging premature deduction of clinical relevance from experimental research with viral or chemical-induced tumors, or with their allogenic transplantation apart from isotransplants of spontaneously arising tumors (2, 3). So despite destructive critical examination of evidence for active host defense against cancer, dating two decades ago, the foundations of immunotherapy for cancer have remained completely unchanged, until now. It should be noted that malignant tumors are very rare in conditions without immunity, as shown in plants. In the evolution, lower vertebrates show a low rate of spontaneous appearance of tumors and a high resistance to carcinogens, while higher vertebrates have progressively lost this assumed tumor defense mechanism. This tendency does not depend on the cell proliferation rate (4). The tumor antigens are uniformly developmental ones, the tumor cells are essentially self, and their response against easily recognized oncodevelopmental antigens can be clearly autoimmune only (5, 6). In turn, autoreactive repertoires are prepared and developed to recognize self antigens of somatic cells in vertebrates for a function control system called homeostasis , like ontogenesis, organogenesis, senility, morphogenesis, regeneration of different kinds as well as a clonal selection. The last one is not specific to tumor cells at all, and mechanism may essentially be prepared to select normal cells in development and organogenesis. Under these conditions, clonal selection theory, wich is used to explain the escape mechanism of tumor cells from the immune system, fuses with the normal developmental process. It should be noted that apoptosis which plays a role in the negative and positive selection of T and B cells development, is not a specific process to immunocyte selection, but rather a universal mechanism of cell death in morphogenesis (7, 8, 9, 10). The so-called programmed death, or clonal deletion of immature lymphocytes is a holocrine pathway of cell secretion for conducting an extracellular microecology in different tissues by the richest spectrum of growth factors (11). So lymphoid cells are associated with, and probably participate in a number of physiological processes, including chronic inflammation, wound healing, tissue repair and/or regeneration, vascularization, compensatory hyperplasia, and possibly general growth of various organs and neoplastic tissues (12, 13, 14). It was first suggested more than half a century ago that lymphocytes support the growth of various organs, and experimental evidence this is abound (15).

Using adoptive transfer studies it was shown that stimulation of in vitro tumor systems and in vivo local tumor growth metastasis by lymphocytes as well as of that many normal tissue proliferation processes can be accomplished by lymphocytes (12). According to our data, compensatory renal hyperplasia in mice following unilateral nephrectomy, and regrowth of RL-67 carcinoma in mice following its X-irradiation have been provided by immature lymphocytes. Moreover, the tumor growth can be delayed by concomitant skin wound healing, showing the competition between two growth processes for morphogenetic resource of the corresponding lymphocytes subset in the host (16). It is interesting to mention that the lymphocytes, at early stage of differentiation, have been directed with the help of the enzyme TdT in at least two functional ways:

- by greatly enhancing the diversity of antigen receptor genes (abundant template-independed N region of DNA) or

- by the prevalence of homology - directed recombination (results in invariant receptors to certain tissues) for example, intraepithelial lymphocytes in skin (17). The presence of quasimonoclonal receptors to specific anatomical locations on immature lymphocytes and their abnormally high sensitivity towards deoxynucleoside level disturbances in extracellular fluid are in concordance with the morphogenetic potentiality of immature lymphocytes, coinciding with earlier predictions (18, 19). Practicable consequences of the hypothesis for morphogenetic support of tumor growth by a special subset of lymphocytes pose a potentially real danger, the so-called immunostimulation with cancer patients (20).

The evidence, in black and white, that what is not there cannot be stimulated, is a modern therapeutical strategy. In recent years we have witnessed an almost dramatic increase in the use of high-dose chemotherapy followed by autologous cryopreserved circulating hemopoietic progenitor cells-CPC to avoid hematological toxicity or to shorten the aplastic phase after high dose therapy with autografted patients (21).

While assessment of the anticancer activity of high-dose intensive therapy, total therapy, rapidly cycled chemotherapy employed with CPC support, could not be a primary study objective, and while it is equally unwise to condone or reject high-dose therapy, many centers now consider it an easy way to balance budgets. The much-reduced prime costs of total treatment and unchanged high fees, have brought extraordinary popularity to the use of CPC, regardless of proven clinical benefits.

Because this modern strategy has aimed to maximize cytotoxic dose intensity by accelerating the speed with which autografted patients recover, mainly normal granulocyte and platelet counts following myeloablative treatments, it is strange the lymphocytes are not even taken into account. The modern strategy of high-dose therapy with CPC appears incompatible with active host defenses against cancer. But it does not contradict the morphogenetic function of lymphocytes, or the latest hypothesis about cancer as a reactive mechanism, whereby, in order to try to save the life of the body. There must be a voluntary stimulation of certain organ or tissue because the lack of physiological functions of other organs (22).

According to our point of view, the inhibition of lymphopoiesis during myelotoxic, or even myeloablative therapy, provides indirect tumor growth control and the control of normal tissue growth as well, owing to limitation of the morphogenetic function of lymphocytes. That is why myelotoxic treatment is obviously only applicable to those patients without tumor induced exhaustion of lymphopoietic resources. In the opposite situation, as is often the case, the treatment needs to be aimed at support of somatic well-being at the lowest acceptable level and, consequently, at stimulation of total morphogenetic capacity, or at selective readdressing directly towards critical normal organs and tissues, avoiding the tumor. Such a point of view is in good accordance with the statement made in: for cancer patients the life quality is its quantity (23, 24). Taking into account the successful competition of the tumor with normal tissues for limited raw substances resource of the host, let us recall the Tumor Necrosis Factor, which was proven inactive as a single agent in clinical trials, but at the same time, is a cachectine (25).

Complete or partial, temporal or permanent, disappearance of all or at least some relevant parameters of a soundly diagnosed malignant disease without any medical treatment or treatment that is considered inadequate for the resulting regression, is defined as spontaneous remission (SR). This definition of SR is unequivocal for tumor regression after treatment failure. It is a rare (1:60000 or 1:100000), but exciting event in oncology, which is seen sporadically in every type of cancer and nowadays there are no more doubts on the validity of the observation (26). The question is how even advanced cancer may be a reversible process. The known offered explanations of SR are founded on the search for factors which are able to act actively against the tumor. One such factor is called local cellular immune activation, which results in inflammatory necrosis following severe local infection with streptococci, measles, viral hepatitis, herpes zoster or chickenpox during peritonitis, pneumonia, artificial graft versus processes. Another assumed mechanism is the angiogenesis inhibition by some endogenous inhibitors, which is positively regulated by interferone, interleukine-12, and even the so-called psychoneuroimmunological mechanisms. Contrary to the above mentioned, SR was also observed among the patients with HIV-compromised T-cell immunity (27, 28). Moreover, incomplete resection of the primary tumor or metastases may, in some manner, favorably change the angiogenic processes in the residual tumor and, in rare cases result in further SR (29).

In most cases of well documented SR it is possible to see the concomitant surgical results in normal tissues like ample excision of abdominal wall, incomplete resection, thoracotomy, bypass surgery with intestine, bowel, followed by a second surgical exploration, postoperative fever, pneumonia, hernia, or prolonged healing of postoperative wounds, and so on. In all such situations the incomplete chronic regeneration of injured normal tissues is the reality (real event) which accompanies SR.

According to our data, the life span of advanced patients with renal carcinoma, after its intravascular embolization, can be predicted before treatment by estimation of the level of immature lymphocytes which are responsible for compensatory regeneration of a collateral organ (19, 30). The level of auto-RFC above the mean normal quantity, but not exceeding its highest limit, was found to be preferable to a good result of treatment. It means the lymphopoiesis needs to be accelerated in a adoptive regime, but not forced over or exhausted before treatment.

The frequency of SR for metastasis of renal carcinoma following nephrectomy is relatively high and has been estimated between 0,3 and 4%. The simplest explanation of the SR phenomena for the cases of long-term tumor dormancy and exceptional treatment related survival should be based on the morphogenetic function of lymphocytes (31, 32). In the competition of normal and tumor tissues for morphogenetic service in the host the privilege belongs to the last one. This privilege has been realized thanks to redistribution of morphogenetic reserve of lymphopoiesis by willingly reorienting hystohomological lymphocytes homing at the special stages of differentiation, to the tumor. This is why the terminal phase of cancer used to be accompanied by loss of body weight. Nevertheless in the presence of acute or chronic damage of normal tissue the additionally challenged lymphocytopoiesis should pledge oneself to share its morphogenetic potential as long as it is demanded for restoration of injured normal structure. Such a simple scheme is able to explain many clinical and biological obscure phenomena in vivo in particular SR (better to say Unexpected Remission - UR), positive result with total body irradiation regardless of incredibly low doses, and so on. In light of the regeneration ability of injured normal tissues to compiete with tumor development, the possible modern mode of tumor control could look like a crazy fantasy. For example, it could be the fracture followed by long-term mechanical stretching of the broken ends to delay the knit-like structure, as used to be done for surgical lengthening of bone with cosmetic aim. There probably are some favorable kinds of normal tissues for morphogenesis support that are the part of a holistic control system, called homeostasis.

The principle advantage of the offered approach, competition therapy, wich is based on the natural switching-over of the morphogenetic lymphocytes to normal host tissues instead of the tumor, is the preservation of a limited lymphopoietic reserve, in contrast with all other kinds of cytotoxic therapy.

So, SR (UR), as well as the positive results of perpetuating many quack treatments, complementary medicine methods, deserve a more scientific systematic registry of cases and sophisticated scrutiny, because a deep understanding of such tumor control may lead to a new, unexpected, unusual therapeutic approach in oncology.

Accordingly, any non-cytotoxic appro-
ach, which is able to control the rate of normal tissue renovation and growth at the level of tissue-organ-system interrelations, could be claimed to have an actual ability to indirectly control the cancer.



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