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S.V. Zinchenko

GBOU DPO "Kazan State Medical Academy" Ministry of Health of the Russian Federation, Kazan

Zinchenko Sergey Viktorovich - Doctor of Medical Sciences, assistant of the Department of Surgery 420012, Kazan, st. Mushtari, 11, tel., e-mail: This email address is being protected from spambots. You must have JavaScript enabled to view it.

Abstract. The results of an analysis of literature data on the use of immunomodulators in the complex treatment of cancer patients are presented. The effectiveness of this type of immunotropic drugs in the rehabilitation and treatment of immune disorders before, after and during special treatment methods for cancer patients (surgical, radiation and chemotherapy) is demonstrated. Key words: immunotherapy, immunomodulators, chemoradiotherapy, oncology.

The use of basic methods of special treatment of cancer patients: surgery, radiation and chemotherapy does not raise any doubts among specialists. The identification of immunotherapy as a separate type of complex cancer therapy remains controversial today. However, the effectiveness of this systemic method of influencing the tumor (especially in a number of localizations: kidney cancer, melanoma) has been absolutely proven and is widely used throughout the world. The use of immunomodulators in the treatment of cancer patients in combination with routine treatment methods remains a poorly studied issue.

In order to increase the effectiveness of antitumor therapy, increasingly aggressive radiation and chemotherapy treatment regimens are being developed and applied, which leads to the development of pronounced functional and quantitative disorders in the immune system, which are realized by autoimmune, allergic and infectious complications. Developed complications, in turn, prevent the implementation of basic treatment in an optimal manner, reducing its effectiveness and worsening the quality of life of patients [1-3]. Therefore, at the present stage, special attention is paid to the use of immunocorrective therapy in the process of complex treatment of patients [3, 4]. At the same time, immunocorrection standards are far from perfect. Questions remain open: which immunotropic drugs are most appropriate to use in combination with complex treatment of cancer, and what are the criteria for prescribing these drugs [3].

Today, immunotropic drugs are usually divided into three large groups: immunomodulators (immunocorrectors), immunostimulants, and immunosuppressants. In the complex therapy of cancer patients, immunomodulators are most often used - drugs that, in therapeutic doses, act primarily on altered parameters, normalizing the basic functions of the immune system [5, 3].

In our review, we want to focus on the main properties and differences of modern immunotropic drugs, as well as summarize the experience of using these drugs in cancer patients.

In accordance with a number of existing classifications [1, 5, 6], the following groups of immunomodulators are distinguished:

• preparations of microbial origin (ribomunil, imudon, sodium nucleinate, etc.);

• peptide drugs (tactivin, thymalin, myelopid, etc.);

• synthetic drugs (lykopid, imunofan, polyoxidonium, levamisole, galavit, cycloferon, etc.);

• preparations based on cytokines (interferons (IF), interleukins (IL), colony-stimulating factors (CSF);

• preparations based on natural factors (biobran, derinat, erbisol, plant extracts).

The main feature of drugs of microbial origin is the activation, first of all, of natural resistance factors - the system of mononuclear phagocytes, neutrophil granulocytes and natural killer (NK) cells. The most important is the enhancement of the cytotoxic function of macrophages (MPs), which is manifested by their ability to destroy syngeneic and allogeneic tumor cells in vitro. Activated monocytes and MF synthesize a number of cytokines: IL-1, IL-2, tumor necrosis factor (TNF), colony-stimulating factors (CSF), etc., which leads to increased antitumor resistance of the body [5].

To date, quite a wealth of experience has been accumulated in the clinical use of peptide drugs of thymic origin (thymalin, tactivin, timoptin), which are widely used in the complex therapy of cancer patients [7]. The main target cell for drugs of thymic origin are T-lymphocytes. Thymic drugs affect the proliferation and differentiation of T cells and have the property of inducing the production in the body of substances with thymosin-like activity, IF and TNF. Thymus preparations are used at all stages of antitumor treatment: against the background of radiation therapy for breast cancer, uterine cancer, lung cancer, against the background of polychemotherapy (PCT) for breast cancer and lymphogranulomatosis, in the postoperative period, after radiation therapy and in the intervals between courses PCT for carcinomas of various localizations [8, 9]. At the same time, all researchers note an increase in the stability of leukopoiesis and lymphopoiesis, preservation or restoration of the level of response of lymphocytes to mitogenic stimuli and a decrease in the frequency of complications during radiation and chemotherapy [3].

Synthetic or chemically pure immunomodulators can be divided into 3 subgroups:

• previously synthesized drugs of various groups, additionally possessing immunotropic properties (levamisole, diucifon);

• analogues of drugs of microbial or animal origin (thymogen, lykopid, imunofan);

• obtained as a result of directed chemical synthesis and having no natural analogues (polyoxidonium, galavit).

The drugs of the first subgroup, levamisole and diucifon, have a corrective effect on the T-system of immunity. Levamisole is also an IL-2 inducer and has the ability to stimulate the NK cell system. At the same time, there is an increase in the antitumor effect when using a combination of 5-fluorouracil and levamisole in patients with colorectal cancer [10].

Belonging to the second subgroup, lycopid is a synthetic analogue of muramyl tripeptide, a minimal component of the cell wall of all bacteria. This drug in low doses enhances the absorption and destruction of microbes and tumor cells by phagocytes in vitro, stimulates the synthesis of IL-1 and TNF. In turn, IL-1 and TNF activate B and T lymphocytes, resulting in increased antibody production and cellular immune responses [11, 3].

In recent years, a fourth-generation peptide drug, imunofan, has been used quite effectively in oncology practice [13]. Unlike thymic hormones, imunofan has an immunoregulatory effect on cells of the immune system, regardless of the production of prostaglandins (PG). The prostaglandin-independent nature of the drug’s action creates a certain advantage over the use of thymic hormones and allows one to avoid exacerbation of pericancrotic inflammation and reduce the suppression of antitumor immunity, which is achieved by increased production of PGE2 by malignant cells. This circumstance is of exceptional importance for immunocorrection in cancer patients. The effect of Imunofan begins 2-3 hours after administration (fast phase) and lasts up to 4 months (intermediate and slow phase). During the fast phase, the duration of which is 2-3 days, the detoxification effect of the drug is primarily manifested - the antioxidant defense of the body is enhanced by stimulating the production of ceruloplasmin and lactoferin, and increasing the activity of catalases. Imunofan normalizes lipid peroxidation, inhibits the breakdown of cell membrane phospholipids and the synthesis of arachidonic acid, further reducing blood cholesterol levels and the production of inflammatory mediators. In case of toxic and infectious liver damage, imunofan prevents cytolysis, thereby reducing the activity of transaminases and the level of bilirubin in the blood serum. During the intermediate (middle) phase, which begins after 2-3 days and lasts 7-10 days, the phagocytosis reaction intensifies. The slow phase of the drug’s action begins 7-10 days after administration and lasts up to 4 months, and consists of normalizing the main indicators of cellular and humoral immunity: restoring the immunoregulatory index, increasing the production of specific antibodies, etc. Thus, imunofan has a wide range of regulatory effects, and its clinical effectiveness is based on the ability to partially or completely restore T-cell, phagocytic immunity, normalize the production of pro-inflammatory mediators, and ensure correction of the oxidative-antioxidative system and lipid metabolism [14].

The effect of imunofan on reducing hepato- and myelotoxicity was confirmed by the results of the use of an immunomodulator against the background of chemotherapy in 375 patients with various malignant tumors (N.N. Blokhin Russian Cancer Research Center, Russian Academy of Medical Sciences). In patients receiving Imunofan, liver dysfunction occurred 1.5-2 times less frequently, the incidence of leukopenia decreased by an average of 22%, the percentage of CD4/CD8 was restored or improved, while normalization of the immunoregulatory index was observed in 50% of patients.

Imunofan was included as the main therapeutic agent in the immunocorrective treatment regimen for patients with locally advanced tumors before and after chemoradiotherapy (Moscow Research Oncology Institute named after P. A. Herzen). As a result of the treatment of 54 patients with stage III cervical cancer and 41 patients with stage III-IV esophageal cancer, it was revealed that the therapeutic effect of imunofan is realized in significant positive dynamics of homeostasis indicators, especially its immune link [3].

The drug of a new generation of synthetic immunomodulators obtained as a result of targeted chemical synthesis is polyoxidonium [16]. This is a physiologically active high-molecular compound with pronounced immunotropic activity. The immunomodulatory effect of polyoxidonium is associated with its predominant effect on neutrophils, monocytes/macrophages, natural killer cells and indirectly on B and T lymphocytes. The consequence of this is the activation of the absorption and bactericidal abilities of phagocytes; enhancing NK function; stimulation of the synthesis by monocytes and lymphocytes of a number of cytokines, increasing the production of antibodies by B lymphocytes and the functional activity of T cells. In addition to the immunomodulatory effect, polyoxidonium has pronounced detoxifying, antioxidant and membrane-stabilizing effects [17].

Currently, extensive clinical experience has been accumulated in the use of polyoxidonium for various somatic pathologies. The drug gives a good clinical effect in diseases that differ significantly in etiopathogenesis: tuberculosis and diabetes, psoriasis and burn disease, etc. This breadth of the therapeutic range of polyoxidonium is due to its multifaceted effect on the body [21, 3].

In recent years, polyoxidonium has been widely used in oncological practice. The combination of immunomodulatory, detoxifying, membrane-stabilizing and antioxidant properties makes polyoxidonium a powerful and effective agent for use in the complex treatment of cancer patients. The drug can be used both during and after the end of complex therapy for the purpose of immunorehabilitation, reducing the toxic effect of chemotherapy, and improving the quality of life of patients.

Promising immunomodulators for oncology also include the synthetic drug galavit, which is a derivative of aminophthalhydroside. In a preclinical study of galavit, its ability to enhance antitumor immunity was noted by increasing and/or restoring the effector mechanism mediated through the presentation function of MF, regulation of the synthesis of IL-1, TNF, IL-2, and NK activation. The drug also exhibits pronounced immunomodulatory activity due to the ability to reversibly (for 6-8 hours) inhibit the synthesis of pro-inflammatory cytokines TNF and IL-1 by hyperactivated MPs or stimulate them in case of initial deficiency. At the same time, galavit is able to restore the suppressed phagocytic function of MF and neutrophils and, consequently, anti-infective protection. At the same time, the antigen-presenting function of the MF is restored, the processes of repair of damaged tissues are activated, the clinical symptoms of intoxication are stopped, and the adequate functioning of the immune system is restored [22].

At the Medical Radiological Research Center of the Russian Academy of Medical Sciences (Obninsk), a study was conducted on the effect of Galavit in combination with cyclophosphamide on the growth and metastasis of Lewis carcinoma in mice. The use of Galavit at a dose of 50 μg/mouse contributed to a statistically significant increase in the antimetastatic effect of cyclophosphamide—the number of pulmonary metastases decreased by 4 times compared to the level of metastasis when using only cyclophosphamide [23].

The immunomodulatory properties of the drug Galavit were assessed in a clinical setting. Galavit was used in patients with stage III non-small cell lung cancer in the pre- and postoperative periods. The control group received a placebo. When analyzing the immune status of patients before treatment, there was a decrease in the relative content of such subpopulations of lymphocytes as CD3+, CD4+, CD8+, CD20+, as well as natural killer cells CD16+ in all patients. There were no significant differences in the immunograms of patients in both groups on the first day after surgery. However, at follow-up, 51 days after surgery, significant differences were noted in the immune status of patients. In the group of patients receiving Galavit, all lymphocyte subpopulations returned to normal, while in the control group the decrease in the relative content of lymphocyte subpopulations remained. It should be noted that in 68.2% of patients in the control group, the development of pneumonia was observed in the postoperative period, while in the group of patients who were prescribed Galavit, pneumonia was detected in only 27.5% of patients and was relieved on average 3-5 days earlier against the background similar antibacterial therapy. An important indicator was the length of hospital stay: patients operated on due to galavititis were discharged on average 8 days earlier than patients in the control group. In this study, galavit proved to be a highly effective immunomodulator, the use of which contributed to a 2.5-fold reduction in the number of complications in the postoperative period and a reduction in hospital stay [24].

The drug Galavit was also used against the background of chemotherapy according to the CAF regimen in 65 patients with disseminated breast cancer. A randomized, double-blind, placebo-controlled study showed that the use of Galavit led to an improvement in the immune status of patients, which reduced the incidence of infectious complications and increased the quality of life of patients [25].

Glutoxim is a representative of a new class of synthetic immunomodulators - thiopoietins. Glutoxim stimulates proliferation and promotes differentiation of normal cells, activates the processes of apoptosis of transformed cells, and realizes the effects of many cytokines. In relation to normal cells of the organs of immuno- and hematopoiesis, glutoxim initiates the cytokine system, regulates the endogenous production of interleukins (IL-4, 6, 8, 10, 12) and erythropoietin. The drug belongs to the group of regulators of redox-sensitive gene expression, including the alpha chain of IL-2, TNF, IFα and γ, c-fos, Bax and Bcl-2 genes. Glutoxim is used for immunological support of combination antitumor therapy in order to increase the sensitivity of tumor cells to radiation and chemotherapy and reduce the toxic effects of cytostatics. The use of glutoxim in patients with lung, stomach, breast, ovarian, and bladder cancer ensured stabilization and restoration of clinical, biochemical, and immunological parameters after combination therapy and improved the quality of life of patients [26].

The group of chemically pure immunomodulators also includes inducers of endogenous IF (cycloferon, ridostin, larifan). It should be noted that the spectrum of their action is not limited to enhancing interferonogenesis. To date, the following biological effects of these drugs have been studied: antiviral, antitumor, immunomodulatory and activating effects on bone marrow stem cells. When studying the effect of cycloferon on the secretion of cytokines by human blood mononuclear cells, it was revealed that cycloferon is an inducer of IFγ, IL-1, 2, 6 mRNA, and at the same time has an inhibitory effect on the production of proinflammatory cytokines IL-8 and TNFα. Consequently, IF inducers can induce the production of many cytokines that control hematopoiesis and immunogenesis processes. There is data on the radioprotective effect of IF inductors. In oncological practice, IF inducers are used both for the purpose of immunomodulation after courses of radiation and chemotherapy, and for the purpose of suppressing proliferation against the background of the main methods of treating cancer patients [7].

The most significant place in modern oncology is occupied by cytokines - biologically active substances of peptide nature. The main functions of cytokines are: regulation of hematopoiesis, immune response and inflammatory processes, participation in angiogenesis, apoptosis, chemotaxis, embryogenesis. In oncology, the most widely used cytokines are IF, IL, and CSF [1, 28]. IF and IL are used as a component of antitumor therapy itself, due to their cytostatic properties. Thus, recombinant IFα (intron-A, roferon, realdiron, laferon) is effective in the treatment of patients with kidney cancer, hairy cell leukemia, chronic myeloid leukemia, and follicular lymphoma. Since 1995, IFα has become the main drug of choice in the adjuvant therapy of patients with melanoblastoma, displacing chemotherapy drugs due to its greater effectiveness - 37% of five-year survival rate versus 27% [3].

The results of using ILs, in particular IL-2 (roncoleukin), are encouraging. To date, over 20,000 patients around the world have received IL-2 treatment using various regimens: independently in various doses, together with IF and cytostatics. The best results were obtained in metastatic kidney cancer and melanoma [1, 3].

To date, a large amount of experimental material has been accumulated indicating an increase in the effectiveness of antitumor therapy when combining cytokines and radiation therapy. An increase in the antitumor effect when combining cytokine and radiotherapy has been shown in prostate tumor models in rats, renal carcinoma and metastatic melanoma in mice [3]. Of particular interest are the results of clinical studies in which treatment with cytokines was combined with chemotherapy and radiation therapy, which led to an extension of the disease-free period in patients with nasopharyngeal carcinoma, advanced renal cell carcinoma, and cutaneous angiosarcoma [4, 6].

Cytokines that can stimulate the growth and differentiation of hematopoietic precursor cells are called colony-stimulating factors (CSF). CSFs do not have antitumor properties, but they are necessary for the progression from pluripotent stem cells to mature differentiated blood cells, and have the ability to influence the function of the latter. Due to these properties, CSF have become of great importance in modern clinical chemotherapy of tumors. CSFs include: granulocyte colony-stimulating factor (G-CSF), which stimulates the production of neutrophils; granulocyte-macrophage CSF (GM-CSF), which stimulates the production of granulocytes and MF; macrophage CSF (M-CSF), which stimulates the production of monocytes; IL-3 and IL-11, which have the ability to influence precursor cells of white, red blood and megakaryocytes; erythropoietin (EPO), which affects precursor cells of erythrocytes and megakaryocytes; thrombopoietin, which stimulates the development of megakaryocytes; stem cell growth factor (SCGF), which can stimulate the growth of hematopoietic stem cells and FLT-3, a ligand that stimulates the growth of early precursors in the bone marrow and peripheral blood [1, 26].

Today, G-CSF (Neupogen, granocyte and pegfilgrastim), GM-CSF (Leukomax), EPO (Recormon, Eprex) are widely used in clinical practice. The use of CSF facilitates the implementation of full-fledged treatment regimens with cytostatics: in patients, the period of neutropenia is significantly shortened, thrombocytopenia is less pronounced and the number of infectious complications is reduced. In addition, it is possible to carry out more intensive chemotherapy, because the use of CSF makes it possible to reduce the period between courses of treatment [1].

Immunomodulators of natural origin include drugs such as derinat, erbisol, plant extracts, and BioBran. Derinat (sodium deoxyribonucleate), obtained from sturgeon milt, in addition to immunomodulating, has anti-inflammatory, regenerative and hematopoietic properties. Derinat activates the processes of cellular and humoral immunity, increases resistance to infections, stimulates hematopoiesis, and normalizes the number of leukocytes. The drug is effective for myelodepression that occurs after radiation and chemotherapy. Derinat also promotes the regeneration of the mucous membranes of the oral cavity, intestines, vagina and the healing of radiation ulcers and skin necrosis [26].

Close to derinat is the immunomodulator and reparant erbisol. The drug is a complex of natural low-molecular organic compounds of non-hormonal origin, obtained from chicken embryo tissue, contains glycopeptides, peptides, nucleotides, amino acids. As an immunomodulator, Erbisol normalizes immune status indicators: it activates Th1 helper cells and T-killer cells and inhibits the activity of Th2 helper cells and B lymphocytes, which helps restore specific cellular immunity. The drug also activates MF and NK, induces the synthesis of endogenous IF and TNF. This leads to inhibition of both the growth and metastasis of malignant tumors [3].

Erbisol was used in complex therapy of 147 patients with diagnoses of breast cancer, lung cancer, stomach cancer, pancreatic cancer, rectal and colon cancer, liver cancer and metastatic liver disease. In patients who received erbisol during chemoradiotherapy, subjective tolerability of therapy significantly improved. When studying the immune status after combination therapy in patients who were not administered erbisol, a decrease in the number of total T-lymphocytes, T-helper cells, NK, and an increase in the level of CEC was noted. At the same time, in patients who received erbisol as part of complex therapy, most immunogram parameters approached the values of practically healthy people [3].

Plant extracts (Rhodiola rosea, Eleutherococcus, ginseng root, plantain), which have an immunomodulatory effect, are also adaptogens that increase the overall resistance of the body under physical, chemical and emotional stress. The use of plant extracts in combination with cytostatics can reduce the degree of myelotoxicity and promote the restoration of the intestinal epithelium. There are a number of herbal preparations that have the property of stimulating the growth and functioning of normal cells and at the same time inhibiting the development of tumor cells. Such preparations include, first of all, extracts of Rhodiola rosea, celandine, mistletoe and peony [26].

A new promising drug with powerful immunomodulatory properties is Biobran. Biobran is made from water-soluble dietary fiber hemicellulose B, extracted from rice bran extract. Hemicellulose B of rice bran contains arabinoxylan, the main ingredient of the drug, consisting of the sugars xylose and arabinose. Biobran is obtained by treating hemicellulose B with enzymes from the mycelium of the shiitake mushroom. The peculiarity of this immunomodulator is that its structure comes from the structure of dietary fiber, and at the same time, the polysaccharides have a low molecular weight, which is necessary for its absorption in the intestines.

Arabinoxylan primarily stimulates the activity of NK cells (in a few weeks it can activate NK cells by 300%), and also helps to increase their number. In addition, the drug activates T and B cells by 200 and 150%, respectively. One NK cell can inactivate more than 27 atypical cells during its life [27].

The main indication for the use of biobran is the naturopathic treatment of patients with metastatic tumors who have undergone special treatment. Considering that when taking Biobran, NK cells are activated, which can destroy cancer cells in a 1:1 ratio, it is important to first reduce the tumor burden using surgery, chemotherapy and/or radiation therapy. The antitumor activity of the drug as part of complex therapy has been repeatedly proven in studies by foreign authors [27, 28]. The main feature of this unique drug is the fact that its use is possible in any phase of special treatment, which does not require complex and expensive studies of immune disorders. Biobran, comparable to other known immunomodulators, reduces the negative effects of chemoradiotherapy, while at the same time it has its own quite significant antitumor activity. Studies with long-term use of the drug showed an increase in the disease-free period comparable to the use of cytokines [27-29].

Summarizing the above, we can say that immunocorrection in the treatment of cancer patients is an integral and significant part of complex therapy and rehabilitation of cancer patients, requiring knowledge and skills from oncologists.

The most justified is the use of immunotropic drugs after removal of the primary tumor, even in the presence of metastases, since an increase in antitumor resistance is achieved in the absence of tumor cells in the patient’s body or their presence in a minimal amount [3, 29]. Immunological studies have shown that due to the particular complexity of the functioning of the immune system during tumor growth, it is of great importance to assess the initial state of the immune status and its constant monitoring during treatment, as well as the need for the most complete consideration of immunological parameters. Since most immunomodulators have well-studied mechanisms of action with a predominant effect on one or another part of the immune system, it is necessary to assess the parameters of the immune system in each specific case, followed by the prescription of the appropriate drug or combinations thereof [3].

At the same time, the possibilities and goals of immunotherapy in cancer patients should be considered taking into account the stage of their treatment. In the early postoperative period, it is most advisable to use agents that act on the cells of the mononuclear phagocyte system to prevent postoperative infectious complications. These drugs include: polyoxidonium, galavit, imunofan, biobran. The use of thymic drugs (tactivin, thymalin) is also justified, affecting the proliferation and differentiation of T cells, enhancing the production of IL-2 and its reception by sensitive cells.

During radiation and chemotherapy, preference should be given to drugs that can prevent the development of leukopenia and have an antitoxic effect - biobran, polyoxidonium, erbisol. To correct complications caused by radiation therapy, it is preferable to prescribe drugs that have antioxidant and reparative effects: imunofan, polyoxidonium, derinat. After PCT, drugs are prescribed that restore erythro- and leukopoiesis - CSF, derinat, biobran. Universal accompanying drugs can be immunomodulators with additional properties (detoxification, antioxidant), which have been proven to improve the quality of life of cancer patients. Such drugs are biobran, polyoxidonium, imunofan, glutoxim.

Thus, the use of adequate immunocorrective therapy helps to prevent postoperative complications and eliminate the side effects of chemoradiotherapy, making it possible to implement a full program of treatment and rehabilitation of cancer patients. The choice of adequate methods of immunocorrection should be justified by the results of immunological monitoring during radiation and chemotherapy. Only with qualified prescription and strict indications can immunotherapy significantly improve immediate and long-term treatment results and improve the quality of life of cancer patients.

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