RU2175242C1 - Method of treating uveal melanoma - Google Patents

Abstract

FIELD: ophthalmological oncology. SUBSTANCE: recombinant interleukin-2 (Ronkoleukin) is injected intravenously in dropwise manner in dose 1-1.5 mln Un. , 5 infusions in one course. If regression of tumor and/or metastases is insufficient, the courses are repeated. EFFECT: enabled destruction or diminishing of dimensions of primary or and/or metastatic tumor nodule up to complete regression allowing preservation of eye as organ. 2 cl, 2 ex

Description

 The invention relates to ophthalmology, namely to ophthalmic oncology, and is intended for the treatment of intraocular, epibulbar and conjunctival melanomas.

 Uveal melanoma belongs to the category of intraocular tumors, which pose a threat not only to vision, but also to the patient's life.

The current treatment methods for uveal melanoma should be classified as cytoreductive:
1 - local excision and / or excision through the vitreous when the tumor is located in the technically accessible part of the eye;
2 - local radiation (brachytherapy), aimed at the destruction of the primary tumor node;
3 - enucleation or exentration when the tumor reaches a large size, going beyond the fibrous membrane of the eye, in cases where it is impossible to save the eye as an organ.

 However, none of these methods is intended for the prevention and regression of metastases and / or slowing down the rate of metastasis.

 The use of combined adjuvant chemotherapeutic agents [1] at the generalized stage of uveal melanoma is not accompanied by a significant therapeutic effect or a significant increase in life expectancy for a patient, and its quality is significantly impaired. Patients can hardly withstand one or two courses of chemotherapy, and then are forced to refuse treatment [Albert D. et al. Treatment of metastatic uveal melanoma: review and recommendations. -Surv Ophthalmol. -1992 -vol. 36-N 6-p. 429-438]. This type of treatment is currently justified only with the dissemination of the process.

 So, according to Pyrhonen S. et al. The results are officially established: 20% partial regression and 50% stabilization for a period of 2 months. Median experience = 11.8 months, 4 patients lived more than 2 years and 2 others remained alive 17 and 20 months after the start of treatment. For comparison: median survival without treatment is 7-8 months. [Pyrhonen S., et al. Four Drug Chemotherapy (BOLD) and Human Leukocyte Interferon for metastatic uveal melanoma-Abstract book-international ophthalmooncology congress 1997 Israel .; Nathan N.E. et al. A BOLD + lnterferon in the treatment of metastatic uveal melanoma: First report of active system therapy.-J. Exp. Clin. Cancer Res.- 1997- vol.l6- N 2- P.201-218] [2].

 Randomized trials for the treatment of uveal melanoma with DTIC adjuvant therapy in 348 patients showed that there was no significant difference in the survival time of patients treated and untreated: 72% for 5 years in the group of treated patients versus 68% for untreated. [Desjaedins L. et al. Randomized study of adjuvant therapy by DTIC in choroidal melanoma.// Ophthalmologie -1998 - vol. 12, N 3 - p. 168-173] [3].

 In order to increase the effectiveness of adjuvant combination therapy, preliminary local resection of single liver metastases is sometimes used to reduce the total “total oncological mass” and facilitate the task of chemotherapy. Surgery of metastases and adjuvant therapy in the form of intraarterial administration of photmustine increase the effect to 40% in patients with single liver metastases [Pyrhonen S The treatment of metastatic uveal melanoma. - Eur. J. Cancer-1998 vol. 34 / Suppl. 3-S. 27-S30].

 However, in this case, traditional intra- and postoperative complications are not excluded [1]. It is possible in limited cases: with single liver metastases [2]. And with uveal melanoma, multiple metastatic foci are characteristic with a tendency to merge. The surgical stage of treatment introduces an additional component that aggravates the somatic state of the patient and suppresses the body's own defenses [3].

In order to eliminate secondary cancer-associated immunodeficiency and increase the effectiveness of chemotherapeutic agents, attempts are being made to include modern cytokine immunocorrectors in the treatment regimen. So, adjuvant therapy of uveal melanoma with fotmustin + IFN-α2b + IL-2 causes partial regression with a remission term of 49 months in 1 case out of 17 and in the remaining patients (n = 16) the disease is stabilized in the period from 8 to 16 months. The duration of the experience increases from 14 to 59 months. [Terheyden R. et al. Immunochemotherapy of metastatic uveal melanoma with intrferon, alpha 2b interleukin2 and fotemustine: case report. -Hautrzat. - 1998 - vol. 49- N 10-p. 770-773.]
However usable herein IFN-α2b (10 million. U / m ² subcutaneously days 1-5) and IL-2 (18 million IU / m ² 6,12 24 h, then 13.5 U / m ² every 72 hours ) administered in high doses. Their introduction is accompanied by a toxic effect (IV degree of toxicity on a scale) inherent in other chemotherapeutic agents, which also affects the quality of life of patients.

 Thus, the results of existing methods of treating the generalized stage of eye melanoma today do not satisfy either the doctor or the patient. Meanwhile, its incidence in various regions of Russia is from 2.6 to 7 people per 1 million of the population. However, only 43% of patients survive a 10-year period [Gradoudae ES et al. Survival of patientes with metastases from uveal melanoma. -Ophthalmology.-1991-vol. 98. p. 383-389]. The life expectancy of patients with a generalized stage of uveal melanoma, according to various authors and their own, ranges from 113 + 23 days [Gradoudae ES et al. Survival of patientes with metastases from uveal melanoma.-Ophthalmology.- 1991-vol. 98. p. 383-389.] Up to 268 + 54 days (own observations). In general, patients almost with difficulty survive 1 year from the moment of diagnosis of liver metastases.

 The rate of generalization of the process is largely determined by the number, location of metastases, the primary organ of invasion and the number of organs involved in the process [Kath R et al Prognosis and treatment of disseminated uveal melanoma. Cancer.-1993-vol. 72-p. 2219 -2223].

 The levers for controlling the generalization process are not known. Some authors attribute it to the appearance of gross defects in the immune system, with evidence of cases of spontaneous regression of metastases after removal of the primary tumor node or spontaneous regression of the primary node, as well as cases of metastases 25 years after removal of the eye with the tumor [Charles J Kent et al Adjuvant therapy in malignant melanoma, in Recent Advances in Ocular Oncology by Lippincott-Raven, Philadelphia Pensylvania].

 Attempts to modulate the immune response according to the type of HRT reaction with the rejection of a tumor transplant using the designed bio-vaccines are described only at the experimental stage. Along with the development of HRT with tumor destruction, eye death occurs [Hoon D. et al. Melanoma patientes immunized with melanoma cell vaccine induce antibody response to recombinant MAGE I antigen J Immunology- 1995-vol. 154-N 2-p. 730-737].

 In general, the problem of treating the late stages of uveal melanoma is far from being resolved.

 The essence of our invention lies in the fact that recombinant yeast interleukin-2 (IL-2) (Roncoleukin) is introduced into the body, characterized in that the drug is administered intravenously in a dose of 1 to 1.5 million units every other day, for a course of 5 infusions , in case of insufficient regression of the tumor and / or metastases, the drug is re-administered in the same way every 8 weeks until a clinical effect is obtained.

 That is, we made an attempt to control the situation using monotherapy with a well-known cytokine drug. Our choice fell on the domestic drug Roncoleukin, which is essentially a recombinant interleukin 2 (IL-2). The choice of drug is not accidental.

 The mechanism of antitumor action p IL-2 has not yet been studied. It is believed that the effect of IL-2 on tumor cells is not direct, but indirect through the immune system. This mechanism is very complex, a significant place in it belongs to EK cells, tumor-specific T lymphocytes, LAC cells and tumor-infiltrating lymphocytes (TIL), which express a high affinity receptor for IL-2. Strengthening the body's natural immune defense, especially the EK-cell system, is apparently one of the leading factors. It has been shown that in the treatment of IL-2, both the number and cytotoxic activity of EK cells significantly increase. Moreover, there is a good correlation between the degree of increase in the number, activity of EK cells and the tumor response to rIL-2 (Atzpodien et., 1993).

 The anti-carcinogenic effect of rIL-2 is also largely realized through the T-system (with the participation of MHCs). Under the influence of IL-2, the cytotoxicity of tumor-specific T-lymphocytes is clearly enhanced and, possibly, the resistance of the target cells decreases. It has been shown that rIL-2 therapy significantly increases the expression of the T-cell receptor, which is reduced on the blood lymphocytes of patients with mPCA. Adding rIL-2 to the culture of tumor cells suppresses their growth and proliferation [Vozianov AF et al. Cytokines. - Naukova Dumka. -Kiev. -1998, p. 78-92].

 When approaching the solution of the problem of treating patients with a generalized stage of uveal melanoma, we took into account several points.

 1. Preliminary studies of the immune status of patients with various stages of uveal melanoma have shown that cytolytic mechanisms with the participation of HK cells are dominant from the moment of the appearance of the tumor primordium in the eye to the transition to a disseminated form. However, while in the initial stages there is an increase in the cytolytic activity of HK cells with hyperplasia of this pool of cells, in the later stages, due to the long-term involvement of this link of the antitumor mechanism, all signs of depletion and decompensation are observed, which are manifested in a decrease in the cytolytic activity of HK cells of target K cells -562 and a decrease in the absolute number of HK cells themselves. These indicators correlate with an increased likelihood of metastasis and the rate of generalization [Yokoyama T. et al. Experimental model for metastasis of intraocular melanoma: preventive role of natural killer cells.- Jpn J. Opthalmol.-1989-vol.33-p.76-84 .; Yokoyama T. et al. Role of natural cells in intraocular metastasis.-Invest Ophthalmol Vis Sci-1986-vol. 27-p. 516-518].

 2. Using enzyme-linked immunosorbent assay and commercial test systems to determine the quantitative indicators of IL-2, we found that the vast majority of our patients (98%) have a profound deficiency of IL-2 at all stages of the development of the neoplastic process. Taking into account the important role of this cytokine in the regulation of the number of cytolytic populations of lymphocytes and their functional activity, as well as the deficit of its production revealed by us, associated with the above immune status defects, we suggested that elimination of IL-2 deficiency by exogenous administration of recombinant cytokine will restore balance in the cytokine network and the correction, if not all, of the most important cytolytic mechanism and thus support the tumor-bearing organism in the fight against the tumor.

 3. Preliminary studies of paraffin and freshly frozen blocks of uveal melanoma showed the practical absence of IL-2 receptors on tumor cells, which excluded the possibility of stimulating the progression of the neoplastic rIL-2 process.

 4. A wide range of biological properties of rIL-2, including the regulation of proliferation and differentiation of lymphocytes, including HK cells (and especially HK cells) with an increase in their cytolytic activity and stimulation of other immune mechanisms of the antitumor response (production of TNF-alpha cytokines, IFN-gamma), which also inhibit tumor growth, increased tumor infiltration by cytotoxic lymphocytes, etc.

 In the cytokine network, IL-2 is by far one of the most effective drugs in immunotherapy of such malignant tumors as renal cell cancer and melanoma. By the end of 1993, rIL-2 therapy was carried out in more than 2000 patients [AF Vozienko. et al. Cytokines. Biological and antitumor properties. -Kiev. -Naukova thought. S.131-158].

 For the first time, the successful use of human recombinant IL-2 was reported by Rosenberg et al. in 1987, together with autologous lymphokine-activated killer cells (LAC cells) for the treatment of advanced metastatic forms of cancer. This therapeutic approach is essentially an attempt to cause a regression of human malignant neoplasms using mechanisms to enhance immune defense [ibid.]. These points were the rationale for the preference of rIL-2 over all other cytokines. It was necessary to solve the question of the dosage of the drug and the regimen.

According to the primary protocol developed by the Rosenberg group, the drug was administered intravenously in the form of a bolus at high doses (1,500 μg / m ² x day or 720,000 ME / kg every 8 hours) for 5 days per course (1987). During the second course, LAC cells were infused simultaneously with IL-2. They were obtained by incubating the blood lymphocytes of patients with rIL-2 in vitro.

 According to Rosenberg et al. intravenous administration of high doses of rIL-2 together with LAK cells (lymphokine-activated killer cells) leads to complete regression of the primary tumor and metastases in 10% of patients with progressive forms of malignant melanoma and renal cell carcinoma (PAC) and improvement in 255 patients course of the disease.

 In 1994, Rosenberg et al. published the results of 7-year observation of treatment with high doses of rIL-2 (720,000 IU / kg administered x 3 per day for 5 days) of patients with PKK and melanoma, conducted at the National Cancer Institute in the USA. An objective reaction was observed in 17% of PAC patients; in 19 patients, complete remission lasted from 7 to 91 months.

 At the end of 1997, Rosenberg et al. presented data from 11 years of treatment with high doses of rIL-2 (alone or in combination with rIFN-alpha, TIL or LAC cells). Prior to immunotherapy, such patients underwent cytoreductive surgery (simultaneously with the removal of the primary tumor, the greatest possible number of metastases available for removal in various organs was resected). 8 weeks after surgery, IL-2 was prescribed in high doses according to various schemes. However, the authors indicate a high toxicity of the drug at high doses, which increases the requirements for assessing the status of patients with the exception of somatically severe patients in this type of treatment.

To reduce the toxicity of large doses of rIL-2 E Escudier et al. in 1994, they proposed their own scheme, according to which IL-2 at a dose of 24 million ED / m ² per day is administered as a prolonged 48-hour infusion x once a week for the following weeks. As a result of such treatment with rIL-2, objective remission was observed in 20 of 104 patients with PAC (in 4 - complete, and in 16 - partial). The median survival was 13 months. Grade 3 and 4 toxicity was rare. However, hypotension was observed in 53% of cases.

 The second drawback of the method of treatment with large doses of rIL-2 (alone or together with autologous LAC cells) in the clinic is the limited duration of the course in time (up to a month). Longer courses cause multiple side effects. Large masses of LAK cells formed after the introduction of IL-2, interact with the endothelial cells of the vessels, adhere to them and then lyse them. As a result, vascular permeability is impaired, blood plasma penetrates from the capillaries into interstitial tissue spaces, life-threatening fluid retention, hypotension, pulmonary edema, and body weight increase, i.e. a phenomenon called “vascular permeability syndrome” develops (Damle et al 1991).

 Due to the significant toxicity of large doses of IL-2, especially administered intravenously, and the impossibility of their prolonged use since 1990, attempts have been made to use lower doses of rIL-2 (20–40 times less doses) for the treatment of kidney cancer (PAC) recommended by Rosenberg).

 Atzpodien ct al. Was one of the first to apply small doses. 1991-1997 in Germany, Bellegrum et al 1991-1996 and others. In contrast to the Rosenberg regimen, these authors propose protocols in which rIL-2 is treated in small doses on an outpatient basis, the drug is administered subcutaneously.

The protocol begins with a starting dose of rIL-2 of 1.8 million ME / m ^{2 for} 6 days during the first week. Then, within 4 weeks, the dose of rIL-2 is daily increased by 100%, adjusted to 14.4 million / m ² per day. When remission occurs or the disease does not progress, a maintenance dose of 10.8 million ME / m ^{2 is} prescribed, which is administered once a week for a maximum of 12 weeks (Atzpodien et al. 1990; Schombuig et al, 1992) (Table 1) .

A treatment protocol in which rIL-2 of 9 million ME / m ² is administered every 12 hours for 5 days a week for 6 weeks (Atzpodien et., 1993).

 As a result of the application of treatment regimens with small doses of p IL-2 in the form of sc injection for 4 weeks, about half of patients with PAC have a stabilization of the disease, and 7% have partial remission. Patients have a good tolerance to the drug, mild side effects were observed (Atzpodien et al. 1990; Schomburg et al., 1992).

 When examining patients who underwent therapy with the indicated doses of rIL-2, it was found that after a 24-hour daily administration of low doses of rIL-2, the natural killer activity of blood mononuclear cells increases; the cytotoxicity of lymphocytes after preliminary incubation with rIL-2 (600 ME / ml) for 7 days is 65% versus 40% in the control. Therapy with low doses of p IL-2 leads to the same increase in the activity of EK cells as in the treatment with high doses, but, unlike the latter, does not have toxicity.

 In 1996, a group of scientists from the University of California (Bellegrun et al, Franklin et al., 1996) summarized data on the treatment of small doses of rIL-2 in 181 patients with kidney cancer (MPCC) from 1987 to 1995. Survival of the patients was a year later - 68%; after 2 years - 38% and after 3 years - 26%. In patients who were additionally given TIL, life expectancy after 3 years was even higher (36%). Objective remission in patients with MPCC receiving basic therapy (i.e., only IL-2) was 19% (3% - complete remission + 16% - partial), and in patients who received TIL infusion, 31% (12% -full remission, 16% - partial remission, p <0,093). The median duration of partial remission was 8 months, a full -41 + months. In 55 patients treated with IL-2 + TIL, 40 days after a nephrectomy, a positive therapeutic reaction occurred in 33% of cases (13% of patients had complete remission, 20% had partial remission).

In 1997, Figin et al. reported the results of treatment of 62 patients with MPCK with small doses of rIL-2 (2 million ME / m ² ) per day in the form of a long, 96-hour intravenous infusion once a week) together with the CD8 + TIL fraction. As a result of the therapy, 9.1% of patients had complete remission and 25.5% partial. The median survival, common to all patients, was 22 months (fluctuations from 2 to 70+ months).

A study of the anti-neoblastic effect of small doses of rIL-2 (0.18-6.0 million ME / m ² ) per day, close to the lowest, was carried out by Z Vlasveld et al. (1993) from the University of the Netherlands. When using the indicated doses of rIL-2 in patients with MPCC, the toxic effect of the drug appears only at the end of the 3rd week of therapy, while after the administration of high doses of rIL-2 recommended by Rosenberg, side effects develop within a week. In addition, adverse events at low doses of rIL-2 were transient without significant organ dysfunctions. After 5-18 weeks of intravenous administration of rIL-2 in doses of 0.18; 0.6, 1.8 or 6.0 million ME / m ² per day in patients there was a relative and absolute dose-dependent increase in the number of EK cells (CD16 + and CD56 + cells) in the blood. Bright CD56 + cells with low expression of CD antigen prevailed within this population of EK cells. The increase in the content of CD56 + cells in the blood was accompanied by an increase in the cytotoxicity of mononuclear cells with respect to the target cells of the K-562 culture, as determined in the test with radioactive Cr. The number and activity of T cells did not change; eosinophilia was observed. In assessing the clinical results, short-term remission was recorded in 1 of 13 patients undergoing therapy.

An increase in the number of CD3-CD56 + CD16 + cells in the blood of patients after therapy with small doses (3 million ME / m ² day) p IL-2 by other authors (Forties et al. 1990) has been proven.

Along with the study of the antitumor effect of low doses of rIL-2 (100-200 μg / m ² day), attempts were also made to treat with doses close to "physiological" (10-30 μg).

Parallel studies in 1989 by scientists from several laboratories of various US research institutes showed that intravenous administration of rIL-2 at a dose of 3 μg / m ² x day for 3 months does not lead to a change in the content of EK cells in the blood of cancer patients, while as a dose of 30 μg / m ² days during a 3-month course, it increases their content tenfold (Caligiuri et al 1991, 1993; Soiffer et al. 1994).

After a 4-month intravenous infusion of rIL-2 at a dose of 30 μg / m ² days, the content of EK cells in the blood of patients reached 1.0 • 10 ⁹ cells / l, accounting for 60-80% of all types of lymphocytes in the peripheral blood. Their number increases in proportion to the duration of the administration of p IL-2, mainly due to the brightly lit highly active CD56 +. According to M Caligiuri (1993), bright CD56 + cells are a unique subpopulation of EK cells, which is characterized by the expression of both high affinity IL-2P and c-Kit receptors on its membrane. Activation of bright CD56 + in the presence of c-Kit ligand leads to a double or triple increase in the proliferative activity of EK cells at low concentrations of IL-2.

 T. about. under the influence of low doses of p IL-2, there is an increase (by 60-80%) in the content of SPZ-56 + cells and an increase in their EK activity in the blood of patients with malignant diseases, but this does not lead to a pronounced regression of tumors. Nevertheless, the authors who proposed them consider that the prolonged use of low doses of rIL-2 is ideal for increasing the immune reactivity of cancer patients, including MPKK and melanoma, especially their treatment on an outpatient basis, during remission after radiation, chemotherapy and surgical interventions. Low concentrations of IL-2 do not cause toxic complications and can be used for a long time (within 3-4 months).

 T. about. the authors suggesting rIL-2 monotherapy of malignant tumors relied, when choosing a dose, on the dynamics of immunological parameters during treatment: an increase in the absolute and relative number, as well as the functional activity of HK cells involved in the mechanisms of tumor destruction, which was subsequently associated with improvement or stabilization clinics. However, the clinical effect in its pure form is really evaluated only after 8-10 weeks, according to the principles for evaluating the effectiveness of a chemotherapeutic drug adopted by WHO in 1994. A significant difference in the shifts in immunological parameters due to rIL-2 monotherapy in patients with regressed metastases and stabilization of the process not observed.

 When developing our protocol, we approached the issue in a fundamentally different way. We proceeded from the direct clinical effect (tumor destruction against the background of IL-2), which was evaluated using thermography, ultrasonography, scintigraphy, or computed tomography (equivalent methods) simultaneously with the administration of the drug. Empirically, following the route of dose escalation, it was found that the most optimal result is achieved with the introduction of from 1 to 1.5 million units of recombinant IL-2 (Roncoleukin).

Thus, by administering to patients with a disseminated stage of uveal melanoma (where the primary tumor was detected simultaneously with metastases in the liver), not subject to surgical treatment, various doses of rIL-2 from 250 thousand ME to 2.5 million ME per day under the control of thermography with glucose load , we determined the increase in the temperature gradient (Δt ^o ) directly above the tumor on the sclera (with its anterior location) or in the center of the cornea (with juxtapappillary localization). This made it possible to determine the most optimal dose of administration. So, for example, the temperature difference when measuring it at symmetrical points on paired eyes, if there is a tumor on one of them, before treatment is -0.6-1 ^o (the temperature is higher on the eye with the tumor, where the metabolic processes exceed those on the paired healthy eye). And Δt ^o rises to 4 degrees on the background of treatment with rIL-2 with an inversion of a larger indicator t ^o on a paired healthy eye. An increase in the administered dose of rIL-2 above 1.5 million units or a decrease below 1 million units was not accompanied by a large increase in Δt ^o in pair eyes. In our opinion, this indicates a maximum in the possibilities of tumor decay during treatment with IL-2, which is associated with administered doses of 1-1.5 million units.

 Decay is known to have a lower temperature during thermographic recording [Smith D.B.-A quantitative thermographic scanner. -J. Acta Thermographica-1979-vol. 4-N 2-p. 79].

Similar studies of thermographic parameters under conditions of carbohydrate loading (with the introduction of per os 100 g of glucose, which increases the sensitivity of the evaluation method) of patients with liver metastases in the background of 1-1.5 million units of RIL-2 revealed similar changes, confirming the correctness of our approach to selection doses of rIL-2 and assessment of the effectiveness of the treatment. Thus, foci of hyperthermia (Δ 0.6-1.2 ^o ) compared with surrounding tissues before treatment were replaced by hypothermia and an increase in the temperature gradient to 4 degrees against the background of the treatment with IL-2 in cases associated with subsequent complete or partial regression of metastases.

 Similar results were obtained with scintigraphy with radioactive technetium (reduction in the size of the "cold nodes").

 The same pattern was revealed in the duration of the course of treatment. 5 infusions were the best course. A further increase in the number of infusions did not produce an additional increase in the temperature gradient. The effect of the treatment lasted at least 8 weeks. Further, we observed either the appearance of new metastatic lesions, the appearance of which required a second course, or the stabilization of the process. The condition was ascertained by any of the listed control methods. Conducting additional courses caused additional regression of the primary tumor and / or metastases in some cases. No addiction to the drug was observed.

 Ultrasound treatment with the indicated doses of rIL-2 was accompanied by detection of cysts in the tumor (foci of hypoechogenic density appeared).

 Treatment of patients in whom the primary lesion and metastases were detected simultaneously, rIL-2 (Roncoleukin), followed by enucleation of the eye due to secondary hypertension, uncontrolled medication, and developed pain syndrome, confirmed the destruction of the tumor with the formation of cysts. Cell fragments, tissue detritus, pigmented slag blocked the drainage pathways of the outflow of intraocular fluid and caused hypertension. Destroyed tumor cells were histomorphologically revealed, and it was not even possible to determine the cellular type of structure.

 Enucleation or exentration (a type of cytoreductive therapy), carried out with a paliative purpose, during therapy with the same doses of rIL-2 in patients with a generalized stage (n = 30) was accompanied by complete regression of metastases in 10% of cases, partial regression in 23.3% of cases with a duration of remission from 1.5 months to 2 years (table. 2). The median remission was 8 months, which suggests a slowdown in the rate of progression of metastases.

 At the same time, the quality of life did not deteriorate, either remained unchanged or improved, since treatment was associated with the elimination of the secondary cancer-associated chronic fatigue syndrome, which is based on secondary immunodeficiency.

 Thus, we have empirically found a way to treat patients with uveal melanoma.

 The technical result of the invention is to reduce the size of the primary or metastatic tumor until complete regression.

 The technical result is achieved by the intravenous administration of recombinant yeast interleukin-2 (Roncoleukin), which is administered intravenously in a dose of 1-1.5 million units every other day, for a course of 5 infusions, in case of insufficient regression of the tumor and / or metastases, the drug repeatedly according to the same scheme every 8 weeks until a clinical effect is obtained.

 The method is as follows.

 1. When diagnosing eye melanoma, the patient is thermographed under conditions of carbohydrate loading in a standard way with measuring the temperature gradient at symmetrical points (directly above the tumor or at the point of projection) of both eyes. They state the result.

 If the patient has metastasis, the temperature is measured directly above the metastatic focus and the area of healthy surrounding tissue. Find the difference (temperature gradient). They state the result.

 2. A patient with uveal melanoma is injected with recombinant yeast IL-2 (Roncoleukin) intravenously drop 1 million units in 400 million physiological saline, slowly, at a rate of 26-52 drops per minute.

 3. The next day, repeat the thermography under conditions of a carbohydrate load. Report data.

4. If the temperature gradient increases to 4 ^o or higher, treatment with doses of 1 million units of Roncoleukin is continued, bringing the number of infusions to 5. Infusions are carried out every other day. If this indicator is less, the dose is increased to 1.5 million units and also the number of infusions is adjusted to N 5, spending them every other day.

 5. The courses are repeated as necessary (when new foci of liver metastases appear or old ones progress).

 Example 1

 Patient K. was admitted in February 1996 with a diagnosis of uveal melanoma in the T3-4N0M0 stage. Enucleated eyes. The uveal melanoma of the epithelioid cell structure was verified. The presence of extraocular growth nodes is confirmed.

On a follow-up examination in May 1997, focal metastatic changes in the liver were detected. They were measured with the determination of the maximum diameter (according to Karnofsky). The temperature gradient is determined under conditions of carbohydrate load (0.7 ^o ) using thermography. Roncoleukin started with an initial dose of 1 million units of rIL-2. The next day, re-carried out thermographic control with a carbohydrate load: the increase in temperature gradient was 3.7 ^o and reached a maximum (4.3 ^o ).

 The course of treatment with Roncoleukin was continued with the same dose administered - 1 million units. The number of infusions was brought to 5. After 8 weeks, at the end of the course, control was performed using scintigraphy with radioactive technetium and computed tomography: a complete regression of metastases was recorded. The duration of remission to date is 2 years 10 months. The last appearance for control was in March 2000.

Claims (2)

 1. A method of treating uveal melanoma, including the introduction of recombinant interleukin-2 (Roncoleukin) into the body, characterized in that the drug is administered intravenously in a dose of 1-1.5 million units every other day for a course of 5 infusions.  2. The method according to claim 1, characterized in that in case of insufficient regression of the tumor and / or metastases, the drug is administered repeatedly according to the same scheme every 8 weeks until a clinical effect is obtained.

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