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Publications (8)7.38 Total impact

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    ABSTRACT: This paper describes the clinical results and immunologic changes in cutaneous melanoma patients receiving active specific immunotherapy with autologous dendritic cell vaccine (DCV) in combination with cyclophosphamide used as immunologic adjuvant. Twenty eight patients with morphologically verified stage III-IV cutaneous melanoma receiving therapy in N. N. Petrov Research Institute of Oncology between 2008 and 2011 were included in the study. All patients signed an informed consent form. Nineteen patients (67,9%) received DCV in therapeutic setting, 9 (32,1%) received it in adjuvant setting. DCV therapy was well tolerated. No serious adverse events were registered. Frequent adverse events included Grade 1-2 unspecific symptoms (fever, fatigue, flu-like symptoms) observed in 22% patients after 3,5% of vaccinations. In therapeutic settings the use DCV lead to clinical effect (PR+SD) in 36,6% of patients. PR was observed in 5% of (95% CI 0-15%) patients, SD in 31,6% (95% CI 13-56%). Duration of the objective responses was 168-965+days. Addition of immunologic adjuvant (cyclophosphamide 300 mg/m2 IV 2 hours) 3 days before vaccination increased its efficacy. In this patients group (n=12) the therapy lead to clinical benefit in 42% (95% CI 17-69%) of cases, median time to progression was 91 (95% CI 55-126) days. This regimen was selected for adjuvant therapy. In the adjuvant therapy group (n=9) the median time to progression was 112 (95% CI 58-166) days. Immunologic monitoring showed correlation ofT- and B-cell immune response with DCV clinical efficacy (p<0,05), no correlation with delayed hypersensivity reaction was observed (p>0,1). DCV is well tolerated and shows immunological and clinical response in stage III-IV skin melanoma patients.
    Voprosy onkologii 01/2012; 58(2):212-21.
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    ABSTRACT: Tumor cells can acquire the mechanisms of immune response evasion. One of these mechanisms is synthesis and secretion in the microenvironment of immunosuppressive factors able to block immune cells maturation and function. We investigated plasma levels of TGFbeta1 and IL0 in 10 healthy volunteers and 114 patients with solid tumors (breast cancer--24, gastrointestinal tumors--27, renal cell carcinoma--15, lung cancer--9, ovarian cancer--13, cutaneous melanoma--18, primary multiple tumors--2, prostate cancer--6). TGFbeta and IL10 concentration in supernatants of 37 primary cultures (cutaneous melanoma, renal cell carcinoma and prostate cancer) and 10 cultures of melanoma during cultivation were also studied. VEGF was determined by immunocytochemistry staining in 15 melanoma culture specimens. The lowest level of TGFbeta1 was documented in rectal cancer patients, 30.05 +/- 12.30 ng/ml (p < 0.05), the highest in renal cell cancer and pancreatic cancer patients, 145.61 +/- 11.32 and 146.15 +/- 30.56 ng/ml (p < 0.001), respectively. Primary cultures of tumor cells can synthesize traceable amounts of TGFbeta1 and IL10. Cultures of cutaneous melanoma, renal cell carcinoma and prostate cancer cells did not change expression level of IL-10 after several passages. VEGF was expressed in 20% of cutaneous melanoma cultures. We suppose that tests for TGFbeta1, IL10 and VEGF in culture supernatants from tumor cell lines, on the surface of the cells purposed for cancer vaccines and in serum of patients to be vaccinated are potentially useful.
    Voprosy onkologii 01/2011; 57(6):759-66.
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    ABSTRACT: Due to immunological monitoring, most of aggressive tumor cells are selected capable of producing soluble factors of immunosuppression in their microenvironment. A ligand for NK- and T-cells receptor (MICA/B) activation is one of them. We investigated MICA concentrations in serum of 10 healthy volunteers and 114 patients with solid tumors (breast cancer - 24, gastrointestinal tumors - 27, renal cell carcinoma - 15, lung cancer - 9, ovarian carcinoma - 13, cutaneous melanoma - 18, primary multiple tumors - 2, prostate cancer - 6). The lowest level of MICA was reported in ovarian carcinoma (91.19 +/- 29.42 pg/ml), the highest - in rectal cancer (311.13 +/- 50.11 pg/ml) while mean concentration in healthy volunteers was (19.38 +/- 5.91 pg/ml). Cells of melanoma, renal cell carcinoma and prostate cancer became capable of producing MICA during cultivation and antitumor vaccine preparation. It is suggested that culture supernatants be tested for MICA contents as well as patients screened for vaccination. Selection of patients should be carried out on the basis of MICA molecules detection in blood flow.
    Voprosy onkologii 01/2010; 56(5):576-82.
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    ABSTRACT: There is a great variety of histological patterns of skin melanoma and, in particular, that of its metastatic patterns. Malignant melanocytes are capable of influencing tumor-associated antigen expression. As of now, several varieties of melanoma-associated antigens (MAA) have been identified: MART1/melan A, tyrosinase, MITF, gp100, members of MAGE family, S100, CD63 and CD146. Peptides isolated from such molecules can induce MHC-restricted response of cytotoxic T-lymphocytes. It has been shown that level and nature of specific antigen expression caused by melanocytes correlate with tumor stage and a relationship between survival and MAA expression on tumor cells identified. Morphological features, growth pattern and proliferation rate varied in melanoma cell cultures used in our study. Our experiments involved evaluation of changes in the properties of antigens HLA (class 1 and 2), tumor tissue samples and cells isolated from them, which were capable of stable proliferative activity during passages 5, 10, 15, 20, 25, 30 and 35, and assay for MAA content. Levels of the antigens were significantly lower following long-term culturing melanoma cell melanoma cells in vitro. At initial passages (1-5), antigen profile in most cultures was similar to that in tumor tissue samples. Later on each cell population showed greater antigen expression heterogeneity matched by increased number of cells going through mitotic cycle; their nuclei were stained with antibodies to Ki-67. No HLF A/B/C molecule expression took place during tumor cell culturing: stained cells--in 68.9% of cultures (passages 1-5) and 36.3% (passage 35). However, HLA DQ/DP/DR molecule identification showed an inverse relationship: 44.1% (passage 5) while virtually all the cell lines did synthesize those molecules after passage 35. Hence, MAA and MHC (class 1 and 2) antigens expression in tumor cell should be monitored when they are used for preparation of autologuos and allogenic vaccines. In case of allogenic vaccine production, cell lines capable of stable production of MAA should be selected.
    Voprosy onkologii 01/2008; 54(3):303-14.
  • V M Moiseenko, A B Danilova, N V Tiukavina
    Voprosy onkologii 02/2006; 52(3):258-66.
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    ABSTRACT: The use of genetically modified autologous tumor cells appears to be a promising approach for cancer therapy. A phase I/II trial was undertaken to define the feasibility, safety and antitumor effects of the autologous vaccine prepared by transferring tag7/PGRP-S gene into malignant melanoma and renal cell carcinoma cells. Twenty-one patients (17 with disseminated malignant melanoma and four with metastatic renal cell carcinoma) were enrolled in this study. Cytoreduction was performed in all cases prior to therapy. Autologous tumor cells were transfected with the tag7/PGRP-S gene, irradiated and injected intradermally every 3 weeks. Vaccinations were well tolerated by all patients, without clinically significant signs of toxicity. Delayed-type hypersensitivity was observed in 48% of cases. Antitumor immune response was observed in 95% of patients. There were no complete or partial responses; however, a minor response was achieved in one patient with renal cell carcinoma. The stabilization of neoplastic disease was observed in eight patients (seven with malignant melanoma and one with renal cell carcinoma). Median time to tumor progression was 3 months. The approach suggested here appears to be well tolerated and produces a number of durable clinical effects. Further studies are required to determine whether promising effects on immune activation will result in an actual clinical benefit for patients with malignant melanoma and renal cell carcinoma.
    Annals of Oncology 02/2005; 16(1):162-8. · 7.38 Impact Factor
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    ABSTRACT: A prospective (phase I-II) trial was undertaken to study the efficacy and toxicity of gene therapy with tag 70-modified autologous tumor cells in 32 patients with metastatic renal cell carcinoma (RC) (5) and melanoma (MBL) (27) treated at the Institute's Clinic (2001-2003). Resected material was reduced to cell culture, which was transfected with tag 70 gene and devitalized by irradiation. Immune blotting was used for gene expression. Clinical and immunological effectiveness was evaluated in 22 patients (MBL--17 and RC--5) who received 1-6 injections (3 on the average). Full course of vaccination was given to 8 (MBL--6 and RC--2). No complete or partial response was reported while least regression (50%) was registered in a case of RC metastatic to the lung. According to CT and ultrasound evidence, stabilization was achieved in 5 (23.8%) (MBL--4 and RC--1). Relapse-free period was 6.5+/-3.5 months beginning from the start of treatment. The vaccine was well tolerated while DHT reaction was observed in 47.6% (10 out of 17) of primary immunized patients. A trend of increased content of T- and B-cells in peripheral blood and intensified functional activity was established.
    Voprosy onkologii 02/2004; 50(3):293-303.
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    ABSTRACT: Resected material was used from 108 patients with disseminated skin melanoma and 47 patients suffering metastasized renal tumors to test procedures of tumor cell culture preparation and to search the best parameters. Gene tag 7 transfer, liposome delivery and electroporation were employed to stimulate immunogenic tumor cells. The transfer results were evaluated by expression of beta-galactosidase and EGFP genes whose products were detected microscopically. Transfer efficiency was boosted by 30% due to selecting suitable parameters of tumor cell modification. Maximum effectiveness was attained by individualized choice of the parameters. Yet, undoubtedly, the best way of cell isolation was mechanical fragmentation of tumor. To speed up cell production, DMEM/F12 medium should be recommended. It should contain cattle embryonic serum (20%), conditioned medium of cultured fibroblasts of human embryonic lungs (20%), transferin, insulin and selenium (standard dose).
    Voprosy onkologii 02/2004; 50(2):219-27.