"PL597" Dotaz Zobrazit nápovědu
Závěrečná zpráva o řešení grantu Interní grantové agentury MZ ČR
Přeruš. str. : il. ; 32 cm
Optimalizace genové léčby nádorů využitím kombinací cytokinových genů navzájem a s chemoterapií. Účinek léčby a "homing" geneticky modifikovaných buněk je monitorován pomocí průtokové cytofluometrie. XXX XXX XXX
- Konspekt
- Patologie. Klinická medicína
- NLK Obory
- embryologie a teratologie
- onkologie
- alergologie a imunologie
- genetika, lékařská genetika
- NLK Publikační typ
- závěrečné zprávy o řešení grantu IGA MZ ČR
- MeSH
- cytokiny genetika škodlivé účinky terapeutické užití MeSH
- imunoterapie MeSH
- interferony imunologie terapeutické užití MeSH
- interleukiny terapeutické užití MeSH
- lidé MeSH
- nádory patologie terapie MeSH
- tumor nekrotizující faktory imunologie terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Cytokine gene therapy has recently become a new prospective modality in the treatment of cancer. Active immunization with gene-modified tumour cells in experimental systems employs either live Vaccines at subthreshold, non-tumorigenic doses, or irradiated cytokine-producing vaccines. The effects exerted on tumour cells by the vaccine-produced cytokines are usually pleiomorphic, either direct (cytolysis, upregulation of MHC, TAA, or adhesion molecule expression, terminal differentiation) or indirect (recruitment, amplification and activation of APC, helper and defence effector cells, damage of the blood supply) or both. The aim of this article is to review and summarize recent results of the cytokine gene therapy in experimental tumour systems, as well as to discuss the prospects and limitations of this novel approach in the management of cancer patients. The review is primarily focused on the therapeutic vaccination; however, when relevant, the results obtained with preventive vaccination are also briefly discussed.
The present prospective study was designed to assess whether the renal cell carcinoma (RCC) patients treated with recombinant interferon alpha (IFN alpha), whose tumours respond (responders) and do not respond (non-responders) to IFN alpha therapy, differ with regard to in vitro sensitivity of peripheral blood lymphocytes (PBL) to interleukin 2 (IL-2), IFN alpha, and IFN gamma signals prior to therapy. Twenty-one patients with advanced RCC after nephrectomy, 15 responders and 6 non-responders, were entered into a protocol. The protocol involved isolation and freezing of PBL samples followed by IFN alpha treatment of patients, assessment of proliferative and activating PBL responses, and evaluation of the therapeutic results. Freezing of PBL samples allowed us to compare the in vitro reactivity of PBL from individual RCC patients, repeatedly and under standard conditions. Substantial differences in proliferative responses to the mitogenic IL-2 signal of PBL derived from IFN alpha responders and nonresponders were found. Whereas the IL-2-induced proliferative responses of PBL from normal blood donors and IFN alpha responders were comparable, the proliferative responses of PBL from IFN alpha non-responders were significantly decreased, suggesting an immune dysfunction in non-responders. Cultivation of PBL from RCC patients in medium supplemented with IFN alpha increased the lytic activity of PBL from IFN alpha responders directed against RCC targets; no such increase could be observed with non-RCC targets, with PBL from IFN alpha non-responders, or with PBL from normal blood donors. Detection of phytohaemagglutinin (PHA)-stimulated IFN gamma secretion by PBL at the single cell level using enzyme-linked immunospot (ELISpot) assay revealed that the ability to produce IFN gamma was substantially decreased in IFN gamma non-reponders, as compared to IFN alpha responders and to normal blood donors.
The present study was designed to examine the kinetics and function of peritoneal exudate cells (PEC) during local interleukin 2 (IL-2) gene therapy of the X63-Ag8.653 plasmacytoma growing in the peritoneal cavity. BALB/c mice were inoculated i.p. on day 0 with a tumorigenic dose of the syngeneic plasmacytoma and on day 1 with non-tumorigenic plasmacytoma cells carrying an inserted IL-2 gene and producing constitutively IL-2. At regular time intervals the experimental mice were sacrificed and their peritoneal exudate cells were used for phenotypic analysis and Cr-51 microcytotoxicity assay. On the first day after i.p. inoculation of the genetically modified plasmacytoma cells the percentage of Thy 1.2+, CD3+, TCR alphabeta+ T lymphocytes and NK+ cells in the peritoneal fluid dramatically increased. The levels of the positive cells continually decreased until day 11, when the values of normal, healthy mice were obtained. The percentage of Thy 1.2+ and CD3+ cells remained at these, or slightly lower values, until the end of the observation period. A similar, though more slowly descending kinetics was seen in the CD5+ cell population, whereas the CD8+ cells, compared to the controls, exhibited only a short-term peak between days 3 and 5, and the values of TCR alphabeta+ and NK+ cells exhibited a second peak between days 25 and 48. The percentage of TCR gammadelta+ cells showed a permanent, moderately elevated plateau from day 1 till the end of the observation period. In control, untreated mice, inoculated i.p. with the X63-Ag8.653 plasmacytoma, the kinetics of peritoneal exudate cells was different. A moderate, permanent elevation of all of the T and NK cell subsets examined occured during the observation period. In addition, the percentage of TCR alphabeta+, TCR gammadelta+ and NK+ cells further increased continually from day 11 till the end of the observation period. The cytolytic activity of the peritoneal exudate cells was examined in vitro concurrently with FACS phenotyping. Free tumour-specific killer cells generated in the peritoneal fluid due to the local IL-2 gene therapy were found only on day 6, and these cells were cytolytic for both, the parental X63-Ag8.653 and the genetically modified X63-m-IL-2 plasmacytoma cells.
- MeSH
- genetická terapie MeSH
- interleukin-2 MeSH
- myši inbrední BALB C MeSH
- nádory terapie MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- MeSH
- biomedicínský výzkum MeSH
- buňky NK fyziologie MeSH
- dospělí MeSH
- fixní kombinace léků farmakologie MeSH
- imunoterapie MeSH
- interleukin-2 farmakologie imunologie MeSH
- karcinom z renálních buněk farmakoterapie imunologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- senioři MeSH
- spolupráce lymfocytů MeSH
- vinblastin farmakologie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
The toxicity of high IL-2 doses required for therapy of generalized neoplasms limits at present the large-scale application of IL-2 treatment to the management of cancer. In 1988, it was proposed that insertion of a cloned IL-2 gene into the genome of somatic cells, followed by transfer of the genetically engineered cells constitutively producing IL-2 to the vicinity of the growing tumour, may help overcome the problem of the IL-2 toxicity (Bubenik et al, Immunol Lett 19: 279-282, 1988). It has been demonstrated that this novel approach can be utilized for the treatment of tumors growing in syngeneic, allogeneic and xenogeneic hosts and that both local and systemic administration of the genetically engineered somatic cells can substantially inhibit tumour growth. The aim of this article is to review and summarize recent results of the local and systemic transfer of genetically engineered cells and to discuss the prospects and limitations of the IL-2 gene therapy of cancer. The review is primarily focused on IL-2; however, when relevant, the results obtained with other cytokine gene therapy are also briefly discussed.
- MeSH
- experimentální nádory terapie MeSH
- genetická terapie MeSH
- interleukin-2 MeSH
- nádory terapie MeSH
- Publikační typ
- přehledy MeSH
- MeSH
- buněčná imunita MeSH
- buňky NK cytologie MeSH
- genetická terapie metody MeSH
- interleukin-2 genetika terapeutické užití MeSH
- myši MeSH
- plazmocytom imunologie terapie MeSH
- rekombinantní proteiny terapeutické užití MeSH
- T-lymfocyty cytologie MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
