Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0684249 (lung carcinoma)
 23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We conducted a clinical trial of adoptive immunotherapy with lymph node-lymphokine-activated killer (LN-LAK) cells and recombinant interleukin 2 (rIL-2) for a surgical adjuvant therapy of pathologic stage I non-small cell lung cancer. The regimen consisted of the subcutaneous administration of low-dose rIL-2 for 6 consecutive days and the transfer of ex vivo generated LAK cells from regional lymph node lymphocytes, obtained at the time of surgical operation. A group of 19 patients with primary lung cancer received the immunotherapy about 2 weeks after surgery (pulmonary lobectomy). The regimen was postoperatively well tolerated by the patients. In peripheral blood lymphocytes (PBL) obtained after the treatment, the proportion of CD3+ T cells predominantly increased with the increase of CD4+ T cell subsets. On the other hand, the proportion of CD20+ B cells decreased. Both NK and LAK activity of PBL significantly increased. However, the immunomodulatory effects did not result in a prolongation of the postoperative survival time in comparison to the postoperative survival of patients (n = 21) with surgery alone during the same period. These results suggested that the treatment with low-dose LN-LAK cells and concurrent low-dose IL-2 could, therefore, neither reduce nor eradicate minimal micrometastatic diseases.
Lung Cancer 1999 Dec
PMID:Postoperative adjuvant adoptive immunotherapy with lymph node-LAK cells and IL-2 for pathologic stage I non-small cell lung cancer. 1059 24

Cyclooxygenase-2 (COX-2), the enzyme at the rate-limiting step of prostanoid production, has been found to be overexpressed in human lung cancer. To evaluate lung tumor COX-2 modulation of antitumor immunity, we studied the antitumor effect of specific genetic or pharmacological inhibition of COX-2 in a murine Lewis lung carcinoma (3LL) model. Inhibition of COX-2 led to marked lymphocytic infiltration of the tumor and reduced tumor growth. Treatment of mice with anti-PGE2 mAb replicated the growth reduction seen in tumor-bearing mice treated with COX-2 inhibitors. COX-2 inhibition was accompanied by a significant decrement in IL-10 and a concomitant restoration of IL-12 production by APCs. Because the COX-2 metabolite PGE2 is a potent inducer of IL-10, it was hypothesized that COX-2 inhibition led to antitumor responses by down-regulating production of this potent immunosuppressive cytokine. In support of this concept, transfer of IL-10 transgenic T lymphocytes that overexpress IL-10 under control of the IL-2 promoter reversed the COX-2 inhibitor-induced antitumor response. We conclude that abrogation of COX-2 expression promotes antitumor reactivity by restoring the balance of IL-10 and IL-12 in vivo.
 ...
PMID:Specific inhibition of cyclooxygenase 2 restores antitumor reactivity by altering the balance of IL-10 and IL-12 synthesis. 1060 31

A total of 29 previously untreated patients with histologically proven malignant pleural mesothelioma, with an ECOG score of < or = 2 and UICC stage I-II disease, were enrolled between May 1994 and October 1996. On days 1 and 2, 18 x 10(6) IU/day of rIL-2 was administered by continuous intravenous infusion, and 6 x 10(6) IU/day of rIL-2 by subcutaneous injection on days 5--20 inclusive of a 42-day cycle. Further treatment was administered if no radiological disease progression was demonstrated. A total of 29 patients were assessable for toxicity and 25 for response, and 49 cycles of IL-2 were administered with a median of one per patient (range, < 1-4). Toxicity included mild fever, nausea and vomiting, and skin rashes, < grade II. Three patients failed to complete one cycle of treatment because of toxicity and one died of disease before response evaluation. Two patients achieved a partial response (8%, 95% CI 1-26%) surviving 18.1 and 18.7 months from diagnosis. A total of 11 patients (44%, 95% CI 24-65%) with stable disease had a median survival of 13.6 months (range 6.5-33.8). The median survival was 8.6 months (range 3.7-34.5) for the 12 patients with progressive disease (48%, 95% CI 28-69%). This regimen of rIL-2 is well tolerated and shows limited activity in mesothelioma.
Lung Cancer 2001 Jan
PMID:A phase II study of combined intravenous and subcutaneous interleukin-2 in malignant pleural mesothelioma. 1116 68

Malignant pleural mesothelioma is often unresectable at diagnosis, is refractory to cytotoxic agents and is frequently complicated by pleural effusion. The expected survival range for patients with or without involvement of visceral pleura is respectively 1-9 and 9-12 months; mesothelioma-related pleural effusion severely impairs the patients' quality of life and easily relapses after conservative treatments. Intrapleural administration of IL-2 is reported to be effective both in tumor-associated malignant pleurisy and on primary mesothelioma, whereas few data exist about IL-2 systemic administration. In order to assess the palliative and therapeutic activity of IL-2 in unresectable pleural malignant mesothelioma with pleural effusion, we performed a phase II study on 31 consecutive patients (M/F 16/15; median age 61 years, range 40-84; PS ECOG 0 n=7; ECOG 1 n=15; ECOG 2 n=9; stage IA n=13; IB n=9; II n=7; IV=2) who received first-line therapy with intrapleural repeated instillation of 9000000 I.U. IL-2 twice/weekly for 4 weeks, after needle thoracenthesis. In nonprogressing patients, 3000000 I.U. IL-2 were subcutaneously administered thrice weekly for up to 6 months. Toxicity (WHO criteria) with intrapleural IL-2 consisted of grade 3 fever in 6/31 (19%) patients and of cardiac toxicity (failure) grade 3 in one patient (3%); toxicity during subcutaneous treatment was mild to moderate, mainly a flu-like syndrome. In 28/31 (90%) of patients there was no further or minimal (asymptomatic) pleural fluid collection (according to Paladine criteria); pleurisy relapsed only in 1/28 patients after 19 months. Tumor objective response (WHO criteria), evaluated by CT, occurred in seven patients (one CR and six PR; ORR 22%); ten patients achieved SD and 14 patients progressed. Median overall survival was 15 months (range 5-39) in all patients. IL-2 intrapleural administration followed by low-dose IL-2 subcutaneously in pleurisy-complicated malignant mesothelioma is feasible and active both in palliation of pleural effusion and on primary tumor, with manageable toxicity. The overall survival observed in nonprogressing patients warrants further randomized studies with IL-2 aimed to the patient outcome.
Lung Cancer
PMID:Palliative and therapeutic activity of IL-2 immunotherapy in unresectable malignant pleural mesothelioma with pleural effusion: Results of a phase II study on 31 consecutive patients. 1116 11

PDT has been reported to induce cancer cell expression of cytokines, such as IL-6 and TNF-alpha, but it has been unclear whether cytokine expression by cancer cells is directly related to the antitumor effect of PDT. We treated Lewis lung carcinoma (LLC) cells with a new photosensitizer, mono-L-aspartyl chlorin e6 (NPe6) and light from a diode laser and found that expression of the mRNA of IL-2, IL-6, and TNF-alpha was increased by NPe6-mediated-PDT 6 hr later. To elucidate the mechanism of the direct anti-tumor effect of cytokine expression, we examined the photosensitivity of cytokine-gene-transfected cells, namely LLC-IL-2, LLC-IL-6, and LLC-TNF-alpha cells, by MTT assay. The IL-6 gene transfected, LLC-IL-6 cells were significantly more sensitive to cytotoxic effects than the parent LLC cells and other cytokine gene-transfected cells. This finding indicates that IL-6 expression modulates cellular sensitivity to PDT and that IL-2 and TNF-alpha expressions does not. In addition, the apoptosis of LLC-IL-6 cells induced by NPe6-PDT was greater than in the other cells as determined by DNA fragmentation and staining of apoptotic nuclei. Because IL-6 has been reported to induce apoptosis by downregulating expression of Bcl-2, we analyzed the expression of apoptosis-related Bcl-2, Bax, and cytochrome C by Western blot analysis. Decreased expression of Bcl-2 and cytochrome C was observed in both LLC cells and LLC-IL-6 cells. Bax protein increased in a time-dependent manner, and the ratio of Bax to Bcl-2 rose markedly after PDT in LLC-IL-6 cells. These results suggest that the increased sensitivity of LLC-IL-6 cells to PDT-induced cytotoxicity results from the high ratio of Bax to Bcl-2 in the IL-6-dependent apoptotic pathway. In conclusion, IL-6 expression plays a role in cellular sensitivity to PDT, and combination of IL-6 and PDT may provide a new strategy for cancer treatment.
 ...
PMID:Increased cytotoxic effects of photodynamic therapy in IL-6 gene transfected cells via enhanced apoptosis. 1147 50

Increased production of immunosuppressive IL-10 by non-small cell lung cancer (NSCLC) and increased plasma IL-10 concentrations in NSCLC-patients have recently been correlated to reduced survival. We earlier demonstrated suppression of IL-2 secretion in NSCLC-patients. We now analyzed the influence of IL-2 suppression on survival in NSCLC-patients and influence of IL-10 on IL-2 secretion. The correlation of the IL-2-concentration in whole blood cell cultures from 90 NSCLC-patients at the time of diagnosis to survival was analyzed by using crit-level, the Kaplan-Meier method and the log-rank test. IL-2 secretion capacity at the time of diagnosis significantly influenced survival in NSCLC-patients. With a cut-off value for IL-2 of 1100 pg/ml, the difference in survival was significant with a P-value of 0.014 in the whole patient group. In the subgroup of surgically treated patients (n=33), survival was different with a P-value of 0.011. Moreover, secretion of IL-2 was inhibited in a dose-dependent manner upon addition of IL-10 in whole blood cell cultures from normal individuals. Thus, suppression of IL-2 secretion is predictive for survival of NSCLC-patients and may be mediated by tumor-derived IL-10.
Lung Cancer 2001 Dec
PMID:Cytokine secretion: clinical relevance of immunosuppression in non-small cell lung cancer. 1172 Jul 46

Interleukin (IL)-12 enhances natural killer (NK) activity and induces interferon gamma (IFN-gamma) production. Recently, it was shown that IL-12 induces IL-10 production by human T cells and NK cells, as a negative feedback for IL-12-induced immune responses. In the present study, in order to investigate the functions of host immune cells existing in contact with cancer cells, we examined the effect of IL-12 on the induction of non-major histocompatibility complex (MHC)-restricted killer activity and of IFN-gamma and IL-10 production by pleural and peripheral blood mononuclear cells (MNC), isolated from 40 lung cancer patients and 20 control subjects. IL-12 induced significant killer activity in pleural MNC from lung cancer patients, as well as those in peripheral blood, against a small cell lung cancer cell line (SBC-3). In lung cancer patients, pleural MNC incubated with IL-12 produced more IFN-gamma than blood MNC. In addition, when stimulated with both IL-12 and IL-2, pleural MNC produced more IL-10 than blood MNC. This is the first study reporting that MNC from pleural effusions of patients with lung cancer can produce both type 1 (IFN-gamma) and type 2 (IL-10) cytokines following exposure to IL-2 and IL-12. These observations suggest that control of IL-10 production at the microenvironment level may be important for the efficacy of human lung cancer immunotherapy with IL-12.
Lung Cancer 2002 Feb
PMID:IL-12-induced production of IL-10 and interferon-gamma by mononuclear cells in lung cancer-associated malignant pleural effusions. 1180 90

The majority of patients with advanced lung cancer die within a few years. Accordingly, new therapeutic modalities need to be developed. Interleukin (IL)-12 was previously known as natural killer (NK) cell stimulatory factor or cytotoxic lymphocyte maturation factor. By virtue of its effects on T cells and NK cells, IL-12 seems to be one of the key cytokines that regulates cell-mediated anti tumor immune responses. Recently, there has been a substantial interest in the potential applications of IL-12 in the treatment of lung cancer. However, there have been no reports about the effect of IL-12 on peripheral blood mononuclear cells (PBMCs) obtained from lung cancer patients in an autologous setting. In this study, we examined the cytotoxicity of PBMC activated by IL-2, IL-12 or both against K562 or autologous lung cancer cells. In contrast to the effect of IL-2 on NK activity, IL-12 alone augmented NK activity against K562 cells, but not against autologous lung cancer cells. IL-12 augmented the IL-2 mediated cytotoxicity of PBMC against both K562 and autologous lung cancer cells. In the absence of IL-2, IL-12 alone cannot induce an autologous anti-tumor effect in vivo. In summary, our results clearly demonstrated that IL-12 can augment the cytolytic activity of PBMC against K562 and autologous lung cancer cells when combined with IL-2, although, IL-12 alone was unable to induce a marked increase in the cytotoxicity against autologous lung cancer cells. These results suggest that an administration of IL-12 in combination with IL-2 may be a useful therapeutic option for solid tumors.
Lung Cancer 2002 Mar
PMID:Interleukin-12 augments cytolytic activity of peripheral blood mononuclear cells against autologous lung cancer cells in combination with IL-2. 1184 9

We have developed a novel immunostimulatory molecule against tumor cells, composed of an anti-FcgammaRIII (CD16) scFv fused to the platelet-derived growth factor receptor (PDGFR) transmembrane region. This fusion molecule was stably expressed on the tumor cell surface and retained the ability of the parental antibody to bind soluble CD16. Tumor cells expressing anti-CD16 scFv triggered the release of IL-2 by Jurkat-CD 16/gamma cells and of TNFalpha by monocytes when co-cultured with these cells. Furthermore, NK cells could kill scFv-transfected HLA+ class I H1299 lung carcinoma tumor cells, but not the parental cells, indicating that anti-CD16 scFv tumor expression prevents the killer inhibitory receptor (KIR)-mediated inhibition of NK cell cytotoxicity. This anti-CD16 scFv tumor expression also enhanced tumor phagocytosis by IFNgamma-activated macrophages, a mechanism known to induce a protective long-term adaptative immunity to tumors. In vivo Winn tests performed in SCID mice showed that the expression of anti-CD16 scFv on tumor cells, but not of the negative control anti-phOx scFv, prevented tumor cell growth. Thus, expression of FcR antibodies or other FcR-specific ligands on tumor cells represents a novel and potent antibody-based gene therapy approach, which may have clinical applications in cancer
 ...
PMID:Bypassing tumor-specific and bispecific antibodies: triggering of antitumor immunity by expression of anti-FcgammaR scFv on cancer cell surface. 1189 40

Chemokine gene transfer represents a promising approach in the treatment of malignancies. Macrophage-derived chemokine (MDC) (CCL22) belongs to the CC chemokine family and is a strong chemoattractant for dendritic cells (DC), NK cells and T cells. Using adenoviral vectors, human MDC gene was transferred in vivo to investigate its efficacy to induce an antitumor response and to determine the immunologic mechanisms involved. We observed that intratumoral injection of recombinant adenovirus encoding human MDC (AdMDC) resulted in marked tumor regression in a murine model with pre-established subcutaneous 3LL lung carcinoma and induced significant CTL activity. The antitumor response was demonstrated to be CD4+ T cell- and CD8+ T cell-dependent. Administration of AdMDC induced chemoattraction of DC to the tumor site, facilitated DC migration to draining lymph nodes or spleen, and finally activated DC to produce high levels of IL-12. Furthermore, a significant increase of IL-4 production within the tumors was observed early after the AdMDC administration and was followed by the increase of IL-12 and IL-2 production. The levels of IL-2, IL-12 and IFN-gamma in serum, lymph nodes and spleen were also found to be higher in mice treated with AdMDC as compared with that in AdLacZ- or PBS-treated mice. The antitumor response induced by AdMDC was markedly impaired in IL-4 knockout mice, suggesting an important role of IL-4 in the induction of antitumor immunity by MDC. These results suggest that MDC gene transfer might elicit significant antitumor effects through efficient induction of antitumor immunity and might be of therapeutic potentials for cancer.
 ...
PMID:Macrophage-derived chemokine gene transfer results in tumor regression in murine lung carcinoma model through efficient induction of antitumor immunity. 1204 Apr 61


<< Previous 1 2 3 4 5 6 7 Next >>