摘要:

Summary:Many studies show defective immune responses in patients diagnosed with cancer. Most of the diverse nonspecific approaches used to stimulate the immune system to recognize and destroy abnormal tumor cells have limited clinical utility. Attempts to identify tumor-specific antigens and to improve the antigen presentation were equally disappointing. It appears that some of these failures can be explained by tumor-induced immunosuppression. A large number of cytokines, hormones, and other molecules secreted by tumors were demonstrated to have immunomodulating properties. The most extensively studied immunosuppressive molecules secreted by tumors are transforming growth factor-β (TGFβ), interleukin 10 (IL-10), and prostaglandin E2(PGE2). TGFβ in particular may play a key role in tumor-induced immunosuppression. It is the most potent immunosuppressor described to date, and it has been consistently isolated from variety of tumor cell lines and detected in plasma of tumor-bearing hosts. Level of TGFβ production by tumor cells correlates with their metastatic potential, and TGFβ neutralization not only prevents development of metastases, but also inhibits growth or completely eradicates tumors as diverse as breast cancer, melanoma, and malignant gliosarcoma in animal models. PGE2may play significant role in early stages of tumor development, promoting the process of tumorigenesis in some tumors. Research on reversal of tumor-induced immunosuppression promises new, more powerful, and less toxic approaches to cancer therapy. Existence of molecule(s) consistently secreted by different types of tumors and responsible for tumor progression raises the possibility of a single, universal assay to monitor progression and recurrence in many malignancies, including those that currently do not have reliable plasma markers.

ISSN:1524-9557    

出版商:OVID    

年代:1997

数据来源: OVID

ISSN:1524-9557    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Summary:Summary: In an attempt to potentiate the therapeutic index of cytokines, recombinant mouse granulocyte/macrophage colony-stimulating factor (GM-CSF) and recombinant human tumor necrosis factor a (TNF-α) were encapsulated in large (0.3-2.2 yam) multilamellar vesicles composed of various lipids, using several encapsulation methods. Liposomal cytokine activity was tested in vitro and in vivo and was compared with that of the soluble cytokines. The main observations were as follows: (a) The mean encapsulation efficiency, as determined by bioassays, was 49-79%, depending on the formulation, for GM-CSF, and 48% for TNF-α; (b) some of the entrapped cytokine preparations displayed high stability at 4°C, with <30% loss of biologic activity during a 4-month period; (c) release of TNF-α, but not of GM-CSF, from the liposomes was required for their biological activity in vitro; (d) plasma half-lives (t1/2α, t1/2β) and the area under the curve (AUC) of the entrapped cytokines were 10-20 times greater than those of the soluble cytokines; (e) the toxicity of liposomal TNF-a was onethird and one-seventh that of soluble TNF-α in normal and tumor-bearing mice, respectively; (f) administration of liposomal GM-CSF (5 X 104-2 X 105U, one to five times) to normal and 5-fluorouracil-treated mice led to a two- to fourfold increase in the absolute number of peritoneal and spleen leukocytes and of GM colony-forming cells in the spleen, as compared with the levels obtained using soluble GM-CSF; and (g) under the experimental conditions used, neither free nor liposomal GM-CSF significantly increased the absolute number of blood leukocytes, although liposomal GM-CSF markedly (threefold) enhanced the level of blood granulocytes. Collectively, these findings suggest that liposomeentrapped GM-CSF and TNF-a may be more efficacious immunomodulators than the soluble cytokines.

ISSN:1524-9557    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Summary:Summary: This investigation is based on a hypothesis that a biological response modifier, interferon-α-2b (IFN), when conjugated with a specific monoclonal antibody (mAb) and given to tumor-bearing animals before the administration of radiolabeled mAb, may not only augment the tumor uptake but may also impede the liver and blood uptake, because the mAb associated with the conjugate may block nonspecific hepatic binding sites and scavenge circulating antigens. ME 31.3 and anti-carcinoembryonic antigen (CEA) F-6 (IgG-2a) specific for human melanoma and colorectal carcinoma, respectively, were chosen as prototype mAbs and conjugated with IFN-α-2b for evaluation in athymic nude mice bearing respective experimental tumors. The mAb specificity for the tumor cell line was examined by binding assays and Kdvalues were determined to be 1.96 x 10-9M and 5.9 x 10-9M for ME 31.3 and anti-CEA F-6, respectively. Thirty micrograms of conjugate, prepared chemically and purified chromatographically (IFN-mAb:l:l), was administered intravenously to each animal and 3 h later followed by an intravenous injection of 20 μg F(ab')2 of corresponding mAb labeled with 300 μCi Tc-99m (1.5 Ci/mmol). Twenty-four hours later, in melanoma-bearing animals, not only did the tumor uptake increase, but also the liver uptake decreased by 75%. Tumor/muscle and tumor/blood ratios also enhanced by 200 and 500%, respectively. Consistent with ME 31.3, the tumor uptake with anti-CEA F-6 also increased (p=0.00) and the liver uptake decreased (p=0.01). Similarly, tumor/muscle (p=0.01) and tumor/blood (p=0.02) ratios also increased significantly. Results indicate that IFN:mAb conjugate may improve diagnostic and therapeutic potential of mAbs, and is worthy of further studies.

ISSN:1524-9557    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Summary:High doses of tumor necrosis factor-α (TNF) seem to be effective in the treatment of solid tumors in the extremities. By applying current intensive care technology, systemic administration of high doses of TNF levels might be feasible for the treatment of cancer in other localizations. To establish the early and late effects of high systemic TNF levels on the lungs, we determined lung function parameters in 12 patients before and after hyperthermic isolated limb perfusion (HILP) with TNF and melphalan. Because of leakage during perfusion, mean maximum systemic TNF levels of 60.0 ng/ml (range, 0.3-356 ng/ml) were obtained. Significant alterations in the vital capacity (VC), the capillary blood volume (Vc), the diffusing capacity of the alveolocapillary membrane (Dm), and the transfer capacity of the lungs for carbon monoxide per unit alveolar volume (Kco) were observed 1 week after HILP. Eight weeks after HILP, they returned to pretreatment value. Alterations in lung functions were not related to the maximum systemic TNF level. In conclusion, disturbances in pulmonary functions are observed in patients after HILP with TNF and melphalan. These disturbances, which are probably partly caused by high systemic TNF levels, are reversible and would not preclude administration of systemic TNF in high doses.

ISSN:1524-9557    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Summary:In an adjuvant clinical trial for high-risk patients with malignant melanoma by using recombinant interleukin-2 (rIL-2) and recombinant interferon-α2b (rIFN-α2b), we monitored the development of antibodies against rIFN-α and various immunoparameters as biologic markers for IFN activity in vivo. Thirty-one patients (22 men, nine women) with high-risk malignant melanoma received eight 6-week cycles of rIL-2 and rIFN-α. Serum samples of all patients were screened for the presence of antibodies against IFN-α by a solid enzyme immunoassay (EIA). Specimens testing positive in the EIA were assessed for their ability to neutralize the antiviral effects of IFN-α in vitro in an antibody-neutralizing bioassay (ANB). Furthermore, serum levels of neopterin, β2-microglobulin, soluble IL-2 receptor (sIL-2R), anticardiolipin and antithyroglobulin were evaluated. Of 31 patients, 11 (36%) developed binding antibodies; three (27%) of them had antibodies with neutralizing capacities (range, 350-28,000 INU/ml). Of male patients, 8 (36%) of 22 versus 1 (11%) of nine female patients developed antibodies. Statistical analysis (unpaired t test) revealed that all patients with antibody titers showed significant (p<0.04) lower serum levels of β2-microglobulin and reproducible decreases in sIL-2R levels, whereby those with neutralizing antibodies showed significantly (p<0.0001) lower values than did those with binding antibodies. Elevations of anticardiolipin (17 of 31) and antithyroglobulin (one of 31) were not correlated to the presence of IFN antibodies. Our results show the in vivo significance of antibodies against rIFN-a, especially of those with neutralizing capacities. Monitoring of antibody formation as well as immunoparameters like β2- microglobulin in clinical trials can contribute to identifying patients who, if necessary, might benefit from alternative IFN treatment, for instance, by using natural IFNs.

ISSN:1524-9557    

出版商:OVID    

年代:1997

数据来源: OVID

ISSN:1524-9557    

出版商:OVID    

年代:1997

数据来源: OVID

ISSN:1524-9557    

出版商:OVID    

年代:1997

数据来源: OVID