Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the present study, we have investigated not only the infiltrative and cytotoxic activities of lymphokine-activated killer (LAK) cells on a tumor mass, but also the ultrastructural cell-to-cell interaction between LAK effector cells and target tumor cells during the cytolytic process within a three-dimensional solid tumor. A multicellular tumor spheroid (MTS) of a human malignant glioma cell line (U-251MG) was utilized as a solid tumor model. LAK cells were generated from peripheral blood lymphocytes (PBL) of a healthy donor after 4-day culture in the presence of interleukin-2 (IL-2). MTSs of 500 microns diameter were cocultivated with either LAK cells or non-activated PBL, and then time-sequential kinetic, morphological, and ultrastructural examinations were carried out. It was demonstrated that the number of viable tumor cells present within MTSs gradually decreased in parallel with the increase in the number of LAK cells. Morphological analyses revealed that LAK cells directly infiltrated toward the inner areas of MTSs and caused a progressive tumor destruction. In contrast, PBL hardly exhibited such activities. Ultrastructurally, it was found that the infiltrating LAK effector cells were composed of heterogeneous subpopulations, T-like cells and large granular lymphocyte (LGL)-like cells, and that both types of lymphocytes tightly adhered to the tumor cells and extended their cytoplasmic extensions deeply into the targets which underwent a progressive degeneration. Concerning the cellular interaction, it was found that these two kinds of LAK cells displayed some distinct ultrastructural feature in the process of target cell killing. Particularly, it should be stressed that LGL-like LAK cells exhibited a significant development of the intracytoplasmic secretory granules, suggesting an association with the lethal hit of target cell lysis.
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PMID:[Infiltrative and cytolytic activities of lymphokine-activated killer (LAK) cells against a human glioma mass: ultrastructural analysis using a three-dimensional multicellular spheroid model]. 213 Jul 68

A bifunctional hetero-F(ab')2 antibody fragment was developed that contained the Fab portions from anti-CD3 and anti-glioma monoclonal antibodies. The antibody simultaneously recognized two different molecules, the CD3 complex on effector T cells and a human glioma-associated antigen; thus, it could cross-link effector and target cells. This bispecific F(ab')2 fragment induced peripheral blood mononuclear cells (PBMC's) from healthy donors to lyse cells of the human glioma cell line, U251MG, which are resistant to natural killer cell-mediated cytolysis. The effect of the bispecific antibody on lymphokine-activated killer (LAK) cell activity was tested in patients suffering from malignant glioma. For this study, PBMC's from these patients were preactivated with recombinant interleukin-2 and their killer activity against U251MG cells was investigated in vitro with and without the bispecific antibody. The LAK cell activity of the PBMC's from patients with malignant gliomas was found to be suppressed compared with those of healthy donors. However, after preincubation with bispecific antibody, the patients' LAK cells exhibited marked cytolytic activity against U251MG cells. These findings suggest that this bispecific antibody may be a useful addition to anti-glioma immunotherapy.
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PMID:Induction of cytotoxicity in human T cells coated with anti-glioma x anti-CD3 bispecific antibody against human glioma cells. 213 33

Over the past few years, we and a number of other groups have conducted laboratory experiments and clinical trials of human recombinant interleukin-2 (rIL-2) alone or in combination with autologous 'activated' lymphocytes expressing in vitro tumoricidal activity in order to define toxicity and indicate its potential efficacy in patients with high-grade glioma. Because high rIL-2 concentrations can be attained with considerably less toxicity than with a systemic approach, all of the clinical trials, to date, have chosen a direct route; injecting lymphokine and cells into tumor tissue, the cystic cavity remaining after tumor excision, and/or neural parenchyma surrounding the site of tumor excision. While the rIL-2 therapies, as they have been applied in animal glioma models and patients, are safe, cerebral edema around the site of treatment has been a consistent finding. We have also seen, however, that steroid medications used by patients to control their cerebral edema may depress the anti-tumor activity of rIL-2 by depressing the capacity of lymphocytes to develop normal LAK activity. Although none of the immunotherapies involving rIL-2 have produced cures, the fact that sustained clinical responses have been reported, suggests that such therapies may slow a recurrence of tumor at the site of treatment. Efforts to improve outcome from rIL-2--based immunotherapies for malignant glioma are continuing with manipulation of rIL-2 dosing and scheduling and also with combinations of rIL-2 and other recombinant cytokines.
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PMID:Immunotherapy for malignant glioma using human recombinant interleukin-2 and activated autologous lymphocytes. A review of pre-clinical and clinical investigations. 219 21

Local brain tumor therapy using lymphokine-activated killer (LAK) cells and recombinant interleukin-2 (rIL-2) has not proved to be effective in preliminary clinical trials. One obstacle to effective use of this therapy is ignorance about the events that follow contact of the LAK cells with glioma tissue. We used multicellular spheroids grown from human glioma cell lines as targets to study, in vitro, the effect of LAK cells against three-dimensional glioma tissue. Here we describe the ultrastructural changes in spheroids of H-2 glioma cells incubated in pellets of LAK cells for up to 24 hours. In H-2 spheroids, cellular damage was not restricted to the effector cell-target cell (effector-target) contact; it extended farther, at least partly because of nonspecific changes in the spheroid micromilieu. Formation of cytoplasmic blebs, a characteristic effect of T cells, natural killer cells, and LAK cells on single target cells, also occurs in H-2 spheroids, and it is not limited to the effector-target contact area either. These findings suggest that LAK cells release membrane-damaging agents that remain active outside the effector-target area, in the micromilieu of H-2 spheroid tissue.
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PMID:Damage to multicellular human H-2 glioma spheroids incubated with LAK cells: an ultrastructural study. 231 22

In phase-I clinical trials of adoptive immunotherapy using lymphokine-activated killer (LAK) cells plus recombinant interleukin-2 (rIL-2) (Cetus) for the treatment of malignant glioma, we observed that blood mononuclear cells (MNC) from patients dependent on dexamethasone for management of cerebral edema produced substantially less LAK activity as compared to MNC of normal blood donors or glioma patients not receiving steroid therapy. Therefore, we examined the in vitro effects, brought about by therapeutically attainable concentrations of various corticosteroids, on the proliferative response, production of gamma interferon (IFN-gamma), and induction of LAK activity from blood MNC of normal donors. Incubation in media containing rIL-2 (1000 U/ml) with either dexamethasone, hydrocortisone, methylprednisolone, or prednisolone profoundly affected all of these parameters. First, while 0.01 micrograms/ml of either dexamethasone or hydrocortisone caused a slight enhancement of the mitogenic response of lymphocytes to phytohemagglutinin, a dose-dependent decline occurred as concentrations increased to 10 micrograms/ml. The addition of prednisolone and methylprednisolone elicited a dose-dependent inhibition of lymphocyte proliferation over the entire concentration range tested. At 0.1 microgram/ml or higher, dexamethasone, hydrocortisone, methylprednisolone and prednisolone significantly (P less than 0.02) inhibited the production of IFN-gamma: respectively 18.9%, 4.4%, 2.2%, and 12.3% of the IFN-gamma produced by MNC in the absence of steroids. All four corticosteroids inhibited the induction of LAK activity. Compared to MNC that had been incubated with 1000 U/ml rIL-2 alone, MNC cultured with rIL-2 and 10 micrograms/ml either dexamethasone or prednisolone demonstrated significantly lower cytotoxicity (P less than 0.05) for the natural-killer-cell-resistant cell line, Daudi. Culturing MNC with hydrocortisone had a more dramatic result, causing a significant decline (P less than 0.01) in lytic activity at both 1.0 micrograms/ml and 10 micrograms/ml, while incubation with methylprednisolone produced a significant drop (P less than 0.02) in LAK-mediated cytotoxicity at 0.1 micrograms/ml as well as 1.0 micrograms/ml and 10 micrograms/ml. When cytotoxicity was expressed as lytic units per million effectors, a dose-response decline in lytic activity was once again apparent, with hydrocortisone, methylprednisolone and prednisolone showing significant inhibition (P less than 0.05) at both 1.0 micrograms/ml and 10 micrograms/ml and dexamethasone at 10 micrograms/ml (P less than 0.01). These results indicate that corticosteroids commonly used in the management of cere
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PMID:Corticosteroids inhibit the generation of lymphokine-activated killer activity in vitro. 249 21

Human glioblastoma cells secrete an inhibitory factor termed "glioblastoma-derived T-cell suppressor factor" (G-TsF). A member of the transforming growth factor beta (TGF beta) family, G-TsF is identical to TGF beta 2. The present study investigated the effect of G-TsF/TGF beta 2 on the proliferative and cytotoxic properties of tumor-infiltrating lymphocytes (TIL's) isolated from malignant gliomas after expansion in vitro with interleukin-2 (IL-2). The results demonstrate that the IL-2 (5 to 20 U/ml)-dependent proliferative response of glioma-derived TIL's was inhibited 70% to 85% by G-TsF/TGF beta 2 and that the inhibitory effect could be reduced by using increasing concentrations of IL-2 (100 to 200 U/ml). Tumor necrosis factor alpha (TNF alpha) enhanced the IL-2-dependent proliferation of TIL's cultured in low concentrations of IL-2 (10 U/ml); however, neither TNF alpha nor interferon gamma was able to reduce the inhibitory effect of TGF beta 2 on TIL proliferation. In addition, TGF beta 2 suppressed 60% to 100% the cytotoxic response of glioma-derived TIL's against several tumor targets, including autologous glioma cells, and the suppressive effect was shown to be reduced by increasing concentrations of IL-2.
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PMID:Inhibition of lymphocyte function by glioblastoma-derived transforming growth factor beta 2. 254 42

Earlier, we conducted Phase I clinical trials to determine any acute toxicity of adoptive immunotherapy with intralesional injections of autologous lymphocytes expressing lymphokine-activated killer (LAK) activity and recombinant interleukin-2 (rIL-2) in patients with malignant glioma. Within six weeks of craniotomy and intralesional injection of autologous LAK cells plus rIL-2, 3 of 29 patients demonstrated a decline in clinical status and evidence on computed tomographic and magnetic resonance imaging scans of edema and mass of unknown character at the site of previous surgery and immunotherapy. Craniotomy was performed to remove the tissue and reduce intracranial pressure. Microscopic examination of the excised material indicated no new tumor growth within the resected mass, but rather that the tissue had the histological characteristics of a chronic sterile abscess including necrosis, fibrosis, and influx of inflammatory cells. Factors that may have contributed to this reaction in the 3 patients were age, Karnofsky score, the extent of tumor excision, and immune status. All 3 had also been treated with greater than average numbers of rIL-2 activated lymphocytes that demonstrated significant in vitro LAK activity. The results suggest that in patients whose clinical status is good and who are not immunosuppressed by corticosteroids, the dose-limiting toxicity of intraparenchymal immunotherapy with LAK cells plus rIL-2 for glioma may be related to the total, absolute number of activated cells injected, and this toxicity develops over time and is manifested by development of a sterile abscess.
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PMID:Sterile abscesses in glioma patients treated by intraparenchymal injection of lymphokine-activated killer cells and recombinant interleukin-2: case reports. 258 34

Adoptive immunotherapy using lymphokine-activated killer (LAK) cells and interleukin-2 (IL-2) offers the possibility of a new treatment for patients with malignant glial tumors. In a clinical trial, the effectiveness of a 5-day treatment cycle of direct intratumoral administration of both LAK cells and IL-2 via a reservoir/catheter system in patients with recurrent malignant gliomas was studied. Ten patients were entered into the study, nine of whom were treated with 15 cycles of LAK cells (0.9 to 21.0 x 10(9) cells) and IL-2 (49 to 450 x 10(3) U/kg). The 10th patient in the study was not treated because of the onset of severe neurological deficits prior to beginning immunotherapy. Of the nine patients treated, one had a partial tumor response to immunotherapy as documented by computerized tomography. Neurological side effects occurred in all patients undergoing treatment and were related to increases in cerebral edema that appeared to be mediated by the immunotherapy. This report demonstrates the present limitations of regional adoptive immunotherapy with LAK cells and IL-2 in the treatment of human glial tumors.
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PMID:Intratumoral LAK cell and interleukin-2 therapy of human gliomas. 264 85

Tumor-infiltrating lymphocytes (TIL's) were isolated from human glioma biopsy specimens by immunomagnetic separation using T cell-specific monoclonal antibodies coupled to paramagnetic beads, and were expanded in culture with feeder cells and interleukin-2 (IL-2). The infiltrating cells from five of seven patients proliferated in culture. When tested after 2 to 3 weeks of culture, virtually all of the cells stained with antibodies against the CD2 and CD3 antigens. Most cells also expressed human leukocyte antigen class II molecules, while varying percentages of cells stained with antibodies against the IL-2 receptor and the CD4 and CD8 antigens. The cytotoxicity of the cultured TIL's against autologous and allogeneic glioma cells and the K562 and Daudi cell lines was measured and compared with that of lymphokine-activated killer (LAK) cells from the same patients. None of the TIL's showed significant cytotoxicity against these targets, whereas LAK cells lysed all of the targets.
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PMID:Immunomagnetic separation of infiltrating T lymphocytes from brain tumors. 266 96

Some recent immunological approaches to therapy of cancer are briefly considered. The possibility of the application of immunotherapy to malignant gliomas was investigated in vitro, evaluating the cytotoxic activity of Interleukin-2-activated lymphocytes against cultured human glioma cells. The possibility of generating valid cytotoxic effectors from glioma patients peripheral blood was also investigated in consideration of the immunological alterations reported in such patients.
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PMID:Immunotherapy of malignant gliomas. 267 61


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