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)

Methods have recently been described for the isolation and expansion of lymphocytes that have trafficked into animal and human tumors. These CD8-positive tumor-infiltrating lymphocytes (TIL's) have exceptional trafficking ability to, and efficacy against, tumor targets in extracranial sites. Prior to Phase I clinical trials for patients with gliomas, adoptive immunotherapy with TIL's was studied in a mouse model of primary brain tumors to determine if intracerebral tumors have a similar response. Glioma 261 (GL261) tumors were grown in the subcutaneous space of C57BL/6 mice. After enzymatic digestion, the cells were incubated in vitro with interleukin-2 (IL-2) until a confluent population of T lymphocytes was present. The in vitro efficacy of these TIL's was tested against fresh GL261 targets with a chromium release assay; the in vivo efficacy was tested against GL261 tumors in the liver and against irradiated and nonirradiated GL261 tumors in the brain. Mice received one of the following: intraperitoneal saline; intraperitoneal IL-2 (7500 to 50,000 U three times daily for 5 days); IL-2 plus intravenous TIL's (1 to 3 x 10(7) cells); 10 Gy cranial irradiation; irradiation plus IL-2; or irradiation plus IL-2 plus TIL's. The TIL preparation killed 77% of tumor targets in 4 hours at an effector:target ratio of 100:1. In animals with GL261 tumors in the liver, at 2 weeks there were 93 +/- 37, 128 +/- 45, and 21 +/- 14 liver metastases in the control, IL-2, and IL-2 plus TIL groups, respectively. However, in animals with GL261 tumors in the brain, no treatment group had an increased survival rate compared to the control group. It is concluded that, although TIL and IL-2 immunotherapy can be used effectively to treat brain tumors in vitro and at sites outside the central nervous system, it is ineffective against the same type of tumor in the brain. Different methods of delivery or different combinations of these immunomodulators may be more effective; however, based on these findings, treatment of patients with IL-2 and TIL cannot be recommended until efficacy has been demonstrated in an animal model.
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PMID:Treatment of murine primary brain tumors with systemic interleukin-2 and tumor-infiltrating lymphocytes. 173 33

Human glioblastoma cells secrete factors, such as prostaglandin E (PGE) and transforming growth factor beta type 2, which are capable of suppressing several immune functions. The present study investigated the effect of PGE2 and agents known to increase intracellular cyclic adenosine monophosphate (cAMP) levels on 1) the induction of lymphokine-activated killer (LAK) cell activity from the peripheral blood lymphocytes (PBL) of both normal and glioma patients and on 2) the cytolytic activities of tumor-infiltrating lymphocytes (TIL's) isolated from malignant gliomas after expansion in vitro with interleukin-2 (IL-2). Cytolytic activity was measured against autologous and allogeneic tumor cells and the natural killer-resistant Daudi cell line. The results demonstrate that PGE2 and agents known to increase intracellular cAMP levels can significantly suppress the IL-2-dependent generation of cytolytic activity from the PBL of normal and glioma patients and from glioblastoma-derived TIL's. The inhibitory effects of these agents could not be reduced by higher concentrations of IL-2 or by cyclic guanosine monophosphate. Although the suppressive effect of PGE2 was most significant during the early stages of LAK cell generation, an inhibitory effect was still evident when PGE2 was added directly to the cytotoxicity assay. Secretion of PGE2 by glioblastoma cells in vivo may regulate both the generation of an immune response and the effectiveness of adoptively transferred immune cells.
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PMID:Influence of PGE2- and cAMP-modulating agents on human glioblastoma cell killing by interleukin-2-activated lymphocytes. 196 67

In summary, many actual interactions between tumors in the CNS and the immune system have been demonstrated. The normal brain does not possess a lymphatic system and is partially hidden from the systemic immune system by the BBB, furthermore brain cells do not express MHC antigens which are necessary for the initiation of an immune response. In pathological conditions however, immunocompetent cells may find their way through transformed endothelial cells. Microglia and astrocytes may function as antigen presenting cells. Glioma cells when stimulated by cytokines such as IFN gamma can be induced to express MHC class I and class II antigens, thus making them more susceptible to an immune attack. In addition glioma cells are capable of secreting several cytokines including IL 1, IL 3 and IL 6 also involved in the generation of an immune response. Indeed, a functional analysis of lymphocytes infiltrating gliomas has revealed the accumulation at the tumor site of cytotoxic T lymphocytes as well as NK cells. However host-immune responses against gliomas seem to be weak in comparison to other cancers. Glioma cells are known to secrete TGF beta 2 and PGE 2 which may in part be responsible for this lack of immune response, thus shielding themselves from immune attack. In order to be recognized by the immune system the tumor cells must express TAA in addition to MHC antigens, and such TAA have been identified by MAbs. These MAbs can be used for "targeted" therapy when coupled to toxic agents or radionuclides. Preclinical studies have shown that, after intravenous or intracarotid injection, there is specific accumulation of the MAb in the tumor but in insufficient amounts for therapeutic use. The relatively small amount of MAb binding to the tumor in vivo can be due to several factors: not all the cells in a single tumor express a given tumor-associated antigens, the MAb may have a low affinity for the antigen, the BBB may hinder the passage of the MAb. Attempts have been made to overcome these drawbacks by opening the BBB for example. In addition MAbs can readily be used for the treatment of carcinomatous meningitis. There has been little success in the development of immunotherapy with IFN beta 1 and even less with adoptive immunotherapy using LAK cells plus IL 2. TIL as well as LAK cells can be expanded in vitro with IL2 and it is feasible to reinject these cells into the tumor site.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Immunobiology of brain tumors. 218 Apr 10

To ascertain whether tumor-specific immune response occurs in patients with malignant brain tumors, lymphocyte blastogenetic responses to tumor cells were examined in 18 patients prior to operation and other treatment. Among 12 patients with malignant glioma, the peripheral blood lymphocytes (PBL's) showed a positive blastogenetic response to their own glioma cells in seven (58.3%), whereas the tumor-infiltrating lymphocytes (TIL's) showed a positive response in only three (25%). In four (66.7%) of six patients with metastatic brain tumors, however, both the PBL's and TIL's showed a positive blastogenetic response to their own tumor cells. In these four patients, this lymphocyte blastogenetic response to tumor cells were at a much lower level compared with phytohemagglutinin P or allogeneic lymphocyte stimulation. Furthermore, these responses were increased when the cells were cultured with interferon-gamma (500 U). Other lymphokines had no effect on the response. This method appears to be useful in identifying the tumor-specific immune response in patients with malignant brain tumor.
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PMID:Analysis of mixed lymphocyte-tumor culture in patients with malignant brain tumor. 252 72

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

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

To analyze the phenotypic profile of lymphoid cells freshly isolated from surgically resected human gliomas, a double-immunostaining technique was developed which permitted the investigators simultaneously to distinguish between hematogenous and tumor cell populations and to detect expression of lymphocyte-monocyte subset-specific antigens on hematogenous cells. With this technique, the profiles of tumor-infiltrating lymphocytes (TIL's) derived from high- and low-grade gliomas were compared with phenotypes of lymphocytes concurrently isolated from peripheral blood. The total leukocyte cell yield from high-grade glioma cases exceeded that of low-grade cases. In nine high-grade glioma cases the proportion of CD8-positive cells was increased within the TIL population (41.2% +/- 1.9%, mean +/- standard error of the mean) as compared to the corresponding peripheral blood lymphocyte (PBL) population (30.8% +/- 4.1%, p less than 0.05). The proportion of natural killer HNK-positive cells, some of which bear the CD8 antigen (although not necessarily the pan T cell antigens CD2 and CD3), was also increased in the TIL's (41.9% +/- 4.2%) compared to that found in PBL's (32.1 +/- 5.6%, p less than 0.05) of high-grade glioma cases. The observed phenotypic pattern of high-grade glioma TIL's is similar to that reported based on immunohistochemical analysis of tumor tissue sections, suggesting that the techniques described here resulted in isolation of lymphoid cells representative of TIL's.
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PMID:Characterization of lymphoid cells isolated from human gliomas. 279 72

Mononuclear cells infiltrating human brain tumors were isolated from seven of nine surgical biopsy specimens. These cells were small T11+, T3+ lymphocytes that did not express DR antigens or the receptor for interleukin-2. In addition, large granular lymphocytes were recovered from two of these tumors. The clonogenic potential of tumor-infiltrating lymphocytes (TIL's) was assessed by limiting-dilution analysis (LDA) using a microculture system that permits proliferation of virtually 100% of normal peripheral blood T lymphocytes (PBL-T's). In comparison to normal and autologous PBL-T's, TIL's had a strikingly reduced proliferative potential revealed by a decrease in the frequency of proliferating T lymphocyte precursors calculated by LDA. On average, only one of every 100 T cells from TIL's was able to proliferate, as compared to one of every two or all of the T cells from the patient's peripheral blood or from normal donors. Furthermore, the TIL populations showed depressed proliferative responses to the lectins phytohemagglutinin and concanavalin A and to the phorbol ester 12-0-tetradecanoyl-phorbol-13-acetate. Clonal analysis performed on the proliferating microcultures from three tumors demonstrated that the majority of these clones possessed cytolytic activity against various tumor cell targets. Among clones tested for cytolytic activities with glioma cells, four lysed cultured autologous tumor cells, and the specific lysis was greater than 50% in all cases. Numerous clones with natural killer (NK)-like activity were obtained from two TIL preparations, and the frequency of cytolytic T lymphocyte precursors with NK-like activity was determined for one of these preparations and was found to be higher than that in the patient's peripheral blood. Glioma cells grown in culture and then mixed with normal peripheral blood lymphocytes (PBL's) were capable of inhibiting the PBL's response to lectins. This inhibitory property may account in part for the observed poor clonogenicity of TIL's from brain tumors. Nevertheless, nearly all proliferating clones displayed cytotoxicity against either autologous or allogeneic tumor cell targets and may imply selective accumulation of cytolytic effector cells at the tumor site.
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PMID:In situ characterization, clonogenic potential, and antitumor cytolytic activity of T lymphocytes infiltrating human brain cancers. 325 92

Brain tumors were induced in inbred Fischer rats (F344) by administration of methylnitrosourea in the drinking water. One of the induced tumors, a pleomorphic glioma (78-219), was established in vitro and propagated as 78FR-G-219 permanent cell line. The tumorigenicity of the established line was investigated by intracerebral or subcutaneous inoculation of 1X10 (6) - 10X10(6) cells. Lymphocytes infiltrating secondary tumors (TIL) were enriched by a single step centrifugation on different discontinuous Percoll density gradients, while blood lymphocytes (PBL) and lymphocytes from spleen and lymph node (SL and LNL) were enriched by Ficoll - Isopaque flotation. The reactivity spectrum of the isolated lymphocytes raised against cultured 78FR-G-219 cells was monitored by means of two different assays: Lymphocyte microcytotoxicity test (LMC) and colony inhibition assay (CIA). Reactivity of PBL, SL and LNL of glioma-bearing animals was clearly reduced, while TIL showed no natural killer (NK) activity, no cytotoxicity against syngeneic 78FR-G-219 pleomorphic glioma cells and no colony inhibition in mixed lymphocyte/target cell cocultivation. NK activity of TIL was only slightly reduced against target cells of a non-cross-reacting syngeneic astrocytoma line (78FR-G-299).
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PMID:Reactivity of tumor-infiltrating, blood, spleen and lymph node lymphocytes against syngeneic glioma target cells. 734 50

These studies report the identification of a population of myeloid suppressor cells (MSC) that are preferentially enriched in the spleens and tumor-infiltrating mononuclear cells (TIMC) from T9.F-vaccinated animals. In this model designed to mimic immunotherapy for an established intracranial (i.c.) glioma, animals were given an i.c. inoculum with 5 x 10(4) T9 glioma cells at day 0, followed by a subcutaneous (s.c.) injection of 5 x 10(6) irradiated T9.F glioma cells 5 days later. Unexpectedly, we found that the survival of these T9.F-vaccinated animals was dramatically shorter than their age-matched counterparts who received only saline injections. Since MSC have previously been demonstrated to be associated with tumor progression, the question arose of whether MSC might play a role in the rapid tumor progression observed in this model. Analysis of the spleen cells and TIMC revealed an increase in the population of myeloid cells expressing granulocytic and monocytic markers. Both the polyclonal and tumor-specific proliferation of splenic T cells and tumor-infiltrating T lymphocytes (T-TIL) from T9.F-vaccinated animals were significantly inhibited in the presence of these myeloid cells. Furthermore, the adoptive transfer of MSC into animals bearing a 5-day T9 glioma caused rapid tumor progression. Reduced survival of the glioma-bearing vaccinated rats was associated with enhanced tumor growth, as well as with an increased density of T-TIL. However, purified T-TIL did not show any discernable signs of inherent defects in terms of their effector functions and T cell receptor (TCR) signal transduction protein levels. Therefore, we believe that an MSC population is responsible for inhibiting the anti-tumor T cell response, resulting in the enhanced growth of the i.c. glioma, and may represent a significant obstacle to immune-based therapies.
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PMID:Irradiated tumor cell vaccine for treatment of an established glioma. II. Expansion of myeloid suppressor cells that promote tumor progression. 1201 6


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