Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have cultured peripheral blood lymphocytes (PBL) from glioblastoma patients in recombinant interleukin-2 (IL-2) containing medium for a period of 5 days. The cytotoxicity of these cells was tested on 51Cr-labelled autologous dissociated glioblastoma cells which had not been cultured. Significant cytotoxicity against glioma cells was observed in seven out of nine cases. IL-2 activated PBL from normal donors were equally cytotoxic against these glioma cells. Autologous lymphocytes activated by phytohaemagglutinin were also lysed in most cases, and the erythroleukemia cell line K562 was highly susceptible to the cytotoxic capability of the IL-2 activated PBL. In cold target inhibition experiments, K562 inhibited the cytotoxicity against both autologous and allogenic glioma cells, and glioma cells inhibited the cytotoxicity against K562. Following immunomagnetic separation, the IL-2 activated cells demonstrated cytotoxicity against glioma cells, K562 cells, and PHA blasts in both the CD8+ and the CD8- subsets.
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PMID:Human interleukin-2 activated cytotoxic cells kill autologous glioma cells in vitro. 326 Sep 42

For a single-dose toxicity assessment, five patients with recurrent malignant glioma (ages 29-46 years) were treated with intracavitary alloreactive cytotoxic T lymphocytes (CTL) and interleukin-2 (IL-2). The trial tested the hypothesis that alloreactive CTL, sensitized to the major histocompatibility complex (MHC) proteins of the patient, offer selective, targeted killing of glioma cells that express MHC. Patient lymphocytes, which also express MHC, were irradiated and placed into CellMax artificial capillary systems with lymphocytes from MHC-disparate donors and CTL developed over a 2- to 3-week period with a low concentration of IL-2. The CTL largely expressed CD3 and CD11a/CD8 markers and lysed targets displaying patient MHC. CTL were implanted into the tumor bed at surgery and a catheter was used for subsequent infusions. Patients received one to five treatment cycles every other month; one cycle generally consisted of two or three CTL infusates administered within a 1- to 2-week period. Different unrelated donors were used for each cycle. Treatment was well tolerated; transient toxicity at grades 1-3 was recorded by NCI Common Toxicity Scale criteria. Two glioblastoma patients have died; one from tumor recurrence locally and the other from recurrence at a site distant from the treatment. Two of the five patients completed five cycles; one anaplastic oligodendroglioma patient shows no evidence of tumor 30 months from the start of immune therapy and an anaplastic astrocytoma patient shows stable disease 28 months after initiation of therapy. One anaplastic oligodendroglioma patient, who dropped the protocol during her second treatment cycle, has no evidence of tumor 28 months after recurrence.
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PMID:Treatment of recurrent glioma with intracavitary alloreactive cytotoxic T lymphocytes and interleukin-2. 939 Jan 98

Anaplastic astrocytoma and glioblastoma are frequent and malignant brain tumors that are infiltrated by T lymphocytes. Whether these cells result from non-specific inflammation following blood-brain barrier disruption or an antigen-driven specific immune response is unknown. In this study, an in-depth characterization of TCR diversity in tumor and blood RNA biopsies was performed in a series of 16 patients with malignant astrocytoma. Whilst there was no obvious restriction of the AV and BV gene segment usage, complementarity-determining region 3 size analysis and sequencing of amplified TCR transcripts revealed multiple T cell oligoclonal expansions in all astrocytomas analyzed. Unique T cell clones were present in different adjacent areas of a given tumor, but never detected in the blood. Quantification of the number of TCR clonal transcripts per microg of tumor RNA indicated that certain T cell clonal expansions may represent at least 300 cells/10(6) tumor cells. Furthermore, we demonstrated that the in vivo expanded clones were almost exclusively confined to the CD8(+) subset. Overall, these data suggest that spontaneous antigen-driven immune responses may be elicited against human astrocytoma despite the immunosuppressive microenvironment generated by the brain and the tumor itself. However, the ultimate failure of the immune system to control tumor growth could be the consequence of a deficient CD4 T(h) component of the response. This observation could have important consequences for the development of immunotherapies for astrocytoma patients.
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PMID:Astrocytoma infiltrating lymphocytes include major T cell clonal expansions confined to the CD8 subset. 1042 91

The long-term consequences of adenovirus-mediated conditional cytotoxic gene therapy for gliomas remain uncharacterized. We report here detection of active brain inflammation 3 months after successful inhibition of syngeneic glioma growth. The inflammatory infiltrate consisted of activated macrophages/microglia and astrocytes, and T lymphocytes positive for leucosyalin, CD3 and CD8, and included secondary demyelination. We detected strong widespread herpes simplex virus 1 thymidine kinase immunoreactivity and vector genomes throughout large areas of the brain. Thus, patient evaluation and the design of clinical trials in ongoing and future gene therapy for brain glioblastoma must address not only tumor-killing efficiency, but also long-term active brain inflammation, loss of myelin fibers and persistent transgene expression.
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PMID:Chronic brain inflammation and persistent herpes simplex virus 1 thymidine kinase expression in survivors of syngeneic glioma treated by adenovirus-mediated gene therapy: implications for clinical trials. 1054 91

Depressed natural killer (NK) cell activity has been showed in family members of patients with different types of cancer. The present work aimed to evaluate T cell subsets and NK cell cytotoxic activity in 15 members of a family with high incidence of tumors, such as glioblastoma, gastric, pancreas and colon rectal carcinoma, chronic myelocitic leukemia, melanoma and osteoblastoma. As controls, 19 healthy subjects with the age range equivalent were studied. The enumeration of CD3+ lymphocytes and their CD4+ and CD8+ subsets were defined by monoclonal antibodies and NK cell cytotoxicity towards K562 target cells were evaluated by single cell-assay. The results showed in family members low percentage of total T cells (CD3+), and their CD4+ subset and impairment of CD4/CD8 ratio in relation to control group. All family members presented percentage of NK-target cell conjugate formation below the minimum value observed in control group. Thirteen people were examined and followed up during five years, in order to assure that there was no undiagnosed or unsuspected disease at the moment of evaluation. One of them developed osteoblastoma and other malignant melanoma. Two cancer patients, with glioblastoma and chronic myelocytic leukemia were studied during illness. All the corresponding values were comparable. The persistence of low percentage of conjugate formation may be related to a defect on adhesion molecules expression in the surface of NK cells that was probably responsible for the low activity of these cells presented by the family group. Thus, the inheritance mechanism of low adherence of NK cells should have a prognostic value in determining the risk of developing tumors.
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PMID:Familial cancer: depressed NK-cell cytotoxicity in healthy and cancer affected members. 1129 23

HLA-G is a nonclassical MHC molecule with highly limited tissue distribution that has been attributed chiefly immune regulatory functions. Glioblastoma is paradigmatic for the capability of human cancers to paralyze the immune system. To delineate the potential role of HLA-G in glioblastoma immunobiology, expression patterns and functional relevance of this MHC class Ib molecule were investigated in glioma cells and brain tissues. HLA-G mRNA expression was detected in six of 12 glioma cell lines in the absence of IFN-gamma and in 10 of 12 cell lines in the presence of IFN-gamma. HLA-G protein was detected in four of 12 cell lines in the absence of IFN-gamma and in eight of 12 cell lines in the presence of IFN-gamma. Immunohistochemical analysis of human brain tumors revealed expression of HLA-G in four of five tissue samples. Functional studies on the role of HLA-G in glioma cells were conducted with alloreactive PBMCs, NK cells, and T cell subpopulations. Expression of membrane-bound HLA-G1 and soluble HLA-G5 inhibited alloreactive and Ag-specific immune responses. Gene transfer of HLA-G1 or HLA-G5 into HLA-G-negative glioma cells (U87MG) rendered cells highly resistant to direct alloreactive lysis, inhibited the alloproliferative response, and prevented efficient priming of cytotoxic T cells. The inhibitory effects of HLA-G were directed against CD8 and CD4 T cells, but appeared to be NK cell independent. Interestingly, few HLA-G-positive cells within a population of HLA-G-negative tumor cells exerted significant immune inhibitory effects. We conclude that the aberrant expression of HLA-G may contribute to immune escape in human glioblastoma.
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PMID:A functional role of HLA-G expression in human gliomas: an alternative strategy of immune escape. 1197 Oct 28

Lymphocytes are frequently observed in human malignant glioma, the mechanism(s) underlying their appearance is not fully understood. To clarify tumor immunity in malignant gliomas, we analyzed the expression of 8 novel lymphocyte-specific chemokines in human glioma cell lines and glioma tissues by RT-PCR, Northern blot, immunoblot and immunohistochemistry, and examined the correlation with the infiltration of various subsets of lymphocytes. For the 8 chemokines examined (LARC, TARC, ELC, SLC, PARC, LEC, HCC-2, and SCM-1alpha), expression of LARC was clearly detectable in all 12 glioma cell lines by RT-PCR. Additionally, expression of TARC and SCM-1alpha was detectable in the majority of glioma cell lines. However, the expression level of most chemokines was low, so that Northern blot analysis could not demonstrate their expression with the exception of LARC in 2 cell lines. Expression of LARC mRNA and LARC protein was strongly induced by phorbol myristate ester in U87 MG cells. The production of LARC protein was demonstrated in 4 of 8 glioblastoma tissues by immunoblotting, and 9 of 33 samples (27.3%) by immunohistochemistry. Interestingly, the positivity of LARC staining was significantly correlated with the infiltration of CD8-, CD4-, and CD45R0-positive cells (p<0.001). Although the constitutive expression level of LARC is low, certain stimulations could strongly induce its expression, and play a crucial role in the tumor immunity of human malignant glioma.
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PMID:Expression of lymphocyte-specific chemokines in human malignant glioma: Essential role of LARC in cellular immunity of malignant glioma. 1223 8

Granzyme B (GzmB) is a serine protease involved in many pathologies, including viral infections, autoimmunity, transplant rejection, and antitumor immunity. To measure the extent of genetic variation in GzmB, we screened the GzmB gene for polymorphisms and defined a frequently represented triple-mutated GzmB allele. In this variant, three amino acids of the mature protein Q(48)P(88)Y(245) are mutated to R(48)A(88)H(245). In CD8(+) cytotoxic T lymphocytes, GzmB was expressed at similar levels in QPY homozygous, QPY/RAH heterozygous, and RAH homozygous individuals, demonstrating that RAH GzmB is a stable protein. Active RAH GzmB expressed in glioblastoma cell lines displayed proteolytic activity, but in contrast to QPY GzmB, it did not accumulate in the nucleus and was unable to induce Bid cleavage, cytochrome c release, or apoptosis. Molecular modeling showed that the three amino acid substitutions clustered near the C-terminal alpha-helix of the protein, indicating that this region of the protein may be involved in the intracellular targeting of GzmB. The triple-mutated GzmB allele that we describe appears to be incapable of inducing apoptosis in tumor cell lines, and its presence could, therefore, influence both the prognosis of cancer patients and the success rates of antitumor cellular immunotherapy.
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PMID:A triple-mutated allele of granzyme B incapable of inducing apoptosis. 1259 35

A mouse glioblastoma cell line, termed GL261, was shown to express high levels of proteins involved in melanin biosynthesis such as the tyrosinase-related protein-2 (TRP-2), which is commonly overexpressed in melanoma cells. Mice injected with GL261 cells developed a CD8(+) T-cell response to TRP-2 and a DNA vaccine expressing human (h)TRP-2 induced CD8(+) T cells that recognized TRP-2 expressed by GL261 cells indicating that this melanoma-associated antigen may be suited for active immunotherapy of glioblastoma. Mice vaccinated with a DNA vaccine expressing TRP-2 were partially protected against subcutaneous, intravenous, or intracerebral challenge with the glioblastoma cells. Vaccine-induced protection against intracerebral challenge required both CD4(+) and CD8(+) T cells. Vaccine efficacy was enhanced upon addition of IL-12 as a genetic adjuvant. These results indicate that this well-defined melanoma-associated antigen can induce an adaptive immune response, which limits the intracerebral progression of a glioblastoma.
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PMID:A DNA vaccine expressing tyrosinase-related protein-2 induces T-cell-mediated protection against mouse glioblastoma. 1294 87

We designed a phase I clinical trial of vaccinations with autologous glioma cells expressing transgene-derived interleukin-4 (IL-4), and treated one patient with a right temporal lobe recurrent glioblastoma. This 62-year-old man underwent craniotomy and partial tumor removal, at which time autologous tumor cells were obtained for vaccine preparation. After confirming the patient's cellular immune function by skin test, two cycles of vaccination with irradiated autologous glioma cells admixed with gene transfected fibroblasts were given intradermally. The patient demonstrated no evidence of allergic encephalitis throughout this course. Immunohistochemistry with biopsy samples taken from the vaccine sites demonstrated that the infiltration level of CD4, CD8 and CD1a positive cells increased proportionally to the amount of IL-4 produced at the each site, suggesting that there was local immune response induced at the vaccine site. While it is premature to assess effectiveness of the vaccine, this initial patient's course suggested a transient response to the vaccine, and he survived 10 months after treatment.
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PMID:Autologous glioma cell vaccine admixed with interleukin-4 gene transfected fibroblasts in the treatment of recurrent glioblastoma: preliminary observations in a patient with a favorable response to therapy. 1295 82


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