Cytokine Gene Vaccine Therapy for Treatment of a Brain Tumor.

A glioma is a malignant brain tumor with a poor prognosis. Attempts at the surgical removal of the tumor are the first approach, but additional treatment strategies, including radiation therapy and systemic or local chemotherapy, are necessary. Furthermore, the treatments are often associated with significant adverse side effects.

Designing a broad-spectrum integrative approach for cancer prevention and treatment.

Targeted therapies and the consequent adoption of "personalized" oncology have achieved notable successes in some cancers; however, significant problems remain with this approach. Many targeted therapies are highly toxic, costs are extremely high, and most patients experience relapse after a few disease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistant immortalized cells that have adopted alternate and compensatory pathways (i.

Immune evasion in cancer: Mechanistic basis and therapeutic strategies.

Cancer immune evasion is a major stumbling block in designing effective anticancer therapeutic strategies. Although considerable progress has been made in understanding how cancers evade destructive immunity, measures to counteract tumor escape have not kept pace. There are a number of factors that contribute to tumor persistence despite having a normal host immune system.

Imaging-Based Features of Headaches in Chiari Malformation Type I.

Background: Suboccipital cough-induced headaches are considered a hallmark symptom of Chiari malformation type I (CMI). However, non--Valsalva-related suboccipital headaches and headaches in other locations are also common in CMI. The diagnostic significance and the underlying factors associated with these different headaches types are not well understood.

Immunogene therapy.

Antigenic differences between normal and malignant cells of the cancer patient form the rationale for clinical immunotherapeutic strategies. Because the antigenic phenotype of neoplastic cells varies widely among different cells within the same malignant cell-population, immunization with a vaccine that stimulates immunity to the broad array of tumor antigens expressed by the cancer cells is likely to be more efficacious than immunization with a vaccine for a single antigen. A vaccine prepared by transfer of DNA from the tumor into a highly immunogenic cell line can encompass the array of tumor antigens that characterize the patient's neoplasm.

Investigation of immunosuppressive mechanisms in a mouse glioma model.

The development of an immune competent mouse model for the study of immunosuppressive mechanisms is important for improving the efficacy of brain tumor immunotherapy. In the present study we investigated regulatory T cells (Tregs), TGF-beta1 and other putative immunosuppressive cytokines using GL261 mouse glioma in C57BL mice. We explored whether tumor growth factor-beta1 (TGF-beta1) is expressed and secreted by glioma cells constitutively or in response to a T-cell mediated immunity (simulated by conditioned media from T cells (TCM) activated by anti-CD3 antibody).

PPAR-gamma Thiazolidinedione Agonists and Immunotherapy in the Treatment of Brain Tumors.

Thiazolidinediones (TZDs) are selective agonists of the peroxisome proliferator-activated receptor (PPAR) gamma, a transcription factor belonging to the superfamily of nuclear hormone receptors. Although activation of PPARgamma by TZDs has been best characterized by its ability to regulate expression of genes associated with lipid metabolism, PPARgamma agonists have other physiological effects including modulating pro- and anti-inflammatory gene expression and inducing apoptosis in several cell types including glioma cells and cell lines. Immunotherapeutic approaches to reducing brain tumors are focused on means to reduce the immunosuppressive responses of tumors which dampen the ability of cytotoxic T-lymphocytes to kill tumors.

Enhanced immunity to intracerebral breast cancer in mice immunized with a cDNA-based vaccine enriched for immunotherapeutic cells.

Structural differences between malignant and nonmalignant cells of the same individual form the basis of clinical immunotherapeutic strategies. Previously, we reported the therapeutic properties of a vaccine prepared by transfer of a cDNA-expression library from breast cancer cells into a highly immunogenic allogeneic fibroblast cell line where genes specifying an array of breast cancer antigens were expressed. Here, we report the application of this cell-based vaccination strategy for breast cancer metastatic to the brain.

Prolonged survival of mice with established intracerebral glioma receiving combined treatment with peroxisome proliferator-activated receptor-gamma thiazolidinedione agonists and interleukin-2-secreting syngeneic/allogeneic fibroblasts.

Object: In this study the authors explored the benefits of treating C57B1/6 mice with an established intracerebral glioma by combining immunotherapy with interleukin (IL)-2-secreting syngeneic/allogeneic fibroblasts administered into the tumor bed along with the chemotherapeutic agent pioglitazone, a thiazolidinedione (TZD). The TZDs are agonists of the peroxisome proliferator-activated receptor-gamma. They have been found to exert antiproliferative effects on several transformed cell lines.

Differential effects of PPARgamma agonists on the metabolic properties of gliomas and astrocytes.

Recent studies show that thiazolinediones (TZDs), agonists of the peroxisome proliferator-activated receptor gamma (PPARgamma), induce apoptosis in glioma and glioblastoma cells. Here we compared the effects of troglitazone (Trog), a TZD with low affinity for binding to PPARgamma but with potent metabolic effects, on survival and metabolism in GL261 glioma cells versus primary astrocytes. Trog dose-dependently induced cell death in GL261 cells (with over 90% death at 30 microM) but did not cause any toxicity in astrocytes at the same doses.

Antigenic Differences Between Normal and Malignant Cells as a Basis for Treatment of Intracerebral Neoplasms Using a DNA-Based Vaccine.

Antigenic differences between normal and malignant cells of the cancer patient form the rationale for clinical immunotherapeutic strategies. Because the antigenic phenotype of neoplastic cells varies widely among different cells within the same malignant cell-population, immunization with a vaccine that stimulates immunity to the broad array of tumor antigens expressed by the cancer cells is likely to be more efficacious than immunization with a vaccine for a single antigen. A vaccine prepared by transfer of DNA from the tumor into a highly immunogenic cell line can encompass the array of tumor antigens that characterize the patient's neoplasm.

Early experience from the application of a noninvasive magnetic resonance imaging-based measurement of intracranial pressure in hydrocephalus.

Objective: The decision for surgical intervention in hydrocephalic patients presenting with symptoms suggesting raised intracranial pressure (ICP) is challenging because radiographic ventricular size often lacks the specificity to predict abnormal ICP. An early assessment of the potential clinical usefulness of a noninvasive magnetic resonance imaging-based measurement of ICP (MR-ICP) in symptomatic hydrocephalic patients is reported.

Methods: Twenty-seven symptomatic hydrocephalic patients (18 with shunts and 9 without shunts) underwent brain magnetic resonance imaging-based studies that included measurements of cerebrospinal fluid and blood flows to and from the cranial vault, from which measurements of ICP were derived using a previously described algorithm.

Advantages of a unique DNA-based vaccine in comparison to paclitaxel in treatment of an established intracerebral breast cancer in mice.

In this study we compared the benefits of treating C3H/He mice with an established intracerebral breast carcinoma by immunization with a unique DNA-based vaccine to chemotherapy with paclitaxel. Prior studies revealed the immunotherapeutic properties of a vaccine prepared by transfer of genomic DNA from breast cancer cells into a highly immunogenic cell line. Here, C3H/He mice with an established intracerebral breast cancer were treated either by injection into the tumor bed through a unique cannula system with the cell based vaccine or with paclitaxel administered intraperitoneally.

Immunogene therapy as a treatment for malignant brain tumors in young mice.

Object: New and innovative forms of effective treatments for malignant brain tumors in children are urgently needed. The authors have previously shown that intracerebral injection into the tumor bed of allogeneic fibroblasts genetically engineered to secrete interleukin-2 (IL-2) results in prolongation of survival and an antitumor immunocytotoxic response in adult mice that harbor intracerebral gliomas. The first goal of this study was to determine if malignant gliomas (GI261) could be treated in mice (C57BL/6) in the pediatric age group (weanlings [2-3 weeks old] and adolescents [3-4 weeks old]).

Magnetic resonance imaging-based measurements of cerebrospinal fluid and blood flow as indicators of intracranial compliance in patients with Chiari malformation.

Object: The diagnosis of Chiari malformation (CM) is based on the degree of tonsilar herniation, although this finding does not necessarily correlate with the presence or absence of symptoms. Intracranial compliance (ICC) and local craniocervical hydrodynamic parameters derived using magnetic resonance (MR) imaging flow measurements were assessed in symptomatic patients and control volunteers to evaluate the role of these factors in the associated pathophysiology.

Methods: Seventeen healthy volunteers and 34 symptomatic patients with CM were studied using a 1.

Intratumoral injection of IL-secreting syngeneic/allogeneic fibroblasts transfected with DNA from breast cancer cells prolongs the survival of mice with intracerebral breast cancer.

Prior studies have revealed the immunotherapeutic properties of a vaccine prepared by transfer of genomic DNA from breast cancer cells into a highly immunogenic cell line. The rationale for this type of vaccine is that genes specifying an array of weakly immunogenic, unique tumor antigens associated with the malignant cells will be expressed in a highly immunogenic form by the transfected cells. Here, the immunotherapeutic properties of a vaccine prepared by transfection of mouse fibroblasts with DNA from a breast carcinoma (SB-5b) that arose spontaneously in a C3H/He mouse (H-2Kb) were tested in mice with intracerebral breast cancer.

Noninvasive intracranial compliance and pressure based on dynamic magnetic resonance imaging of blood flow and cerebrospinal fluid flow: review of principles, implementation, and other noninvasive approaches.

Current techniques for intracranial pressure (ICP) measurement are invasive. All require a surgical procedure for placement of a pressure probe in the central nervous system and, as such, are associated with risk and morbidity. These considerations have driven investigators to develop noninvasive techniques for pressure estimation.

Evaluating the effect of decompression surgery on cerebrospinal fluid flow and intracranial compliance in patients with chiari malformation with magnetic resonance imaging flow studies.

Objective: To quantify the effect of decompression surgery on craniocervical junction hydrodynamics and on global intracranial compliance (ICC) in patients with Chiari I malformation by use of magnetic resonance measurements of cerebrospinal fluid and blood flow. Studying the effect of decompression surgery may improve our understanding of the pathophysiological characteristics of Chiari I malformation and aid in identifying patients who will benefit from the procedure.

Methods: Twelve patients were studied with a 1.

Effect of age on the duration and extent of amyloid plaque reduction and microglial activation after injection of anti-Abeta antibody into the third ventricle of TgCRND8 mice.

We have previously shown that anti beta-amyloid (Abeta) antibody injected into the third ventricle of mice is distributed throughout the brain within 24 hr and is completely washed out of brain within 36 hr after injection and that, in Tg2576 animals, a single injection of antibody reduces cerebral Abeta and restores presynaptic deficits 1 month after injection without producing hemorrhage or inflammation at an early plaque stage. Here we report the effects of a single ICV injection of anti-Abeta antibody on cerebral levels of immunoreactive Abeta and of microglial activation measured by immunoreactive interleukin-1beta (IL-1beta) at 1, 4, and 8 weeks after injections in TgCRND8 mice at two ages, 2 months (sparse plaques) and 8 months (abundant plaques). The data show that parenchymal amyloid accumulates before cerebral microvascular amyloid and that a single ICV injection reduces only parenchymal amyloid by about 70%, without affecting vascular amyloid, and reduces microglial activation by 46-60% at 1 week after injection.

Cytokine immuno-gene therapy for treatment of brain tumors.

The prognosis for patients with an intracerebral (i.c.) neoplasm is poor.

Treatment with allogeneic interleukin-2 secreting fibroblasts protects against the development of malignant brain tumors.

We have reported that mice with an intracerebral (i.c.) malignant glioma or breast cancer treated with i.

Aging potentiates Abeta-induced depletion of SNAP-25 in mouse hippocampus.

Unlabelled: Previously we showed that in Tg2576 mouse hippocampus, synaptosomal-associated protein 25 (SNAP-25) immunoreactivity (IR) is greatly reduced and intracerebroventricular injection of anti-Abeta reverses this depletion. 3- and 24-month-old wild-type mice received juxta-amygdala injection of Abeta42 and hippocampal sections were analyzed for glial fibrillary acidic protein (GFAP)- and SNAP-25-IR at intervals after injections. In young mice, SNAP-IR declined >95% at 1 week in DG-Smi and remained low until 8 weeks, while decreasing in SR, SL and hilum by 8-27% at 1 week and returning to baseline by 2 weeks.

Genomic expression discovery predicts pathways and opposing functions behind phenotypes.

Discovering states of genetic expression that are true to a high degree of certainty is likely to predict gene function behind biological phenotypes. The states of expression (up- or down-regulated) of 19200 cDNAs in 10 meningiomas are compared with normal brain by an algorithm that detects only 1 false measurement per 192000; 364 genes are discovered. The expression data accurately predict activation of signaling pathways and link gene function to specific phenotypes.