PPAR-γ 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 PPARγ by TZDs has been best characterized by its ability to regulate expression of genes associated with lipid metabolism, PPARγ 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. Initial studies from our lab show that combination of an immunotherapeutic strategy with TZD treatment provides synergistic benefit in animals with implanted tumors. The potential of this combined approach for treatment of brain tumors is reviewed in this report

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. Immune editing is one of the key aspects why tumors evade surveillance causing the tumors to lie dormant in patients for years through “equilibrium” and “senescence” before re- emerging. In addition, tumors exploit several immunological processes such as targeting the regulatory T cell function or their secretions, antigen presentation, modifying the production of immune suppressive mediators, tolerance and immune deviation. Besides these, tumor heterogeneity and metastasis also play a critical role in tumor growth. A number of potential targets like promoting Th1, NK cell, γδ T cell responses, inhibiting Treg functionality, induction of IL-12, use of drugs including phytochemicals have been designed to counter tumor progression with much success. Some natural agents and phytochemicals merit further study. For example, use of certain key polysaccharide components from mushrooms and plants have shown possess therapeutic impact on tumor-imposed genetic instability, anti-growth signaling, replicative immortality, deregulated metabolism etc. In this review, we will discuss the advances made towards understanding the basis of cancer immune evasion and summarize the efficacy of various therapeutic measures and targets that have been developed or are being investigated to enhance tumor rejection

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. Normal and malignant cells generally have antigenic differences, and this is the rationale for clinical immunotherapeutic strategies. Cytokines such as IL-15 or IL-2, which stimulate an anti-tumor immune response, have been shown to have a particularly high potential for use in immunotherapy against various tumors. In this review, treatments with either a poxvirus, genetically engineered to secrete IL-15, or allogeneic fibroblasts, transfected with tumor DNA and engineered to secrete IL-2, are shown to be effective strategies in extending the survival of mice with malignant brain tumors upon intracerebral injection of the treatment cells. Future studies with these treatment strategies in patients with intracerebral tumors are urgently needed

Navigated Brain Stimulation (NBS) for Pre-Surgical Planning of Brain Lesion in Critical Areas: Basic Principles and Early Experience

Modern neurosurgery attempts to get the difficult goal of combining an "aggressive" resection of brain tumors with the fundamental purpose of preserving brain functions and best possible quality of life. One of the most important evolutions of neurosurgical therapies is the opportunity to provide a customized surgical intervention by using modern methods to "map" the eloquent areas of the brain. This allows the identification of brain functional areas to be preserved from possible inadvertent intraoperative damage. Direct cortical stimulation (DCS) is an intraoperative technique that uses electrodes placed directly on the exposed cortical surface of the brain to stimulate activity of functional areas by simultaneously recording the evoked responses peripherally. DCS is very precise and reliable and can be considered the gold standard in brain mapping and intraoperative functional monitoring. Nevertheless, the neurosurgeon discovers the spatial relationship between the disease and eloquent cortical surfaces only after having completed a craniotomy and dural opening. A pre-surgical mapping method would give the opportunity to plan the treatment of brain diseases optimizing many aspects of the surgical treatment, including patient positioning, type of anesthesia, size of craniotomy, and extent of resection. Moreover, pre-surgical mapping would allow more precise prediction of the efficacy and risks of treatments that can be discussed with the patient and influence the therapeutic strategy. New techniques have been proposed in an attempt to provide a reliable method for the functional study that can be, however, exploited pre-operatively. The most recent of these methods of mapping cortical activities is navigated brain stimulation (NBS), which is based on the neurophysiological technique of transcranial magnetic stimulation (TMS) of the cerebral cortex combined with the conventional neuronavigation. Basic principles of NBS will be here discussed together with our preliminary experience using this technique in different neurosurgical diseases