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Biomedical subjects

Linda M Liau

Publications and source records attributed to Linda M Liau.

At least 19 recordsLinked to original sources
PubMed2006

NK and CD4 cells collaborate to protect against melanoma tumor formation in the brain.

NK cells represent a potent immune effector cell type that have the ability to recognize and lyse tumors. However, the existence and function of NK cells in the traditionally "immune-privileged" CNS is controversial. Furthermore, the cellular interactions involved in NK cell anti-CNS tumor immunity are even less well understood. We administered non-Ag-loaded, immature dendritic cells (DC) to CD8alpha knockout (KO) mice and studied their anti-CNS tumor immune responses. DC administration induced dramatic antitumor immune protection in CD8alpha KO mice that were challenged with B16 melanoma both s.c. and in the brain. The CNS antitumor immunity was dependent on both CD4+ T cells and NK cells. Administration of non-Ag-loaded, immature DC resulted in significant CD4+ T cell and NK cell expansion in the draining lymph nodes at 6 days postvaccination, which persisted for 2 wk. Finally, DC administration in CD8alpha KO mice was associated with robust infiltration of CD4+ T cells and NK cells into the brain tumor parenchyma. These results represent the first demonstration of a potent innate antitumor immune response against CNS tumors in the absence of toxicity. Thus, non-Ag-loaded, immature DC administration, in the setting of CD8 genetically deficient mice, can induce dramatic antitumor immune responses within the CNS that surpass the effects observed in wild-type mice. Our results suggest that a better understanding of the cross-talk between DC and innate immune cells may provide improved methods to vaccinate patients with tumors located both systemically and within the CNS.

Animals↗
PubMed2006

Distinct transcription profiles of primary and secondary glioblastoma subgroups.

Glioblastomas are invasive and aggressive tumors of the brain, generally considered to arise from glial cells. A subset of these cancers develops from lower-grade gliomas and can thus be clinically classified as "secondary," whereas some glioblastomas occur with no prior evidence of a lower-grade tumor and can be clinically classified as "primary." Substantial genetic differences between these groups of glioblastomas have been identified previously. We used large-scale expression analyses to identify glioblastoma-associated genes (GAG) that are associated with a more malignant phenotype via comparison with lower-grade astrocytomas. We have further defined gene expression differences that distinguish primary and secondary glioblastomas. GAGs distinct to primary or secondary tumors provided information on the heterogeneous properties and apparently distinct oncogenic mechanisms of these tumors. Secondary GAGs primarily include mitotic cell cycle components, suggesting the loss of function in prominent cell cycle regulators, whereas primary GAGs highlight genes typical of a stromal response, suggesting the importance of extracellular signaling. Immunohistochemical staining of glioblastoma tissue arrays confirmed expression differences. These data highlight that the development of gene pathway-targeted therapies may need to be specifically tailored to each subtype of glioblastoma.

Adipokines↗
PubMed2006

The TLR-7 agonist, imiquimod, enhances dendritic cell survival and promotes tumor antigen-specific T cell priming: relation to central nervous system antitumor immunity.

Immunotherapy represents an appealing option to specifically target CNS tumors using the immune system. In this report, we tested whether adjunctive treatment with the TLR-7 agonist imiquimod could augment antitumor immune responsiveness in CNS tumor-bearing mice treated with human gp100 + tyrosine-related protein-2 melanoma-associated Ag peptide-pulsed dendritic cell (DC) vaccination. Treatment of mice with 5% imiquimod resulted in synergistic reduction in CNS tumor growth compared with melanoma-associated Ag-pulsed DC vaccination alone. Continuous imiquimod administration in CNS tumor-bearing mice, however, was associated with the appearance of robust innate immune cell infiltration and hemorrhage into the brain and the tumor. To understand the immunological mechanisms by which imiquimod augmented antitumor immunity, we tested whether imiquimod treatment enhanced DC function or the priming of tumor-specific CD8+ T cells in vivo. With bioluminescent, in vivo imaging, we determined that imiquimod dramatically enhanced both the persistence and trafficking of DCs into the draining lymph nodes after vaccination. We additionally demonstrated that imiquimod administration significantly increased the accumulation of tumor-specific CD8+ T cells in the spleen and draining lymph nodes after DC vaccination. The results suggest that imiquimod positively influences DC trafficking and the priming of tumor-specific CD8+ T cells. However, inflammatory responses induced in the brain by TLR signaling must also take into account the local microenvironment in the context of antitumor immunity to induce clinical benefit. Nevertheless, immunotherapeutic targeting of malignant CNS tumors may be enhanced by the administration of the innate immune response modifier imiquimod.

Adjuvants, Immunologic↗
PubMed2006

Primary glioblastomas express mesenchymal stem-like properties.

Glioblastoma is the most common and aggressive primary brain cancer. Recent isolation and characterization of brain tumor-initiating cells supports the concept that transformed neural stem cells may seed glioblastoma. We previously identified a wide array of mesenchymal tissue transcripts overexpressed in a broad set of primary glioblastoma (de novo) tumors but not in secondary glioblastoma (derived from lower-grade) tumors, low-grade astrocytomas, or normal brain tissues. Here, we extend this observation and show that a subset of primary glioblastoma tumors and their derived tumor lines express cellular and molecular markers that are associated with mesenchymal stem cells (MSC) and that glioblastoma cell cultures can be induced to differentiate into multiple mesenchymal lineage-like cell types. These findings suggest either that a subset of primary glioblastomas derive from transformed stem cells containing MSC-like properties and retain partial phenotypic aspects of a MSC nature in tumors or that glioblastomas activate a series of genes that result in mesenchymal properties of the cancer cells to effect sustained tumor growth and malignant progression.

Antigens, Surface↗
PubMed2006

Targeting stem cells in brain tumors.

Stem cells are commonly defined as undifferentiated cells capable of self-renewing and giving rise to a large number of differentiated progeny. It is becoming increasingly apparent that there exist cancer stem cells (CSCs) from which the cells of any given malignancy arise, whereby only a few cells out of a population of cancer cells are able to initiate tumor formation. These CSCs, like their normal counterparts, are characterized by self-renewal and the ability to "differentiate" into all of the cell types in the original tumor. Current chemotherapeutic strategies involve using non-specific cytotoxic agents that target rapidly cycling cells. Although this may reduce disease burden in many cases, these therapies may miss the rare, self-renewing population that truly gives rise to the malignancy (the CSC). This review will focus on the recent discovery of stem cell-like cells in human brain tumors, putative "brain cancer stem cells," which exhibit the properties of self-renewal and the ability to recapitulate the original tumor heterogeneity. Dissecting the molecular mechanisms that underlie the ability of these cells to self-renew and maintain quiescence may allow the development of novel therapeutic strategies that will allow for more efficacious and less toxic therapies for these devastating malignancies.

Animals↗
PubMed2006

Central nervous system tumor immunity generated by a recombinant listeria monocytogenes vaccine targeting tyrosinase related protein-2 and real-time imaging of intracranial tumor burden.

OBJECTIVE: Previously, we demonstrated that a recombinant Listeria monocytogenes (rLM) vector encoding the melanoma-associated antigen, tyrosinase related protein (TRP)-2, could successfully treat subcutaneous B16 melanomas. The purpose of the present study was twofold: 1) to test whether this rLM-nucleoprotein (NP)/TRP-2 could generate antitumor immunity to a B16 tumor challenge in the immunologically privileged central nervous system (CNS) and 2) to develop a noninvasive imaging modality to monitor tumor progression in the brain after immunotherapy. METHODS: Mice were vaccinated with either a control rLM strain expressing only a viral antigen (rLM-NP) or a strain expressing both the viral epitope and TRP-2 (rLM-NP/TRP-2). These mice were then analyzed for their ability to mount tumor-specific T-cell responses, to generate protective antitumor immunity to a CNS tumor challenge, and for the localization of T cells at the tumor site. To noninvasively measure tumor growth within the CNS in vivo, we developed a B16 cell line expressing firefly luciferase that could be readily detected via bioluminescent imaging. RESULTS: Vaccination with rLM-NP/TRP-2 induced a robust, tumor-specific CD8 T-cell response to the dominant cytotoxic T lymphocyte epitope of TRP-2 and selective interferon-gamma secretion when cocultured with B16 melanoma cells in vitro. Significant decreases in CNS tumor sizes were easily visualized in mice vaccinated with rLM-NP/TRP-2 compared with mice that received a control rLM expressing the NP epitope alone (rLM-NP). The subsequent decreased tumor size and extension of survival induced by rLM-NP/TRP-2 was similarly associated with an early increase of tumor infiltrating T cells. CONCLUSION: The ability to treat tumors arising within the CNS is difficult because of the nature of the anatomic confines of the brain and a microenvironment that may not promote immune responsiveness. These studies describe an in vivo bioluminescent imaging system to monitor CNS tumor growth in mice, which we successfully used to document decreased intracranial tumor progression and size after vaccination with rLM-NP/TRP-2. The results suggest that metastatic tumors in the CNS can be targeted immunotherapeutically without overt autoimmune toxicity.

Animals↗
PubMed2006

Epidermal growth factor receptor activation in glioblastoma through novel missense mutations in the extracellular domain.

BACKGROUND: Protein tyrosine kinases are important regulators of cellular homeostasis with tightly controlled catalytic activity. Mutations in kinase-encoding genes can relieve the autoinhibitory constraints on kinase activity, can promote malignant transformation, and appear to be a major determinant of response to kinase inhibitor therapy. Missense mutations in the EGFR kinase domain, for example, have recently been identified in patients who showed clinical responses to EGFR kinase inhibitor therapy. METHODS AND FINDINGS: Encouraged by the promising clinical activity of epidermal growth factor receptor (EGFR) kinase inhibitors in treating glioblastoma in humans, we have sequenced the complete EGFR coding sequence in glioma tumor samples and cell lines. We identified novel missense mutations in the extracellular domain of EGFR in 13.6% (18/132) of glioblastomas and 12.5% (1/8) of glioblastoma cell lines. These EGFR mutations were associated with increased EGFR gene dosage and conferred anchorage-independent growth and tumorigenicity to NIH-3T3 cells. Cells transformed by expression of these EGFR mutants were sensitive to small-molecule EGFR kinase inhibitors. CONCLUSIONS: Our results suggest extracellular missense mutations as a novel mechanism for oncogenic EGFR activation and may help identify patients who can benefit from EGFR kinase inhibitors for treatment of glioblastoma.

Animals↗
PubMed2006

Immunotherapy for patients with malignant glioma: from theoretical principles to clinical applications.

Malignant gliomas are the most common type of primary brain tumor and are in great need of novel therapeutic approaches. Advances in treatment have been very modest, significant improvement in survival has been lacking for many decades and prognosis remains dismal. Despite 'gross total' surgical resections and currently available radio-chemotherapy, malignant gliomas inevitably recur due to reservoirs of notoriously invasive tumor cells that infiltrate adjacent and nonadjacent areas of normal brain parenchyma. In principle, the immune system is uniquely qualified to recognize and target these infiltrative pockets of tumor cells, which have generally eluded conventional treatment approaches. In the span of the last 10 years, our understanding of the cancer-immune system relationship has increased exponentially, and yet, we are only beginning to tease apart the intricacies of the CNS and immune cell interactions. This article reviews the complex associations of the immune system with brain tumors. We provide an overview of currently available treatment options for malignant gliomas, existing gaps in our knowledge of brain tumor immunology, and molecular techniques and targets that might be exploited for improved patient stratification and design of 'custom immunotherapeutics'. We will also examine major new immunotherapy approaches that are being actively investigated to treat patients with malignant glioma, and identify some current and future research priorities in this area.

Brain Neoplasms↗
PubMed2005

Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors.

BACKGROUND: The epidermal growth factor receptor (EGFR) is frequently amplified, overexpressed, or mutated in glioblastomas, but only 10 to 20 percent of patients have a response to EGFR kinase inhibitors. The mechanism of responsiveness of glioblastomas to these inhibitors is unknown. METHODS: We sequenced kinase domains in the EGFR and human EGFR type 2 (Her2/neu) genes and analyzed the expression of EGFR, EGFR deletion mutant variant III (EGFRvIII), and the tumor-suppressor protein PTEN in recurrent malignant gliomas from patients who had received EGFR kinase inhibitors. We determined the molecular correlates of clinical response, validated them in an independent data set, and identified effects of the molecular abnormalities in vitro. RESULTS: Of 49 patients with recurrent malignant glioma who were treated with EGFR kinase inhibitors, 9 had tumor shrinkage of at least 25 percent. Pretreatment tissue was available for molecular analysis from 26 patients, 7 of whom had had a response and 19 of whom had rapid progression during therapy. No mutations in EGFR or Her2/neu kinase domains were detected in the tumors. Coexpression of EGFRvIII and PTEN was significantly associated with a clinical response (P<0.001; odds ratio, 51; 95 percent confidence interval, 4 to 669). These findings were validated in 33 patients who received similar treatment for glioblastoma at a different institution (P=0.001; odds ratio, 40; 95 percent confidence interval, 3 to 468). In vitro, coexpression of EGFRvIII and PTEN sensitized glioblastoma cells to erlotinib. CONCLUSIONS: Coexpression of EGFRvIII and PTEN by glioblastoma cells is associated with responsiveness to EGFR kinase inhibitors.

Adult↗
PubMed2005

Dendritic cell vaccination in glioblastoma patients induces systemic and intracranial T-cell responses modulated by the local central nervous system tumor microenvironment.

PURPOSE: We previously reported that autologous dendritic cells pulsed with acid-eluted tumor peptides can stimulate T cell-mediated antitumor immune responses against brain tumors in animal models. As a next step in vaccine development, a phase I clinical trial was established to evaluate this strategy for its feasibility, safety, and induction of systemic and intracranial T-cell responses in patients with glioblastoma multiforme. EXPERIMENTAL DESIGN: Twelve patients were enrolled into a multicohort dose-escalation study and treated with 1, 5, or 10 million autologous dendritic cells pulsed with constant amounts (100 mug per injection) of acid-eluted autologous tumor peptides. All patients had histologically proven glioblastoma multiforme. Three biweekly intradermal vaccinations were given; and patients were monitored for adverse events, survival, and immune responses. The follow-up period for this trial was almost 5 years. RESULTS: Dendritic cell vaccinations were not associated with any evidence of dose-limiting toxicity or serious adverse effects. One patient had an objective clinical response documented by magnetic resonance imaging. Six patients developed measurable systemic antitumor CTL responses. However, the induction of systemic effector cells did not necessarily translate into objective clinical responses or increased survival, particularly for patients with actively progressing tumors and/or those with tumors expressing high levels of transforming growth factor beta(2) (TGF-beta(2)). Increased intratumoral infiltration by cytotoxic T cells was detected in four of eight patients who underwent reoperation after vaccination. The magnitude of the T-cell infiltration was inversely correlated with TGF-beta(2) expression within the tumors and positively correlated with clinical survival (P = 0.047). CONCLUSIONS: Together, our results suggest that the absence of bulky, actively progressing tumor, coupled with low TGF-beta(2) expression, may identify a subgroup of glioma patients to target as potential responders in future clinical investigations of dendritic cell-based vaccines.

Adult↗
PubMed2005

The TLR7 agonist imiquimod enhances the anti-melanoma effects of a recombinant Listeria monocytogenes vaccine.

Activation of innate immune cells through TLR triggers immunomodulating events that enhance cell-mediated immunity, raising the possibility that ligands to these receptors might act as adjuvants in conjunction with T cell activating vaccines. In this report, topical imiquimod, a synthetic TLR7 agonist, significantly enhanced the protective antitumor effects of a live, recombinant listeria vaccine against murine melanoma. This tumor protective effect was not dependent on direct application to the tumor and was associated with an increase in tumor-associated and splenic dendritic cells. Additionally, the combination of imiquimod treatment with prior vaccination led to development of localized vitiligo. These findings indicate that activation of the innate immune system with TLR ligands stimulates dendritic cell activity resulting in a bypass of peripheral tolerance and enhanced antitumor activity. The results of these studies have broad implications for future designs of immunotherapeutic vaccines against tumors and the treatment of metastatic melanoma.

Adjuvants, Immunologic↗
PubMed2005

Robustness of gene expression profiling in glioma specimen samplings and derived cell lines.

One of the most promising applications of microarrays is class distinction through gene expression profiling as a diagnostic tool. However, as there is apparent spatial heterogeneity in the morphology of cancer cells within a tumor, it is unclear if tumor sampling can be applied and yield consistent signals. In this report, we examined six brain tumors, four glioblastoma, and two oligodendroglioma biopsies. The six brain tumor tissues from two distinct different classes were dissected in four distinct areas and gene expression was profiled using microarrays. We used hierarchical clustering to compare the variability of gene expression profiles between spatially distinct biopsies of the same tumor as compared to the variability between tumors of the same histologic group. We conclude that, in general, repeat spatially distinct samples are not needed for microarray experiments and the gene expression signatures are robust across the tumor. Predominantly, variation was much greater between samples from different patients than from the multiple samplings of given tumor. Further, we compared biopsy expression profiles to the cell lines derived from those tissues. In general, the tumor cell lines vary greatly from the parental tissues and cluster more strongly with each other than the parental tissue. We select and examine the set of genes altered in expression to allow adaptation to cell culture.

Brain Neoplasms↗
PubMed2005

Gliomas: advances in molecular analysis and characterization.

BACKGROUND: Gliomas represent the most common primary brain tumor. Despite recent advances in diagnostic imaging, neurosurgical technique, radiation therapy, and chemotherapy, significant advances in accurate prognosis and improved survival have not been achieved. Nevertheless, new developments in molecular biology could have potential impact on the clinical management of patients with these brain tumors. This review will describe the technological advances being used to enrich the classification of gliomas, present specific studies that have successfully used the new technologies to identify molecular subtypes of glioblastoma, and discuss the implications of such enhanced classification and molecular characterizations for the prediction of therapeutic response and the design of future brain tumor therapies. RESULTS: Innovative techniques using complementary DNA and oligonucleotide microarrays (gene chips), tissue microarrays (tissue chips), and differential immunoabsorption have provided high throughput and potentially comprehensive approaches for the molecular characterization of human gliomas. Alterations of several tumor suppressor genes and oncogenes have already been identified as being critical to glioma transformation and progression. These approaches have led to the subclassification of glioblastoma multiforme into distinct subtypes based on the molecular signatures of the tumors. CONCLUSIONS: Classifications of gliomas can now be enhanced with new techniques for comprehensive molecular characterization. Improved and efficient molecular profiling of brain tumors is advancing diagnosis/prognosis and identifying targets for novel and rational therapeutic approaches. Neurosurgeons and neuro-oncologists should be aware of these new developments so they can better advise and treat their patients.

Biomarkers, Tumor↗
PubMed2005

Bioluminescent imaging of melanoma in live mice.

Melanoma is highly resistant to conventional chemotherapeutic agents and novel therapeutic approaches are needed. Current animal models of melanoma in animals are sub-optimal. The most commonly used homograft model is the B16 mouse melanoma. Evaluation of potential melanoma therapies with this model is limited by the inaccuracy of caliper measurement of subcutaneous tumors, of counting lung nodules in metastasis models, and the indirect nature of "survival" curves when studying brain metastases. We have developed and characterized an accurate, sensitive, and reproducible bioluminescent B16 melanoma model that allows for serial, real-time analyses of tumor burden in live mice. We demonstrate that this model is applicable to subcutaneous tumors, lung metastases, and intracranial tumors and offers a solution to many of the limitations of previous models. As proof of principle, we use this model to show the efficacy of a live, Listeria monocytogenes vaccine expressing the melanoma antigen tyrosinase-related protein-2 to protect mice against intravenous B16 melanoma challenge. Additionally, we extend our approach to include the human A375 melanoma model and are able to show in vivo differences between sub-lines with varying metastatic potential. These models represent an accurate and reproducible means for in vivo melanoma monitoring in preclinical studies.

Animals↗
PubMed2005

Tumor immunology, immunomics and targeted immunotherapy for central nervous system malignancies.

Although the brain was traditionally considered as 'immunologically privileged', recent findings have implied an involvement of immune mechanisms in neurological disease and illness, including central nervous system (CNS) malignancies. In this review, we initially focus on aspects of the immune system critical for effective antitumor immunity, as an understanding of normal immunological functions and how they relate to tumor immunology will set a foundation for understanding the unique challenges facing the integration of neuro-oncology and neuroimmunology. We summarize current knowledge of immune responses in the 'immunologically quiescent' brain and its role in tumor immunology. We will then discuss the emerging field of 'immunomics' and recent advances in molecular technologies, such as DNA microarray, which are being applied to brain tumor antigen epitope discovery and patient stratification for brain cancer immunotherapy. This, in turn, should have significant importance for ultimately designing and developing efficient and focused strategies for anticancer immunotherapy. Finally, the current state of immune-based treatment paradigms and future directions will be discussed, paying particular attention to targeted antibody strategies, adoptive cellular immunotherapy, and tumor vaccine approaches that have been studied in clinical trials for CNS neoplasms.

Animals↗
PubMed2004

Gene expression profiling of gliomas strongly predicts survival.

In current clinical practice, histology-based grading of diffuse infiltrative gliomas is the best predictor of patient survival time. Yet histology provides little insight into the underlying biology of gliomas and is limited in its ability to identify and guide new molecularly targeted therapies. We have performed large-scale gene expression analysis using the Affymetrix HG U133 oligonucleotide arrays on 85 diffuse infiltrating gliomas of all histologic types to assess whether a gene expression-based, histology-independent classifier is predictive of survival and to determine whether gene expression signatures provide insight into the biology of gliomas. We found that gene expression-based grouping of tumors is a more powerful survival predictor than histologic grade or age. The poor prognosis samples could be grouped into three different poor prognosis groups, each with distinct molecular signatures. We further describe a list of 44 genes whose expression patterns reliably classify gliomas into previously unrecognized biological and prognostic groups: these genes are outstanding candidates for use in histology-independent classification of high-grade gliomas. The ability of the large scale and 44 gene set expression signatures to group tumors into strong survival groups was validated with an additional external and independent data set from another institution composed of 50 additional gliomas. This demonstrates that large-scale gene expression analysis and subset analysis of gliomas reveals unrecognized heterogeneity of tumors and is efficient at selecting prognosis-related gene expression differences which are able to be applied across institutions.

Adolescent↗
PubMed2004

Cellular immunity and immunotherapy of brain tumors.

Factors influencing the host immune response to central nervous system (CNS) tumors are not yet well understood. This review will outline what is known about anti-tumor immune responses against CNS tumors and describe how advances in our knowledge of basic immunology may be applied to brain tumor immunotherapy. We will first focus on cellular immune system interactions involved in peripheral anti-tumor immune responses. Then, we will discuss characteristics of tumors arising within the confines of the CNS that distinguish them from peripheral neoplasms, emphasizing immune defects that seem to limit or curtail specific anti-tumor immunity against brain tumors. Finally, the current state of immune-based treatment paradigms and future directions will be discussed, paying particular attention to adoptive cellular immunotherapy and tumor vaccine approaches for the treatment of malignant gliomas.

Animals↗