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5 Dendritic Cell Vaccines for Gliomas Anne Luptrawan, Gentao Liu, Suzane Brian, and John S. Yu Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, California, U.S.A. INTRODUCTION The total number of new cases of primary malignant brain tumors in the United States in 2005 was 21,690 as estimated by the Central Brain Tumor Registry of the United States (CBRTUS). Astrocytomas are the most common primary brain tumor. Glioblastoma multiforme (GBM) is the most aggressive and malignant form with a median survival of only 15 months despite best possible treatment—surgical resection followed by radiation and chemotherapy. GBM can transition from a lower grade glioma (secondary GBM) or can develop de novo (primary GBM). Despite advances in surgical technique, chemotherapy, and radiation therapy, the prognosis for patients with malignant glioma remains poor. Even after optimal treatment with surgical resection followed by chemoradiation therapy, the median survival of GBM is 15 months. The infiltrative nature of the disease, a central nervous system (CNS) microenvironment that can escape immune surveillance, and resistance of tumor to chemotherapy contribute to a grim prognosis. 83
84 Luptrawan et al. Dendritic cells (DCs) have an ability to promote an effective antitumor immune response and sensitize glioma cells to chemotherapy as demonstrated in recent trials. This chapter will discuss results of recent DC-vaccine clinical trials and explore future strategies of DC vaccines for malignant gliomas. The inherent vulnerability of the brain parenchyma and complex character of the tumor itself can explain the poor response of malignant brain tumors to current therapies (1,2). As the name implies, glioblastoma is multiform, both grossly and genetically. GBM has various deletions and amplifications, and point mutations leading to activation of signal transduction pathways downstream of tyrosine kinase receptors such as epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor (PDGFR), as well as to disruption of cell cycle–arrest pathways by INK4a-ARF loss or by p53 mutations associated with CDK4 amplification or RB loss (3). The brain’s physical isolation from the systemic circulation by the bloodbrain barrier (BBB), absence of lymphatic vessels, lack of resident DCs and human leukocyte antigens (HLA) on brain cells makes it an immunologically privileged organ. The neuronal environment is protected from surveillance by immune cells in part by the BBB which functions to regulate passage of macromolecules and intravascular immune cells from the lumen of vessels in the neural parenchyma into the extravascular compartment. The location of cells within the brain is variable, making complete resection of malignant gliomas difficult (2). Tumor cells can be found centimeters away from the primary tumor site. Invasion of glioma cells into surrounding normal brain parenchyma is accomplished via white matter tracts, perivascular and periventricular spaces. In gliomatosis cerebri, cells spread diffusely and in severe cases, can involve the entire brain. Tumor cells invade critical structures creating mass effect and causing irreversible damage to areas needed for patient survival. The genetic instability, cellular heterogeneity, and disseminated nature of malignant gliomas make current treatment strategies to eliminate all residual intracranial tumor reservoirs unsuccessful (4,5a). Therefore, recurrence of tumor is inevitable and contributes to the lethality of this disease. CELLULAR IMMUNITY Cell-mediated immunity requires T cells to be in direct contact with their targets in order to cause injury to tumor cells. A cellular immune response is dependent on T-cell receptors’ specific recognition of cell-surface antigens and its ability to recognize and destroy foreign cells, including host cells bearing intracellular pathogens. The presence of both foreign antigens and self-antigens on a cell’s surface is needed to activate T cells in response to a foreign antigen. Activation of the cell-mediated immune attack triggers complementary T-cell clone proliferation and differentiation, which yields a large number of activated T cells to carry out various cell-mediated responses. Direct killing of host cells harboring mutated proteins from malignant transformations in cancer cells is done by cytotoxic T cells (killer T cells or CD8 þ cells) (5b).
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Translational Medicine Series 6 Can
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TRANSLATIONAL MEDICINE SERIES 1. Pr
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Informa Healthcare USA, Inc. 52 Van
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Preface Throughout the last 20 year
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Preface vii Table 1 A Diverse Techn
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Preface . . . . v Contributors . .
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Contributors Pedro Alves Ludwig Ins
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1 Factoring in Antigen Processing i
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Factoring in Antigen Processing in
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2 Outlining the Gap Between Preclin
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Multimodality Immunization Approach
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Development of Novel Immunotherapeu
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206 Index Antigenic peptides degrad
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212 Index Langerhans cells, 133, 13
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216 Index TCRL. See TCR-like immuno
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Oncology and Immunology about the b
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