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Dendritic Cell Vaccines for Gliomas 99 The challenge with vaccination strategies is to break tolerance so that the patient’s immune system recognizes cancer cells. Several aspects involving DC vaccines need to be optimized to include the protocol of DC generation, DC subtype, dose and timing interval of vaccination, route of administration, approaches of antigen loading, and especially DC maturation (71). Recently, a group of researchers has identified a small population of cancer stem cells in adult and pediatric brain tumors (72). These cancer stem cells form neurospheres and possess the capacity for self-renewal (72). They also express genes associated with neural stem cells (NSCs) and differentiate into phenotypically diverse populations including neuronal, astrocytic, and oligodendroglial cells (73–76). Cancer stem cells are likely to share many of the properties of normal stem cells that provide for a long life span, including relative quiescence, resistance to drugs and toxins through the expression of several ABC transporters, an active DNArepair capacity, and resistance to apoptosis. Clinically, it is observed that tumors respond to chemotherapies only to recur with renewed resilience and aggression. Although chemotherapy kills most of the cells in a tumor, cancer stem cells may be left behind which allow recurrence of tumor. Recent studies suggest that CD133 þ cancer stem cells are resistant to current chemotherapy (77,78) and radiation therapy (79). However, cancer stem–like cells (CSCs) could be a novel target for DC immunotherapy. More recently, Pellegatta and his colleagues have reported that that neurospheres enriched in CSCs are highly effective in eliciting a DC-mediated immune response against malignant GL261 glioma cells. These findings suggest that DC targeting of CSCs provides a higher level of protection against GL261 gliomas (80). Future vaccination therapies may be directly driven toward CSC lysates or specific tumor antigens of CSCs to improve and ameliorate the DC-vaccine efficacy (mostly evaluated as overall survival) (81). Moreover, the effects of immunotherapy depend on the development of antigen-specific memory CD8 þ T cells that can express cytokines and kill antigen-bearing cells when they encounter the tumor. The induction of specific CD8 þ -mediated antitumor immunity by DC vaccine involves the following six steps: (i) antigen threshold, (ii) antigen presentation, (iii) T-cell response, (iv) T-cell traffic, (v) target destruction, and (vi) generation of memory. Each of these steps could be significantly impacted by chemotherapy (82). Cytotoxic chemotherapy can be integrated with tumor vaccines using unique doses and schedules to break down the barriers to cancer immunotherapy, releasing the full potential of the antitumor immune response to eradicate disease. The development of new protocols by combining chemotherapy with immunotherapy to achieve therapeutic synergy will be applicable to many cancer types (83). Furthermore, synergistic effects of DC immunotherapy followed by chemotherapy have also been observed. Sensitization of malignant glioma to chemotherapy through DC vaccination provides a novel strategy to overcome the immune escape of cancer cells by immunoediting (66,71). Finally, tumor cells can actively downregulate antitumor immunity and even create a state of immunologic unresponsiveness or self-tolerance to tumor (text continues on page 104)
Table 1 Summary of results of phase I and phase II DC-based immunotherapy for malignant gliomas 100 Luptrawan et al. Intratumoral T cells postvaccination on reoperation Response postvaccination Target disease Vaccine Results Patient population Trial phase Senior investigator/ reference 2 of 4 patients elicited robust intratumoral cytotoxic (CD8 þ ) and memory (CD45RO þ ) T-cell infiltration 3 of 6 patients elicited robust CD8 þ T-cell infiltration intratumorally 4 of 7 patients elicited systemic T-cell cytotoxicity Median survival of 455 days (study group) versus 257 days (control group) DC-pulsed tumor lysate, 3 biweekly vaccinations over 6-week period Newly diagnosed HGG Phase I 9 (7 GBM-N, 2 AA-N) Yu et al. (2001) (42) 6 of 10 patients elicited robust systemic cytotoxicity Recurrent GBM (n ¼ 8) 133 weeks versus 30 weeks for 26 control patients DC-pulsed tumor lysate, 3 biweekly vaccinations over 6-week period Recurrent HGG Phase I 14 (3 AA, 9 GBM, 1 GBM-N, 1 AA-N) Yu et al. (2004) (43) Percentage of CD16 þ and CD56 þ cells in peripheral blood monocytes slightly increased after immunization in 4 out of 5 cases tested HGG DC-autologous glioma fusion cells, Intradermal injections given intradermally every 3 weeks for minimum of 3 and maximum of Phase I 8 (Malignant glioma) Kikuchi et al. (2001) (44) 2 of 15 patients demonstrated significant cytolytic activity 50% reduction in tumor size on magnetic resonance imaging in patients 7 immunizations DC autologous glioma fusion cells injected intradermally followed by recombinant IL-12 (30 ng/kg) for week courses Recurrent HGG Phase I 15 (Malignant glioma) Kikuchi et al. (2004) (45)
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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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206 Index Antigenic peptides degrad
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212 Index Langerhans cells, 133, 13
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Oncology and Immunology about the b
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