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Dendritic Cell Vaccines for Gliomas 91 as evidenced by an increase in median survival of 133 weeks for the study group versus 30 weeks for the control group. In a phase I study by Kikuchi and colleagues (44), eight patients were treated with a series of three to seven intradermal vaccinations with DC-autologous glioma fusion cells. Glioma fusion cells were used as a strategy to improve DCmediated TAA presentation by enhancing tumor cell–DC interaction. Although the ability to induce a tumor-specific immune response was demonstrated, only slight temporary responses to therapy were detected in two patients who had tumor progression on follow-up neuroimaging studies. Kikuchi and colleagues reported a clinical trial using DC-glioma fusion cells and recombinant human IL-12 (45) after a mouse brain tumor model demonstrated systemic administration of recombinant IL-12 enhanced antitumor effect of this vaccine (46). The trial involved 15 patients who received vaccine therapy after progression of disease despite standard chemotherapy and/or radiation therapy. The vaccine of DC-autologous glioma fusion cells was given intradermally close to a cervical lymph node followed by recombinant IL-12 (30 ng/kg) injected subcutaneously at the same site on days 3 and 7. Two sixweek courses of this regimen were completed with the second course starting two to five weeks after the last dose of IL-12. However, results of this trial demonstrated limited success of the DC-glioma fusion cell vaccine. Only two patients demonstrated significant increase in cytolytic activity after vaccination, as shown in a Cr-releasing cytolytic assay (13) using peripheral blood lymphocytes and autologous glioma cells. Cytolytic activity was almost nonexistent in the remainder of patients in the study group. CD4 þ T-cell subsets were not observed, although CD8 þ T-cell infiltration was more robust in recurrent tumor specimens, with pathologic findings of larger tumor cells containing multiple nuclei and wide cytoplasm, when compared to primary tumors. Failure of tumor-specific T-helper 1 induction and/or the existence of tolerogenic CD4 þ T-cell subsets may be a reason for the limited success of the DC-glioma fusion cell vaccine. The potential for T-helper 1 and resident APCs to stimulate each other lends to support TAA-specific CTL responses. The development of a successful antiglioma vaccine may depend on the helper activity of the antigen-specific T-helper subset which can interact with APCs to activate them in the tumor microenvironment (47). A direct injection of DCs into tumor is a novel immunotherapeutic approach. DCs acquire and process tumor antigens in situ allowing migration to regional lymphoid organs via lymphoid vessels thereby initiating significant tumor-specific immune responses in the CNS (12,48). Yamanaka and colleagues described results of a phase I/II clinical trial in which five glioma patients received intradermal vaccination of autologous tumor lysate–pulsed DC vaccination, whereas another five patients underwent intratumoral injection of autologous immature DCs in addition to intradermal vaccination of tumor lysate– pulsed DCs (49). This study used immature DCs since the ability to capture, process, and traffic antigens have been demonstrated by DCs only in their immature
92 Luptrawan et al. state (50). Patients who received both the intratumoral and the intradermal vaccines demonstrated reduction in the size of contrast-enhancing tumor on neuroimaging. This indicates that immature DCs injected intratumorally can potentially induce an antitumor immune response by their ability to capture and process TAAs in situ. For patients with surgically unresectable tumors not allowing for sufficient tumor specimen and/or recurrent gliomas, this may be a novel strategy. In a subsequent phase I/II clinical study, Yamanaka and colleagues, describe the clinical evaluation of malignant glioma patients vaccinated with DCs pulsed by an autologous tumor lysate (51). Twenty-four patients with malignant glioma (6 grade III malignant gliomas and 18 grade IV GBM) status postsurgical resection of tumor, external beam radiation therapy, and nitrosoureabased chemotherapy were enrolled in this study. These patients were monitored for recurrence via brain imaging (MRI or CT), and upon evidence of tumor recurrence, DC immunotherapy was initiated. Twelve patients received maintenance glucocorticoid therapy with prednisone 30 mg/day during DC therapy. DCs were injected intradermally close to a cervical lymph node, or intradermally and intratumorally via an Ommaya reservoir. Patients received DC pulsed with autologous tumor lysate every 3 weeks and continued with up to 10 vaccinations depending on the clinical response. The mean number of administrations was 7.4 times intradermally and 4.6 times intratumorally. In the phase I section of the protocol, 17 patients received administration of immatured DCs pulsed by tumor lysate intradermally or both intradermally and intratumorally. Of the 17 patients, 2 had minor response, 6 had no change, and 9 had progressive disease. In the phase II section of the protocol, seven patients received administration of DCs matured with OK-432 pulsed by tumor lysate given intradermally and immatured DCs given intratumorally via an Ommaya reservoir. One out of the seven patients had partial response, one had minor response, four had no change, and one had progressive disease on MRI. Yamanaka and colleagues found that those 7 patients with GBM who received DCs matured with OK-432 had a significantly increased overall survival compared to the 11 patients who received DCs without OK-432 maturation. They also found that the GBM patients that received both intratumoral and intradermal DC vaccinations had a longer overall survival time than the patients who received intradermal administration alone. Survival of 18 DC-vaccinated patients was compared to 27 nonselected age-, gender-, and disease-matched controls that similarly underwent surgical resection, radiation, and nitrosourea-based chemotherapy. In the DC vaccinated group, results demonstrated a median overall survival time of 480 days with a percentage of overall survival 23.5% at 2 years versus 400 days in the control group with a percentage of overall survival 3.7% at 2 years, conferring DC vaccination is associated with prolonged survival. In a phase I, dose-escalation study, Liau and colleagues enrolled 12 patients with GBM (7 newly diagnosed, 5 recurrent) and treated them with 1, 5, or 10 million autologous DCs pulsed with acid-eluted autologous tumor peptides (52). The newly diagnosed patients underwent surgical resection followed by
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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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Preclinical Models and Clinical Sit
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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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