Vaccination of Glioma Patients with Fusions of Dendritic and Glioma Cells and Recombinant Human Interleukin 12

Kikuchi, Tetsuro; Akasaki, Yukio; Abe, Toshiaki; Fukuda, Takahiro; Saotome, Hideo; Ryan, John L.; Küfe, Donald; Ohno, Tsuneya

doi:10.1097/00002371-200411000-00005

Cited by 187 publications

(118 citation statements)

References 13 publications

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“…We have reported that fusions of monocyte-derived immature DCs and autologous breast cancer, ovarian cancer, acute myeloid leukemia, or colorectal cancer cells induce antitumor immune responses against autologous tumor in vitro (10,(12)(13)(14)(15)(16). In phase I clinical trials in patients with melanoma, glioma, gastric, breast, and renal cancer, vaccination with DCs/tumor FCs was associated with immunologic and clinical responses (17)(18)(19)(20)(21)(22). Although the DCs/tumor fusion strategy has enormous potential in mice study, results from early clinical trails have been unsatisfactory (8 -11, 17-22).…”

Section: Endritic Cells (Dcs)mentioning

confidence: 99%

Streptococcal Preparation OK-432 Promotes Fusion Efficiency and Enhances Induction of Antigen-Specific CTL by Fusions of Dendritic Cells and Colorectal Cancer Cells

Koido

Hara

Homma

et al. 2007

The Journal of Immunology

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Dendritic/tumor fusion cell (FC) vaccine is an effective approach for various types of cancer but has not yet been standardized. Antitumor activity can be modulated by different mechanisms such as dendritic cell (DC) maturation state. This study addressed optimal strategies for FC preparations to enhance Ag-specific CTL activity. We have created three types of FC preparations by alternating fusion cell partners: 1) immature DCs fused with autologous colorectal carcinoma cells (Imm-FCs); 2) Imm-FCs followed by stimulation with penicillin-inactivated Streptococcus pyogenes (OK-432) (Imm-FCs/OK); and 3) OK-432-stimulated DCs directly fused to autologous colorectal carcinoma cells (OK-FCs). Both OK-FCs and Imm-FCs/OK coexpressed the CEA, MUC1, and significantly higher levels of CD86, CD83, and IL-12 than those obtained with Imm-FCs. Short-term culture of fusion cell preparations promoted the fusion efficiency. Interestingly, OK-FCs were more efficient in stimulating CD4+ and CD8+ T cells capable of high levels of IFN-γ production and cytolysis of autologous tumor or semiallogeneic targets. Moreover, OK-FCs are more effective inducer of CTL activation compared with Imm-FCs/OK on a per fusion cell basis. The pentameric assay confirmed that CEA- and MUC1-specific CTL was induced simultaneously by OK-FCs at high frequency. Furthermore, the cryopreserved OK-FCs retained stimulatory capacity for inducing antitumor immunity. These results suggest that OK-432 promotes fusion efficiency and induction of Ag-specific CTL by fusion cells. We conclude that DCs fused after stimulation by OK-432 may have the potential applicability to the field of antitumor immunotherapy and may provide a platform for adoptive immunotherapy in the clinical setting.

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Section: Endritic Cells (Dcs)mentioning

confidence: 99%

Streptococcal Preparation OK-432 Promotes Fusion Efficiency and Enhances Induction of Antigen-Specific CTL by Fusions of Dendritic Cells and Colorectal Cancer Cells

Koido

Hara

Homma

et al. 2007

The Journal of Immunology

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“…We have previously reported that immature (Imm) DCs (Imm-DCs) fused with autologous tumor cells can induce Ag-specific polyclonal CTLs in vitro (7)(8)(9)(10)(11). Although immunization with DC/tumor cell FCs in patients with cancer has been associated with immunological responses in phase I clinical trials, early clinical trials have shown only limited success (12)(13)(14)(15)(16)(17). Because this DC/tumor cell FC approach was developed in animal studies, many adjuvants, including IL-2, IL-12, IL-18, and synthetic oligodeoxynucleotides (ODNs) containing specific bacterial unmethylated CpG motifs (CpG ODNs), have been used to enhance the ability of DC/tumor cell FC vaccines to evoke antitumor immune responses (18 -22).…”

Section: Synergistic Induction Of Antigen-specific Ctl By Fusions Of mentioning

confidence: 99%

Synergistic Induction of Antigen-Specific CTL by Fusions of TLR-Stimulated Dendritic Cells and Heat-Stressed Tumor Cells

Koido

Hara

Homma

et al. 2007

The Journal of Immunology

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Dendritic cell (DC)/tumor cell fusion cells (FCs) can induce potent CTL responses. The therapeutic efficacy of a vaccine requires the improved immunogenicity of both DCs and tumor cells. The DCs stimulated with the TLR agonist penicillin-killed Streptococcus pyogenes (OK-432; OK-DCs) showed higher expression levels of MHC class I and II, CD80, CD86, CD83, IL-12, and heat shock proteins (HSPs) than did immature DCs. Moreover, heat-treated autologous tumor cells displayed a characteristic phenotype with increased expression of HSPs, carcinoembryonic Ag (CEA), MUC1, and MHC class I (HLA-A2 and/or A24). In this study, we have created four types of FC preparation by alternating fusion cell partners: 1) immature DCs fused with unheated tumor cells; 2) immature DCs fused with heat-treated tumor cells; 3) OK-DCs fused with unheated tumor cells; and 4) OK-DCs fused with heat-treated tumor cells. Although OK-DCs fused with unheated tumor cells efficiently enhanced CTL induction, OK-DCs fused with heat-treated tumor cells were most active, as demonstrated by: 1) up-regulation of multiple HSPs, MHC class I and II, CEA, CD80, CD86, CD83, and IL-12; 2) activation of CD4+ and CD8+ T cells able to produce IFN- γ at higher levels; 3) efficient induction of CTL activity specific for CEA or MUC1 or both against autologous tumor; and 4) superior abilities to induce CD107+IFN-γ+CD8+ T cells and CD154+ IFN-γ+CD4+ T cells. These results strongly suggest that synergism between OK-DCs and heat-treated tumor cells enhances the immunogenicity of FCs and provides a promising means of inducing therapeutic antitumor immunity.

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“…Kikuchi et al, conducted a study that included 15 patients with anaplastic astrocytoma (AA), anaplastic oligoastrocytoma (AOA), and GBM. Treatment consisted of subcutaneous administration of recombinant IL-12 in combination with a fusion of autologous dendritic and glioma cells [46]. In 2 patients, augmentation of CD8+ cytolytic activity on glioma cells was documented after treatment.…”

Section: Nih-pa Author Manuscriptmentioning

confidence: 99%

Current Immunotherapeutic Strategies for Central Nervous System Tumors

Kushen¹,

Sonabend²,

Lesniak³

2007

Surgical Oncology Clinics of North America

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Immunotherapy has emerged as a promising tool in the management of malignant central nervous system (CNS) tumors. Despite the improvement in patient survival, traditional approaches -which consist mostly of surgery, radiotherapy, and chemotherapy -have been largely unsuccessful in permanently controlling these aggressive tumors. Immunotherapeutic strategies therefore offer not only a novel approach, but also an advantage in a way other modalities have been failing. Specifically, the capabilities of the immune system to recognize altered cells while leaving normal cells intact offer tremendous advantage over the conventional therapeutic approaches. This review summarizes our current understanding of immunotherapeutic treatment modalities employed in clinical trials for management of malignant CNS tumors. Keywordsclinical trials; glioma; glioblastoma; immunotherapy; dendritic cells; cytokines; toxins Immune system and the CNSThe immune system has the ability to recognize and destroy foreign cells via two separate modalities: innate and adaptive immunity. The innate component consists of macrophages, natural killer (NK) cells, monocytes, and granulocytes. These cells identify molecular patterns involved in cellular transformation and release various cytokines and inflammatory mediators. The innate response lacks the memory capability for foreign antigens, a feature present in adaptive immune response. This latter component of immune system also features specificity for foreign antigens, imparted by presence of receptors on lymphocytes. Antigen presenting cells (APCs) also play a role in the adaptive response -they engulf foreign antigens and present them to the lymphocytes in the context of major histocompatibility complex. CD4+ T cells Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Recent advances in research on antigen presentation, specific cytokines, and T-cell cytotoxicity have given new direction to immunotherapeutic strategies against CNS tumors. Evidence of CNS manifestations after peripheral vaccination with brain-specific antigens in EAE and paraneoplastic cerebellar degeneration models have also lead to a search for possible immunotherapy regimens for management of malignant gliomas [32]. Current directions in immunotherapy investigations include the use of various cytokines, dendritic cells, viral and peptide vaccines, and toxins. NIH Public Access CytokinesCytokines augment T cell activation and MHC antigen expression. Antitumor effects mediated by expression of cytokines in cancer models have been demonstrated with IL-2, IL-4, IL-12, IL-23, IFN-α, and ...

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Vaccination of Glioma Patients with Fusions of Dendritic and Glioma Cells and Recombinant Human Interleukin 12

Cited by 187 publications

References 13 publications

Streptococcal Preparation OK-432 Promotes Fusion Efficiency and Enhances Induction of Antigen-Specific CTL by Fusions of Dendritic Cells and Colorectal Cancer Cells

Streptococcal Preparation OK-432 Promotes Fusion Efficiency and Enhances Induction of Antigen-Specific CTL by Fusions of Dendritic Cells and Colorectal Cancer Cells

Synergistic Induction of Antigen-Specific CTL by Fusions of TLR-Stimulated Dendritic Cells and Heat-Stressed Tumor Cells

Current Immunotherapeutic Strategies for Central Nervous System Tumors

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