Marked enhancement of antitumor immune responses in mouse brain tumor models by genetically modified dendritic cells producing Semliki Forest virus—mediated interleukin-12

2002 ◽  
Vol 97 (3) ◽  
pp. 611-618 ◽  
Author(s):  
Ryuya Yamanaka ◽  
Susan A. Zullo ◽  
Jay Ramsey ◽  
Naoki Yajima ◽  
Naoto Tsuchiya ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Brain Tumor ◽  
Tumor Antigens ◽  
Semliki Forest Virus ◽  
Tumor Regression ◽  
Interleukin 12 ◽  
Content Type ◽  
Retrovirus Vector ◽  
Induced Apoptosis ◽  
Fine Print

Object. The authors evaluated dendritic cell (DC)—based immunotherapy for malignant brain tumor to improve its therapeutic efficacy. Methods. Dendritic cells were isolated from bone marrow and pulsed with phosphate-buffered saline, Semliki Forest virus (SFV)—LacZ, retrovirus vector GCsap—interleukin (IL)-12, and SFV—IL-12, respectively, to treat mice bearing brain tumors of the B16 cell line. The results indicated that therapeutic immunization with DCs pulsed with SFV—IL-12 prolonged the survival of mice with established tumors. Semliki Forest virus induced apoptosis in DCs, which in turn facilitated the uptake of apoptotic cells by other DCs, thus providing a potential mechanism for enhanced immunogenicity. Conclusions. Therapy with DCs that have been pulsed with SFV-mediated IL-12 may be an excellent step in the development of new cancer vaccines. Intratumorally injected DCs that have been transiently transduced with IL-12 do not require pulsing of a source of tumor antigens to induce tumor regression.

Enhancement of antitumor immune response in glioma models in mice by genetically modified dendritic cells pulsed with Semliki Forest virus—mediated complementary DNA

2001 ◽  
Vol 94 (3) ◽  
pp. 474-481 ◽  
Author(s):  
Ryuya Yamanaka ◽  
Susan A. Zullo ◽  
Ryuichi Tanaka ◽  
Michael Blaese ◽  
Kleanthis G. Xanthopoulos
Keyword(s):  
Dendritic Cells ◽  
Cancer Vaccines ◽  
Semliki Forest Virus ◽  
Glioma Cell Line ◽  
Tumor Lysate ◽  
Tumor Challenge ◽  
Content Type ◽  
Induced Apoptosis ◽  
Phosphate Buffered Saline ◽  
Fine Print

Object. The aim of this study was to further investigate dendritic cell (DC)—based immunotherapy for malignant glioma to improve its therapeutic efficacy. Methods. Dendritic cells were isolated from the bone marrow and pulsed with phosphate-buffered saline, tumor RNA, tumor lysate, Semliki Forest virus (SFV)-LacZ, SFV-mediated B16 complementary (c)DNA, or SFV-mediated 203 glioma cDNA, respectively, to treat mice bearing tumors of the 203 glioma cell line. The results indicated that preimmunization with DCs pulsed with the same type of cDNA as in the tumor by a self-replicating RNA vector (that is, SFV) protected mice from tumor challenge, and that therapeutic immunization prolonged the survival of mice with established tumors. The SFV induced apoptosis in DCs and their death facilitated the uptake of apoptotic cells by other DCs, thus providing a potential mechanism for enhanced immunogenicity. Conclusions. Therapy with DCs that have been pulsed with SFV-mediated tumor cDNA may be an excellent procedure for the development of new cancer vaccines.

Induction of an antitumor immunological response by an intratumoral injection of dendritic cells pulsed with genetically engineered Semliki Forest virus to produce interleukin-18 combined with the systemic administration of interleukin-12

2003 ◽  
Vol 99 (4) ◽  
pp. 746-753 ◽  
Author(s):  
Ryuya Yamanaka ◽  
Naoto Tsuchiya ◽  
Naoki Yajima ◽  
Junpei Honma ◽  
Hitoshi Hasegawa ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Brain Tumor ◽  
Protective Immunity ◽  
Antitumor Immunity ◽  
Semliki Forest Virus ◽  
Systemic Administration ◽  
Interleukin 18 ◽  
Content Type ◽  
Fine Print

Object. The aim of this study was to investigate further immunogene treatment of malignant brain tumor to improve its therapeutic efficacy. Methods. Intratumoral dendritic cells pulsed with Semliki Forest virus (SFV)—interleukin-18 (IL-18) and/or systemic IL-12 were injected into mice bearing the B16 brain tumor. To study the immune mechanisms involved in tumor regression, we monitored the growth of implanted B16 brain tumor cells in T cell—depleted mice and IFNγ-neutralized mice. To analyze the protective immunity created by tumor inoculation, B16 cells were injected into the left thighs of mice that had received an inoculation, and tumor growth was monitored. The local delivery of dendritic cells pulsed with IL-18 bound by SFV combined with the systemic administration of IL-12 enhanced the induction of the T helper type 1 response from tumor-specific CD4+ and CD8+ T cells and natural killer cells as well as antitumor immunity. Interferon-γ is partly responsible for this IL-18—mediated antitumor immunity. Furthermore, the protective immunity is mediated mainly by CD8+ T cells. Conclusions. Immunogene therapy that combines the local administration of dendritic cells pulsed with IL-18 bound by SFV and the systemic administration of IL-12 may be an excellent candidate for the development of a new treatment protocol. A self-replicating SFV system may therefore open a novel approach for the treatment of malignant brain tumor.

Administration of interleukin-12 and -18 enhancing the antitumor immunity of genetically modified dendritic cells that had been pulsed with Semliki Forest virus—mediated tumor complementary DNA

2002 ◽  
Vol 97 (5) ◽  
pp. 1184-1190 ◽  
Author(s):  
Ryuya Yamanaka ◽  
Naoki Yajima ◽  
Naoto Tsuchiya ◽  
Junpei Honma ◽  
Ryuichi Tanaka ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Antitumor Immunity ◽  
Semliki Forest Virus ◽  
Malignant Gliomas ◽  
Glioma Cells ◽  
Antitumor Effects ◽  
Content Type ◽  
Immunogene Therapy ◽  
Fine Print

Object. Immunogene therapy for malignant gliomas was further investigated in this study to improve its therapeutic efficacy. Methods. Dendritic cells (DCs) were isolated from bone marrow and pulsed with phosphate-buffered saline or Semliki Forest virus (SFV)—mediated 203 glioma complementary (c)DNA with or without systemic administration of interleukin (IL)-12 and IL-18 to treat mice bearing the 203 glioma. To study the immune mechanisms involved in tumor regression, the authors investigated tumor growth of an implanted 203 glioma model in T cell subset—depleted mice and in interferon (IFN) γ—neutralized mice. To examine the protective immunity produced by tumor inoculation, a repeated challenge of 203 glioma cells was given by injecting the cells into the left thighs of surviving mice and the growth of these cells was monitored. The authors demonstrated that the combined administration of SFV-cDNA, IL-12, and IL-18 produced significant antitumor effects against the growth of murine glioma cells in vivo and also can induce specific antitumor immunity. The synergic effects of the combination of SFV-cDNA, IL-12, and IL-18 in vivo were also observed to coincide with markedly augmented IFNγ production. The antitumor effects of this combined therapy are mediated by CD4+ and CD8+ T cells and by NK cells. These results indicate that the use of IL-18 and IL-12 in DC-based immunotherapy for malignant glioma is beneficial. Conclusions. Immunogene therapy combined with DC therapy, IL-12, and IL-18 may be an excellent candidate in the development of a new treatment protocol. The self-replicating SFV system may therefore provide a novel approach for the treatment of malignant gliomas.

Treatment of intracranial gliomas with bone marrow—derived dendritic cells pulsed with tumor antigens

1999 ◽  
Vol 90 (6) ◽  
pp. 1115-1124 ◽  
Author(s):  
Linda M. Liau ◽  
Keith L. Black ◽  
Robert M. Prins ◽  
Steven N. Sykes ◽  
Pier-Luigi DiPatre ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Dendritic Cells ◽  
Tumor Antigen ◽  
Tumor Antigens ◽  
Antigen Presenting Cells ◽  
Content Type ◽  
Cytotoxicity Assays ◽  
Antigen Presenting ◽  
Fine Print

Object. An approach toward the treatment of intracranial gliomas was developed in a rat experimental model. The authors investigated the ability of “professional” antigen-presenting cells (dendritic cells) to enhance host antitumor immune responses when injected as a vaccine into tumor-bearing animals.Methods. Dendritic cells, the most potent antigen-presenting cells in the body, were isolated from rat bone marrow precursors stimulated in vitro with granulocyte—macrophage colony-stimulating factor (GM-CSF) and interleukin-4. Cultured cell populations were confirmed to be functional antigen-presenting cells on the basis of expressed major histocompatibility molecules, as analyzed by fluorescence-activated cell sorter cytofluorography. These dendritic cells were then pulsed (cocultured) ex vivo with acid-eluted tumor antigens from 9L glioma cells. Thirty-eight adult female Fischer 344 rats harboring 7-day-old intracranial 9L tumors were treated with three weekly subcutaneous injections of either control media (10 animals), unpulsed dendritic cells (six animals), dendritic cells pulsed with peptides extracted from normal rat astrocytes (10 animals), or 9L tumor antigen—pulsed dendritic cells (12 animals). The animals were followed for survival. At necropsy, the rat brains were removed and examined histologically, and spleens were harvested for cell-mediated cytotoxicity assays.The results indicate that tumor peptide-pulsed dendritic cell therapy led to prolonged survival in rats with established intracranial 9L tumors implanted 7 days prior to the initiation of vaccine therapy in vivo. Immunohistochemical analyses were used to document a significantly increased perilesional and intratumoral infiltration of CD8+ and CD4+ T cells in the groups treated with tumor antigen—pulsed dendritic cells compared with the control groups. In addition, the results of in vitro cytotoxicity assays suggest that vaccination with these peptide-pulsed dendritic cells can induce specific cytotoxic T lymphocytes against 9L tumor cells.Conclusions. Based on these results, dendritic antigen-presenting cells pulsed with acid-eluted peptides derived from autologous tumors represent a promising approach to the immunotherapy of established intracranial gliomas, which may serve as a basis for designing clinical trials in patients with brain tumors.

Criteria for evaluating patients undergoing chemotherapy for malignant brain tumors

1977 ◽  
Vol 47 (3) ◽  
pp. 329-335 ◽  
Author(s):  
Victor A. Levin ◽  
David C. Crafts ◽  
David M. Norman ◽  
Paul B. Hoffer ◽  
Jean-Paul Spire ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Ct Scan ◽  
San Francisco ◽  
Neurological Examination ◽  
Rating Scale ◽  
Tumor Regression ◽  
Numerical Rating Scale ◽  
Response To Therapy ◽  
Content Type ◽  
Fine Print

✓ The authors describe their criteria for evaluating brain-tumor patients, and present a numerical rating scale devised to designate response to testing. They discuss the reliability of test combinations that permit accurate prediction of response or deterioration during therapy in their experience with 100 patients treated on the Chemotherapy Service at the Brain Tumor Research Center, University of California, San Francisco School of Medicine. Specifically, the paper summarizes the predictive value of the neurological examination, radionuclide scintiscan, computerized tomographic brain scan (CT scan), and electroencephalogram (EEG), in the determination of response (tumor regression) or deterioration (tumor growth) during brain-tumor chemotherapy and chemotherapy-radiotherapy. By retrospective analysis, the neurological examination, radionuclide scintiscan, and CT scan were of equal value individually as tests to predict response to therapy. However, the prognostic values of the neurological examination or the radionuclide scintiscan proved moderately superior to the CT scan in predicting deterioration during therapy. Under circumstances whereby a neurological examination, radionuclide scintiscan, and CT scan were all performed during the same testing session, and steroid dosage was carefully monitored, two of the three tests accurately predicted deterioration in 65% of patients, and response to therapy in 82% of patients. Two of the three tests correctly established deterioration in the remaining 35% of patients, and response in the remaining 18% of patients, when the two positively correlated tests had occurred within a mean period of 7 weeks.

Gamma knife radiosurgery for uveal melanomas: an 8-year experience

2000 ◽  
Vol 93 (supplement_3) ◽  
pp. 184-188 ◽  
Author(s):  
Gerald Langmann ◽  
Gerhard Pendl ◽  
Georg Papaefthymiou ◽  
Helmuth Guss ◽  
Keyword(s):  
Gamma Knife ◽  
Ciliary Body ◽  
Tumor Regression ◽  
Gamma Knife Radiosurgery ◽  
Neovascular Glaucoma ◽  
Content Type ◽  
Prescription Dose ◽  
The Mean ◽  
Fine Print ◽  
Uveal Melanomas

Object. The authors report their experience using gamma knife radiosurgery (GKS) to treat uveal melanomas. Methods. Between 1992 and 1998, 60 patients were treated with GKS at a prescription dose between 45 Gy and 80 Gy. The mean diameter of the tumor base was 12.2 mm (range 3–22 mm). The mean height of the tumor prominence was 6.7 mm (range 3–12 mm). The eye was immobilized. The follow-up period ranged from 16 to 94 months. Tumor regression was achieved in 56 (93%) of 60 patients. There were four recurrences followed by enucleation. The severe side effect of neovascular glaucoma developed in 21 (35%) patients in a high-dose group with larger tumors and in proximity to the ciliary body. A reduction in the prescription dose to 40 Gy or less and excluding treatment to tumors near the ciliary body decreased the rate of glaucoma without affecting the rate of tumor control. Conclusions. Gamma knife radiosurgery at a prescription dose of 45 Gy or more can achieve tumor regression in 85% of the uveal melanomas treated. Neovascular glaucoma can develop in patients when using this dose in tumors near the ciliary body. It is advised that such tumors be avoided and that the prescription dose be reduced to 40 Gy.

Glioblastoma multiforme at the site of metal splinter injury: a coincidence?

1999 ◽  
Vol 91 (6) ◽  
pp. 1041-1044 ◽  
Author(s):  
Michael Sabel ◽  
Jörg Felsberg ◽  
Martina Messing-Jünger ◽  
Eva Neuen-Jacob ◽  
Jürgen Piek
Keyword(s):  
Brain Tumor ◽  
Glioblastoma Multiforme ◽  
Malignant Glioma ◽  
Causal Relationship ◽  
Propionibacterium Acnes ◽  
Glioma Tissue ◽  
Left Frontal Lobe ◽  
Content Type ◽  
Chronic Abscess ◽  
Fine Print

✓ The authors report the case of a man who had suffered a penetrating metal splinter injury to the left frontal lobe at 18 years of age. Thirty-seven years later the patient developed a left-sided frontal tumor at the precise site of the meningocerebral scar and posttraumatic defect. Histological examination confirmed a glioblastoma multiforme adjacent to the dural scar and metal splinters. In addition, a chronic abscess from which Propionibacterium acnes was isolated was found within the glioma tissue. The temporal and local association of metal splinter injury with chronic abscess, scar formation, and malignant glioma is highly suggestive of a causal relationship between trauma and the development of a malignant brain tumor.

scholarly journals WDFY4 is required for cross-presentation in response to viral and tumor antigens

Science ◽  
2018 ◽  
Vol 362 (6415) ◽  
pp. 694-699 ◽  
Author(s):  
Derek J. Theisen ◽  
Jesse T. Davidson ◽  
Carlos G. Briseño ◽  
Marco Gargaro ◽  
Elvin J. Lauron ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Tumor Antigens ◽  
Critical Role ◽  
Tumor Rejection ◽  
Interleukin 12 ◽  
Cross Presentation ◽  
Histocompatibility Complex ◽  
Crispr Screen

During the process of cross-presentation, viral or tumor-derived antigens are presented to CD8+ T cells by Batf3-dependent CD8α+/XCR1+ classical dendritic cells (cDC1s). We designed a functional CRISPR screen for previously unknown regulators of cross-presentation, and identified the BEACH domain–containing protein WDFY4 as essential for cross-presentation of cell-associated antigens by cDC1s in mice. However, WDFY4 was not required for major histocompatibility complex class II presentation, nor for cross-presentation by monocyte-derived dendritic cells. In contrast to Batf3–/– mice, Wdfy4–/– mice displayed normal lymphoid and nonlymphoid cDC1 populations that produce interleukin-12 and protect against Toxoplasma gondii infection. However, similar to Batf3–/– mice, Wdfy4–/– mice failed to prime virus-specific CD8+ T cells in vivo or induce tumor rejection, revealing a critical role for cross-presentation in antiviral and antitumor immunity.

Metastases of glioblastoma multiforme to cervical lymph nodes

1973 ◽  
Vol 38 (5) ◽  
pp. 631-634 ◽  
Author(s):  
Sayed El-Gindi ◽  
Mamdouh Salama ◽  
Mokhtar El-Henawy ◽  
Said Farag
Keyword(s):  
Brain Tumor ◽  
Glioblastoma Multiforme ◽  
Lymph Nodes ◽  
Metastatic Lesion ◽  
Cervical Lymph Nodes ◽  
Content Type ◽  
The Brain ◽  
Fine Print

✓ Two cases of occipital glioblastoma multiforme are reported in which a metastatic lesion involving the cervical lymph nodes on the side of the previous craniotomy was verified during life. This suggests to the authors that the brain tumor metastasized via lymphatic channels.

Correlation of the relationships of brain—tumor interfaces, magnetic resonance imaging, and angiographic findings to predict cleavage of meningiomas

1999 ◽  
Vol 91 (3) ◽  
pp. 384-390 ◽  
Author(s):  
Faruk İldan ◽  
Metin Tuna ◽  
Alp İskender Göcer ◽  
Bülent Boyar ◽  
Hüseyin Bağdatoğlu ◽  
...  
Keyword(s):  
Magnetic Resonance Imaging ◽  
Brain Tumor ◽  
Magnetic Resonance ◽  
Mr Imaging ◽  
Vascular Supply ◽  
Peritumoral Edema ◽  
Resonance Imaging ◽  
Content Type ◽  
Angiographic Findings ◽  
Fine Print

Object. The authors examined the relationships of brain—tumor interfaces, specific magnetic resonance (MR) imaging features, and angiographic findings in meningiomas to predict tumor cleavage and difficulty of resection.Methods. Magnetic resonance imaging studies, angiographic data, operative reports, clinical data, and histopathological findings were examined retrospectively in this series, which included 126 patients with intracranial meningiomas who underwent operations in which microsurgical techniques were used. The authors have identified three kinds of brain—tumor interfaces characterized by various difficulties in microsurgical dissection: smooth type, intermediate type, and invasive type. The signal intensity on T1-weighted MR images was very similar regardless of the type of brain—tumor interface (p > 0.1). However, on T2-weighted images the different interfaces seemed to correlate very precisely with the signal intensity and the amount of peritumoral edema (p < 0.01), allowing the prediction of microsurgical effort required during surgery. On angiographic studies, the pial—cortical arterial supply was seen to participate almost equally with the meningeal—dural arterial supply in vascularizing the tumor in 57.9% of patients. Meningiomas demonstrating hypervascularization on angiography, particularly those fed by the pial—cortical arteries, exhibited significantly more severe edema compared with those supplied only from meningeal arteries (p < 0.01). Indeed, a positive correlation was found between the vascular supply from pial—cortical arteries and the type of cleavage (p < 0.05).Conclusions. In this analysis the authors proved that there is a strong correlation between the amount of peritumoral edema, hyperintensity of the tumor on T2-weighted images, cortical penetration, vascular supply from pial—cortical arteries, and cleavage of the meningioma. Therefore, the consequent difficulty of microsurgical dissection can be predicted preoperatively by analyzing MR imaging and angiographic studies.

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