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Dendritic cell-based immunotherapy of malignant gliomas.
Parajuli P, Sloan AE. Cancer Invest. 2004;22(3):405-16. Comment in: Cancer Invest. 2004;22(3):479-80.
Department of Neurosurgery, Wayne State University and Karmanos Cancer Institute, Detroit, Michigan 48201, USA. pparajuli@neurosurgery.wayne.edu
The failure of conventional treatment modalities for gliomas, in spite of tremendous progress in research in the past two decades, has led to increasing interest in alternative treatment strategies, including immunotherapy. It has become evident that vaccination with dendritic cells (DC), designed to express tumor antigens, is a potent strategy to elicit anti-tumor immune response in both pre-clinical and clinical settings. Various methods have been applied in order to induce DC to express tumor antigens including: pulsing with isolated tumor peptides or whole tumor lysate; fusion with tumor cells; and pulsing with apoptotic tumor cells. Herein, we review the recent progress in DC biology with regard to tumor immunity and discuss current DC-based strategies and future prospects in immunotherapy for malignant gliomas.
Vaccination of Glioma Patients with Fusions of Dendritic and Glioma Cells and Recombinant Human Interleukin 12.
Kikuchi T, Akasaki Y, Abe T, Fukuda T, Saotome H, Ryan JL, Kufe DW, Ohno T. J Immunother. 2004 Nov;27(6):452-459.
From the *Department of Oncology, Institute of DNA Medicine; daggerDepartment of Neurosurgery, double daggerDivision of Neuropathology, Department of Neuroscience, Jikei University, Tokyo, Japan; section signWyeth Research Department, AHP Services Japan Co., Ltd, Tokyo, Japan; Experimental Medicine, Research & Development, Wyeth Pharmaceuticals, Cambridge, Massachusetts; and paragraph signDana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
Despite aggressive treatment, the median survival of patients with high-grade malignant astrocytoma is about 1 year. The authors investigated the safety and clinical response to immunotherapy using fusions of dendritic and glioma cells combined with recombinant human interleukin 12 (rhIL-12) for the treatment of malignant glioma. Fifteen patients with malignant glioma participated in this study. Dendritic cells were generated from peripheral blood. Cultured autologous glioma cells were established from surgical specimens in each case. Fusion cells were prepared from dendritic and glioma cells using polyethylene glycol. All patients received fusion cells intradermally on day 1. rhIL-12 was injected subcutaneously at the same site on days 3 and 7. Response to the treatment was evaluated by clinical observations and radiologic findings. No serious adverse effects were observed. In four patients, magnetic resonance imaging showed a greater than 50% reduction in tumor size. One patient had a mixed response. These results show that administration of fusion cells and rhIL-12 safely induces clinical antitumor effects in some patients with malignant glioma.
Vaccination with tumor lysate-pulsed dendritic cells elicits antigen-specific, cytotoxic T-cells in patients with malignant glioma.
Yu JS, Liu G, Ying H, Yong WH, Black KL, Wheeler CJ. Cancer Res. 2004 Jul 15;64(14):4973-9.
Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, 8631 West Third Street, Suite 800E, Los Angeles, CA 90048, USA. Yuj@cshs.org
The primary goal of this Phase I study was to assess the safety and bioactivity of tumor lysate-pulsed dendritic cell (DC) vaccination to treat patients with glioblastoma multiforme and anaplastic astrocytoma. Adverse events, survival, and cytotoxicity against autologous tumor and tumor-associated antigens were measured. Fourteen patients were thrice vaccinated 2 weeks apart with autologous DCs pulsed with tumor lysate. Peripheral blood mononuclear cells were differentiated into phenotypically and functionally confirmed DCs. Vaccination with tumor lysate-pulsed DCs was safe, and no evidence of autoimmune disease was noted. Ten patients were tested for the development of cytotoxicity through a quantitative PCR-based assay. Six of 10 patients demonstrated robust systemic cytotoxicity as demonstrated by IFN-gamma expression by peripheral blood mononuclear cells in response to tumor lysate after vaccination. Using HLA-restricted tetramer staining, we identified a significant expansion in CD8+ antigen-specific T-cell clones against one or more of tumor-associated antigens MAGE-1, gp100, and HER-2 after DC vaccination in four of nine patients. A significant CD8+ T-cell infiltrate was noted intratumorally in three of six patients who underwent reoperation. The median survival for patients with recurrent glioblastoma multiforme in this study (n = 8) was 133 weeks. This Phase I study demonstrated the feasibility, safety, and bioactivity of an autologous tumor lysate-pulsed DC vaccine for patients with malignant glioma. We demonstrate for the first time the ability of an active immunotherapy strategy to generate antigen-specific cytotoxicity in brain tumor patients.
Invariant natural killer T cells are preserved in patients with glioma and exhibit antitumor lytic activity following dendritic cell-mediated expansion.
Dhodapkar KM, Cirignano B, Chamian F, Zagzag D, Miller DC, Finlay JL, Steinman RM. Int J Cancer. 2004 May 10;109(6):893-9.
Laboratory of Cellular Physiology and Immunology and Chris Browne Center for Immunology and Human Disease, Rockefeller University, New York, NY 10021, USA.
Brain tumors carry a poor prognosis, and newer approaches to their therapy are urgently needed. Natural killer T (NKT) cells are distinct innate lymphocytes with antitumor potentials. Defects in NKT cell function have been observed in patients with other forms of cancer. Here we show that both the frequency and interferon-gamma-producing function of NKT cells are well preserved in adult patients with glioma (n=9) and comparable to findings in healthy controls (n=9). These cells can be readily expanded in culture using autologous mature dendritic cells loaded with the NKT ligand, alpha-galactosyl ceramide. The expanded NKT cells from glioma patients are functional and, importantly, kill glioma cells in a ligand- and CD1d-dependent manner. Expression of CD1d is detected both on primary glioma cells as well as endothelial cells in infiltrating new blood vessels by immunohistochemistry of glioma tissue sections. These data suggest that targeting NKT cells may provide a novel strategy for immunotherapy of glioma. Copyright 2004 Wiley-Liss, Inc.
Surgery and adjuvant dendritic cell-based tumour vaccination for patients with relapsed malignant glioma, a feasibility study.
Rutkowski S, De Vleeschouwer S, Kaempgen E, Wolff JE, Kuhl J, Demaerel P, Warmuth-Metz M, Flamen P, Van Calenbergh F, Plets C, Sorensen N, Opitz A, Van Gool SW. Br J Cancer. 2004 Nov 1;91(9):1656-62.
1Department of Pediatric Oncology, Children's Hospital, University of Wuerzburg, Josef-Schneider-Str. 2, D-97080 Wuerzburg, Germany.
Patients with relapsed malignant glioma have a poor prognosis. We developed a strategy of vaccination using autologous mature dendritic cells loaded with autologous tumour homogenate. In total, 12 patients with a median age of 36 years (range: 11-78) were treated. All had relapsing malignant glioma. After surgery, vaccines were given at weeks 1 and 3, and later every 4 weeks. A median of 5 (range: 2-7) vaccines was given. There were no serious adverse events except in one patient with gross residual tumour prior to vaccination, who repetitively developed vaccine-related peritumoral oedema. Minor toxicities were recorded in four out of 12 patients. In six patients with postoperative residual tumour, vaccination induced one stable disease during 8 weeks, and one partial response. Two of six patients with complete resection are in CCR for 3 years. Tumour vaccination for patients with relapsed malignant glioma is feasible and likely beneficial for patients with minimal residual tumour burden. British Journal of Cancer (2004) 91, 1656-1662. doi:10.1038/sj.bjc.6602195 www.bjcancer.com Published online 12 October 2004.
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