Clinical evaluation of dendritic cell vaccination for patients with recurrent glioma: results of a clinical phase I/II trial.

PURPOSE To investigate the safety and the immunologic and clinical responses of dendritic cell therapy for patients with recurrent malignant glioma. EXPERIMENTAL DESIGN Twenty-four patients with recurrent malignant glioma (6 grade 3 and 18 grade 4 patients) were evaluated in a phase I/II clinical study of dendritic cell therapy. All patients were resistant to the standard maximum therapy. The patient's peripheral blood dendritic cells were generated with granulocyte macrophage colony-stimulating factor, plus interleukin 4 with or without OK-432, and pulsed with an autologous tumor lysate. Dendritic cells were injected intradermally, or both intratumorally and intradermally every 3 weeks. RESULTS The protocols were well tolerated with only local redness and swelling at the injection site in several cases. Clinical responses were as follows: 1 patient with partial response, 3 patients with minor response, 10 patients with stable disease, and 10 patients with progressive disease. The patients whose dendritic cells were matured with OK-432 had longer survival times than the dendritic cells from patients without OK-432 maturation. The patients with both intratumoral and intradermal administrations had a longer survival time than the patients with intradermal administration only. Increased ELISPOT and delayed-type hypersensitivity responses after vaccination could provide good laboratory markers to predict the clinical outcome of patients receiving dendritic cell vaccination. The overall survival of patients with grade 4 glioma was 480 days, which was significantly better than that in the control group. CONCLUSIONS This study showed the safety and clinical response of autologous tumor lysate-pulsed dendritic cell therapy for patients with malignant glioma. Dendritic cell therapy is recommended for further clinical studies in malignant glioma patients.

[1]  M. Nishioka,et al.  Intratumoral injection of OK432 and lymphokine-activated killer activity in peripheral blood of patients with hepatocellular carcinoma. , 1990, European journal of cancer.

[2]  P. Flamen,et al.  Surgery and adjuvant dendritic cell-based tumour vaccination for patients with relapsed malignant glioma, a feasibility study , 2004, British Journal of Cancer.

[3]  T. Iwa,et al.  Clinical value of immunotherapy for lung cancer by the streptococcal preparation OK‐432 , 1984, Cancer.

[4]  K. Black,et al.  Vaccination of malignant glioma patients with peptide-pulsed dendritic cells elicits systemic cytotoxicity and intracranial T-cell infiltration. , 2001, Cancer research.

[5]  Dirk Schadendorf,et al.  Vaccination of melanoma patients with peptide- or tumorlysate-pulsed dendritic cells , 1998, Nature Medicine.

[6]  Edgar G. Engleman,et al.  Vaccination of patients with B–cell lymphoma using autologous antigen–pulsed dendritic cells , 1996, Nature Medicine.

[7]  T. Cascino,et al.  Response criteria for phase II studies of supratentorial malignant glioma. , 1990, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[8]  R. Yamanaka,et al.  Enhancement of antitumor immune response in glioma models in mice by genetically modified dendritic cells pulsed with Semliki forest virus-mediated complementary DNA. , 2001, Journal of neurosurgery.

[9]  R. Figlin,et al.  A Pilot Trial of Tumor Lysate-Loaded Dendritic Cells for the Treatment of Metastatic Renal Cell Carcinoma , 2003, Journal of immunotherapy.

[10]  T. Luger,et al.  Generation of tumor immunity by bone marrow-derived dendritic cells correlates with dendritic cell maturation stage. , 1999, Journal of immunology.

[11]  C. Figdor,et al.  Maturation of dendritic cells is a prerequisite for inducing immune responses in advanced melanoma patients. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[12]  T. Ohno,et al.  Results of a phase I clinical trial of vaccination of glioma patients with fusions of dendritic and glioma cells , 2001, Cancer Immunology, Immunotherapy.

[13]  H. Fujiwara,et al.  Streptococcal preparation OK432 promotes functional maturation of human monocyte-derived dendritic cells , 2003, Cancer Immunology, Immunotherapy.

[14]  S. Nakahara,et al.  Dendritic cells stimulated with a bacterial product, OK-432, efficiently induce cytotoxic T lymphocytes specific to tumor rejection peptide. , 2003, Cancer research.

[15]  G. Fuller,et al.  Central Nervous System , 2007 .

[16]  M. Gnant,et al.  Dendritic Cell Vaccination in Medullary Thyroid Carcinoma , 2004, Clinical Cancer Research.

[17]  R. Tanaka,et al.  Vaccination of recurrent glioma patients with tumour lysate-pulsed dendritic cells elicits immune responses: results of a clinical phase I/II trial , 2003, British Journal of Cancer.

[18]  T. Braun,et al.  Vaccination of pediatric solid tumor patients with tumor lysate-pulsed dendritic cells can expand specific T cells and mediate tumor regression. , 2001, Cancer research.

[19]  D. Bigner,et al.  Subcutaneous vaccination with irradiated, cytokine-producing tumor cells stimulates CD8+ cell-mediated immunity against tumors located in the "immunologically privileged" central nervous system. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[20]  R. Tanaka,et al.  Dendritic cell-based glioma immunotherapy (review). , 2003, International journal of oncology.

[21]  Simon C Watkins,et al.  Sequential delivery of interferon-α gene and DCs to intracranial gliomas promotes an effective antitumor response , 2004, Gene Therapy.

[22]  E. Jaffee,et al.  Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[23]  R. Steinman,et al.  Dendritic cell progenitors phagocytose particulates, including bacillus Calmette-Guerin organisms, and sensitize mice to mycobacterial antigens in vivo , 1993, The Journal of experimental medicine.

[24]  T. Ohno,et al.  Antitumor Effect of Immunizations With Fusions of Dendritic and Glioma Cells in a Mouse Brain Tumor Model , 2001, Journal of immunotherapy : official journal of the Society for Biological Therapy.

[25]  R. Dummer,et al.  Vaccination of patients with cutaneous T-cell lymphoma using intranodal injection of autologous tumor-lysate-pulsed dendritic cells. , 2003, Blood.

[26]  Keith L. Black,et al.  Vaccination with Tumor Lysate-Pulsed Dendritic Cells Elicits Antigen-Specific, Cytotoxic T-Cells in Patients with Malignant Glioma , 2004, Cancer Research.

[27]  Katsuaki Sato,et al.  Results of a phase I clinical study using autologous tumour lysate-pulsed monocyte-derived mature dendritic cell vaccinations for stage IV malignant melanoma patients combined with low dose interleukin-2 , 2003, Melanoma research.

[28]  L. Stewart,et al.  Chemotherapy in adult high-grade glioma: a systematic review and meta-analysis of individual patient data from 12 randomised trials , 2002, The Lancet.

[29]  H. Ragde,et al.  Evaluation of phase I/II clinical trials in prostate cancer with dendritic cells and PSMA peptides , 1998, The Prostate.

[30]  M. Mizuno,et al.  Dendritic cells pulsed with tumor extract–cationic liposome complex increase the induction of cytotoxic T lymphocytes in mouse brain tumor , 2001, Cancer Immunology, Immunotherapy.

[31]  R. Tanaka,et al.  Tumor lysate and IL-18 loaded dendritic cells elicits Th1 response, tumor-specific CD8+ cytotoxic T cells in patients with malignant glioma , 2004, Journal of Neuro-Oncology.

[32]  T. Witham,et al.  7-Hydroxystaurosporine-induced Apoptosis in 9L Glioma Cells Provides an Effective Antigen Source for Dendritic Cells and Yields a Potent Vaccine Strategy in an Intracranial Glioma Model , 2002, Neurosurgery.

[33]  R. McLendon,et al.  Bone marrow-derived dendritic cells pulsed with tumor homogenate induce immunity against syngeneic intracerebral glioma , 2000, Journal of Neuroimmunology.

[34]  R. Steinman,et al.  Dendritic cells in the T‐cell areas of lymphoid organs , 1997, Immunological reviews.

[35]  T. Cloughesy,et al.  Treatment of intracranial gliomas with bone marrow-derived dendritic cells pulsed with tumor antigens. , 1999, Journal of neurosurgery.

[36]  Reto Meuli,et al.  Promising survival for patients with newly diagnosed glioblastoma multiforme treated with concomitant radiation plus temozolomide followed by adjuvant temozolomide. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[37]  A. Gross,et al.  Regression of human metastatic renal cell carcinoma after vaccination with tumor cell–dendritic cell hybrids , 2000, Nature Medicine.