Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients.
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After stimulation, dendritic cells (DCs) mature and migrate to draining lymph nodes to induce immune responses. As such, autologous DCs generated ex vivo have been pulsed with tumour antigens and injected back into patients as immunotherapy. While DC vaccines have shown limited promise in the treatment of patients with advanced cancers including glioblastoma, the factors dictating DC vaccine efficacy remain poorly understood. Here we show that pre-conditioning the vaccine site with a potent recall antigen such as tetanus/diphtheria (Td) toxoid can significantly improve the lymph node homing and efficacy of tumour-antigen-specific DCs. To assess the effect of vaccine site pre-conditioning in humans, we randomized patients with glioblastoma to pre-conditioning with either mature DCs or Td unilaterally before bilateral vaccination with DCs pulsed with Cytomegalovirus phosphoprotein 65 (pp65) RNA. We and other laboratories have shown that pp65 is expressed in more than 90% of glioblastoma specimens but not in surrounding normal brain, providing an unparalleled opportunity to subvert this viral protein as a tumour-specific target. Patients given Td had enhanced DC migration bilaterally and significantly improved survival. In mice, Td pre-conditioning also enhanced bilateral DC migration and suppressed tumour growth in a manner dependent on the chemokine CCL3. Our clinical studies and corroborating investigations in mice suggest that pre-conditioning with a potent recall antigen may represent a viable strategy to improve anti-tumour immunotherapy.
Mice, Inbred C57BL
Viral Matrix Proteins
Published Version (Please cite this version)10.1038/nature14320
Publication InfoMitchell, Duane A; Batich, Kristen A; Gunn, Michael D; Huang, Min-Nung; Sanchez-Perez, Luis; Nair, Smita K; ... Sampson, John H (2015). Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients. Nature, 519(7543). pp. 366-369. 10.1038/nature14320. Retrieved from https://hdl.handle.net/10161/16099.
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Gerald Edward Archer
Assistant Professor of Neurosurgery
My current research focus involves the delivery of therapeutic agents for the treatment of central nervous system neoplasia. Utilizing athymic rat models of central nervous system neoplasia I am investigating compartmental approaches to increase therapeutic efficacy of chemotherapeutic agents and immunoconjugates. Preclinical testing in athymic rats of intrathecal administration of melphalan and 4-hydroperoxycyclophosphamide have resulted in the FDA granting investigational new drug prot
Darell Doty Bigner
E. L. and Lucille F. Jones Cancer Distinguished Research Professor, in the School of Medicine
The Causes, Mechanisms of Transformation and Altered Growth Control and New Therapy for Primary and Metastatic Tumors of the Central Nervous System (CNS). There are over 16,000 deaths in the United States each year from primary brain tumors such as malignant gliomas and medulloblastomas, and metastatic tumors to the CNS and its covering from systemic tumors such as carcinoma of the lung, breast, colon, and melanoma. An estimated 80,000 cases of primary brain tumors were expected to
Assistant Professor in Neurosurgery
Professor of Neurosurgery
Allan Howard Friedman
Guy L. Odom Distinguished Professor of Neurosurgery, in the School of Medicine
At the present time, I am participating in collaborative research in the areas of primary malignant brain tumors, epilepsy and subarachnoid hemorrhage. Primary malignant brain tumors are increasing in frequency. Patients harboring glioblastoma, the most malignant primary brain tumor, have a life expectancy of less than one year. In colloboration with the Division of Neurology and the Department of Pathology, clinical and laboratory trials have been initiated to identify better
Henry Seth Friedman
James B. Powell, Jr. Distinguished Professor of Pediatric Oncology, in the School of Medicine
Overview: Our laboratory is pursuing a comprehensive analysis of the biology and therapy of adult and childhood central nervous system malignancies, particularly high-grade medulloblastoma, glioma, and ependymoma. Laboratory Studies: Active programs, using human adult and pediatric CNS tumor continuous cell lines, transplantable xenografts growing subcutaneously and intracranially in athymic nude mice and rats, and as well as in the subarachnoid space of the ath
Michael Dee Gunn
Professor of Medicine
The focus of my work is on understanding how dendritic cells, monocytes, and macrophages regulate immune responses, contribute to specific disease pathologies, and can be manipulated to stimulate or inhibit specific immune responses. We are also using our knowledge of immunology to develop diagnostics and therapeutics for a variety of human diseases. Lab History The lab started with our discovery of the lymphoid chemokines, which regulate the mi
James Emmett Herndon II
Professor of Biostatistics & Bioinformatics
Current research interests have application to the design and analysis of cancer clinical trials. Specifically, interests include the use of time-dependent covariables within survival models, the design of phase II cancer clinical trials which minimize some of the logistical problems associated with their conduct, and the analysis of longitudinal studies with informative censoring (in particular, quality of life studies of patients with advanced cancer).
Research Associate, Senior
Michael Dee Gunn Lab
Roger Edwin McLendon
Professor of Pathology
Brain tumors are diagnosed in more than 20,000 Americans annually. The most malignant neoplasm, glioblastoma, is also the most common. Similarly, brain tumors constitute the most common solid neoplasm in children and include astrocytomas of the cerebellum, brain stem and cerebrum as well as medulloblastomas of the cerebellum. My colleagues and I have endeavored to translate the bench discoveries of genetic mutations and aberrant protein expressions found in brain tumors to better understan
Smita K Nair
Professor in Surgery
I have 22 years of experience in the field of cancer vaccines and immunotherapy and I am an accomplished T cell immunologist. Laboratory website:https://surgery.duke.edu/immunology-inflammation-immunotherapy-laboratory Current projects in the Nair Laboratory:1] Dendritic cell vaccines using tumor-antigen encoding RNA (mRNA, total tumor RNA, amplified tumor mRNA)<br
Assistant Professor of Neurosurgery
John Howard Sampson
Robert H., M.D. and Gloria Wilkins Professor of Neurosurgery, in the School of Medicine
Current research activities involve the immunotherapeutic targeting of a tumor-specific mutation in the epidermal growth factor receptor. Approaches used to target this tumor-specific epitope include unarmed and radiolabeled antibody therapy and cell mediated approaches using peptide vaccines and dendritic cells. Another area of interest involves drug delivery to brain tumors. Translational and clinical work is carried out in this area to formulate the relationship between various direct intratu
Luis Ariel Sanchez-Perez
Assistant Professor of Neurosurgery
My overall research interests include the elucidation of immune mechanisms underlying the efficacy of novel immunotherapeutic strategies for the treatment of malignant brain tumors. I am currently evaluating the mechanisms of Chimeric Antigen Receptor (CAR) gene-modified T-cells mediated immune tumor cell destruction and the induction of endogenous immunity to individual tumor specific mutations.
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