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A pilot study of IL-2Rα blockade during lymphopenia depletes regulatory T-cells and correlates with enhanced immunity in patients with glioblastoma.

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Date
2012
Authors
Sampson, John H
Schmittling, Robert J
Archer, Gary E
Congdon, Kendra L
Nair, Smita K
Reap, Elizabeth A
Desjardins, Annick
Friedman, Allan H
Friedman, Henry S
Herndon, James E
Coan, April
McLendon, Roger E
Reardon, David A
Vredenburgh, James J
Bigner, Darell D
Mitchell, Duane A
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(16 total)
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Abstract
BACKGROUND: Preclinical studies in mice have demonstrated that the prophylactic depletion of immunosuppressive regulatory T-cells (T(Regs)) through targeting the high affinity interleukin-2 (IL-2) receptor (IL-2Rα/CD25) can enhance anti-tumor immunotherapy. However, therapeutic approaches are complicated by the inadvertent inhibition of IL-2Rα expressing anti-tumor effector T-cells. OBJECTIVE: To determine if changes in the cytokine milieu during lymphopenia may engender differential signaling requirements that would enable unarmed anti-IL-2Rα monoclonal antibody (MAbs) to selectively deplete T(Regs) while permitting vaccine-stimulated immune responses. METHODOLOGY: A randomized placebo-controlled pilot study was undertaken to examine the ability of the anti-IL-2Rα MAb daclizumab, given at the time of epidermal growth factor receptor variant III (EGFRvIII) targeted peptide vaccination, to safely and selectively deplete T(Regs) in patients with glioblastoma (GBM) treated with lymphodepleting temozolomide (TMZ). RESULTS AND CONCLUSIONS: Daclizumab treatment (n = 3) was well-tolerated with no symptoms of autoimmune toxicity and resulted in a significant reduction in the frequency of circulating CD4+Foxp3+ TRegs in comparison to saline controls (n = 3)( p = 0.0464). A significant (p<0.0001) inverse correlation between the frequency of TRegs and the level of EGFRvIII specific humoral responses suggests the depletion of TRegs may be linked to increased vaccine-stimulated humoral immunity. These data suggest this approach deserves further study. TRIAL REGISTRATION: ClinicalTrials.gov NCT00626015.
Type
Journal article
Subject
Adult
Aged
Antibodies, Monoclonal, Humanized
Brain Neoplasms
CD4-Positive T-Lymphocytes
CD8-Positive T-Lymphocytes
Female
Glioblastoma
Humans
Immune System
Immunoglobulin G
Immunosuppressive Agents
Interleukin-2 Receptor alpha Subunit
Lymphopenia
Male
Middle Aged
Pilot Projects
T-Lymphocytes
T-Lymphocytes, Regulatory
Permalink
https://hdl.handle.net/10161/16110
Published Version (Please cite this version)
10.1371/journal.pone.0031046
Publication Info
Sampson, John H; Schmittling, Robert J; Archer, Gary E; Congdon, Kendra L; Nair, Smita K; Reap, Elizabeth A; ... Mitchell, Duane A (2012). A pilot study of IL-2Rα blockade during lymphopenia depletes regulatory T-cells and correlates with enhanced immunity in patients with glioblastoma. PLoS One, 7(2). pp. e31046. 10.1371/journal.pone.0031046. Retrieved from https://hdl.handle.net/10161/16110.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
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Scholars@Duke

Archer

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
Bigner

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
Congdon

Kendra Congdon

Assistant Professor in Neurosurgery
Desjardins

Annick Desjardins

Professor of Neurosurgery
Friedman

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
Friedman

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
Herndon

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).
McLendon

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
Nair

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

Elizabeth Reap

Assistant Professor of Neurosurgery
Sampson

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
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