A pilot study of IL-2Rα blockade during lymphopenia depletes regulatory T-cells and correlates with enhanced immunity in patients with glioblastoma.
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 articleSubject
AdultAged
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
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https://hdl.handle.net/10161/16110Published Version (Please cite this version)
10.1371/journal.pone.0031046Publication Info
(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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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
Kendra Congdon
Assistant Professor in Neurosurgery
Annick Desjardins
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
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).
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
Elizabeth Reap
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
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