Ex vivo functional analysis, expansion and adoptive transfer of cytomegalovirus-specific T-cells in patients with glioblastoma multiforme

Crough, Tania, Beagley, Leone, Smith, Corey, Jones, Linda, Walker, David G. and Khanna, Rajiv (2012) Ex vivo functional analysis, expansion and adoptive transfer of cytomegalovirus-specific T-cells in patients with glioblastoma multiforme. Immunology and Cell Biology, 90 9: 872-880. doi:10.1038/icb.2012.19


Author Crough, Tania
Beagley, Leone
Smith, Corey
Jones, Linda
Walker, David G.
Khanna, Rajiv
Title Ex vivo functional analysis, expansion and adoptive transfer of cytomegalovirus-specific T-cells in patients with glioblastoma multiforme
Formatted title
Ex vivo functional analysis, expansion and adoptive transfer of cytomegalovirus-specific T-cells in patients with glioblastoma multiforme
Journal name Immunology and Cell Biology   Check publisher's open access policy
ISSN 0818-9641
1440-1711
Publication date 2012-04-17
Year available 2012
Sub-type Article (original research)
DOI 10.1038/icb.2012.19
Open Access Status Not yet assessed
Volume 90
Issue 9
Start page 872
End page 880
Total pages 9
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Language eng
Formatted abstract
The frequent detection of human cytomegalovirus (CMV) antigens in glioblastoma multiforme (GBM) has raised the possibility of exploiting CMV-specific T-cell immunotherapy to control this disease in CMV - seropositive patients. Here, we have conducted a comprehensive ex vivo profiling of CMV-specific CD8+ T-cell responses in a cohort of GBM patients. Of the patients analyzed, approximately half exhibited serological evidence of past infection with CMV. Although no CMV-specific CD8+ T-cell responses could be detected in the serologically negative GBM patients, virus-specific CD8+ T-cell responses were detected in all seropositive GBM patients. Using major histocompatibility complex-peptide multimers, the frequency of CMV-specific T-cells in the patients detected ranged from 0.1 to 22% of CD8+ T-cells and a high proportion of these cells were positive for the human natural killer-1 glycoprotein CD57. Furthermore, ex vivo polychromatic functional analysis of the CMV-specific T-cells from GBM patients revealed that large proportions of these cells were unable to produce multiple cytokines (macrophage inflammatory protein (MIP)-1β, tumor necrosis factor (TNF)α and interferon (IFN)γ) and displayed limited cytolytic function (CD107a mobilization) following stimulation with CMV peptide epitopes. However, in vitro stimulation with CMV peptide epitopes in the presence of γC cytokine dramatically reversed the polyfunctional profile of these antigen-specific T-cells with high levels of MIP-1β, TNFα, IFNγ and CD107a mobilization. Most importantly, adoptive transfer of these in vitro-expanded T-cells in combination with temozolomide (TMZ) therapy into a patient with recurrent GBM was coincident with a long-term disease-free survival. These studies provide an important platform for a formal assessment of combination therapies based on CMV-specific T-cells and TMZ for recurrent GBM.
Keyword Glioblastoma
Immune monitoring
Immunotherapy
T-cells
Virus
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Medicine Publications
 
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