Ex vivo functional analysis, expansion and adoptive transfer of cytomegalovirus‐specific T‐cells in patients with glioblastoma multiforme
- 17 April 2012
- journal article
- Published by Wiley in Immunology & Cell Biology
- Vol. 90 (9), 872-880
- https://doi.org/10.1038/icb.2012.19
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.Keywords
Funding Information
- National Health and Medical Research Council
This publication has 41 references indexed in Scilit:
- Is HCMV a tumor promoter?Virus Research, 2011
- SPICE: Exploration and analysis of post‐cytometric complex multivariate datasetsCytometry Part A, 2011
- A pilot study on the immunogenicity of dendritic cell vaccination during adjuvant oxaliplatin/capecitabine chemotherapy in colon cancer patientsBritish Journal of Cancer, 2010
- A Distinct Subset of Self-Renewing Human Memory CD8+ T Cells Survives Cytotoxic ChemotherapyImmunity, 2009
- Cytomegalovirus Immunity after Vaccination with Autologous Glioblastoma LysateThe New England Journal of Medicine, 2008
- Detection of human cytomegalovirus in different histological types of gliomasActa Neuropathologica, 2008
- Skewed association of polyfunctional antigen-specific CD8 T cell populations with HLA-B genotypeProceedings of the National Academy of Sciences of the United States of America, 2007
- Superior control of HIV-1 replication by CD8+ T cells is reflected by their avidity, polyfunctionality, and clonal turnoverThe Journal of Experimental Medicine, 2007
- Immunization with vaccinia virus induces polyfunctional and phenotypically distinctive CD8+ T cell responsesThe Journal of Experimental Medicine, 2007
- Human cytomegalovirus-encoded chemokine receptor US28 promotes tumorigenesisProceedings of the National Academy of Sciences of the United States of America, 2006