CD27 costimulation augments the survival and antitumor activity of redirected human T cells in vivo

The costimulatory effects of CD27 on T lymphocyte effector function and memory formation has been confined to evaluations in mouse models, in vitro human cell culture systems, and clinical observations. Here, we tested whether CD27 costimulation actively enhances human T-cell function, expansion, an...

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Bibliographic Details
Published in:Blood 2012-01, Vol.119 (3), p.696-706
Main Authors: Song, De-Gang, Ye, Qunrui, Poussin, Mathilde, Harms, Gretchen M., Figini, Mariangela, Powell, Daniel J.
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Blotting, Western
Breast Neoplasms - genetics
Breast Neoplasms - immunology
Breast Neoplasms - therapy
CD28 Antigens - genetics
CD28 Antigens - immunology
Cell Proliferation
Cytokines - metabolism
Female
Flow Cytometry
Fluorescent Antibody Technique
Hematologic and hematopoietic diseases
Humans
Immunotherapy, Adoptive
Lymphocyte Activation
Medical sciences
Mesothelioma - genetics
Mesothelioma - immunology
Mesothelioma - therapy
Mice
Mice, Inbred NOD
Mice, SCID
Ovarian Neoplasms - genetics
Ovarian Neoplasms - immunology
Ovarian Neoplasms - therapy
Receptors, Antigen, T-Cell - genetics
Receptors, Antigen, T-Cell - immunology
T-Lymphocytes - immunology
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
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Summary:The costimulatory effects of CD27 on T lymphocyte effector function and memory formation has been confined to evaluations in mouse models, in vitro human cell culture systems, and clinical observations. Here, we tested whether CD27 costimulation actively enhances human T-cell function, expansion, and survival in vitro and in vivo. Human T cells transduced to express an antigen-specific chimeric antigen receptor (CAR-T) containing an intracellular CD3 zeta (CD3ζ) chain signaling module with the CD27 costimulatory motif in tandem exerted increased antigen-stimulated effector functions in vitro, including cytokine secretion and cytotoxicity, compared with CAR-T with CD3ζ alone. After antigen stimulation in vitro, CD27-bearing CAR-T cells also proliferated, up-regulated Bcl-XL protein expression, resisted apoptosis, and underwent increased numerical expansion. The greatest impact of CD27 was noted in vivo, where transferred CAR-T cells with CD27 demonstrated heightened persistence after infusion, facilitating improved regression of human cancer in a xenogeneic allograft model. This tumor regression was similar to that achieved with CD28- or 4-1BB–costimulated CARs, and heightened persistence was similar to 4-1BB but greater than CD28. Thus, CD27 costimulation enhances expansion, effector function, and survival of human CAR-T cells in vitro and augments human T-cell persistence and antitumor activity in vivo.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2011-03-344275