In vivo persistence, tumor localization, and antitumor activity of CAR-engineered T cells is enhanced by costimulatory signaling through CD137 (4-1BB).

Details

Serval ID
serval:BIB_CB5225E1D1A4
Type
Article: article from journal or magazin.
Collection
Publications
Title
In vivo persistence, tumor localization, and antitumor activity of CAR-engineered T cells is enhanced by costimulatory signaling through CD137 (4-1BB).
Journal
Cancer Research
Author(s)
Song D.G., Ye Q., Carpenito C., Poussin M., Wang L.P., Ji C., Figini M., June C.H., Coukos G., Powell D.J.
ISSN
1538-7445 (Electronic)
ISSN-L
0008-5472
Publication state
Published
Issued date
2011
Volume
71
Number
13
Pages
4617-4627
Language
english
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov'tPublication Status: ppublish
Abstract
Human T cells engineered to express a chimeric antigen receptor (CAR) specific for folate receptor-α (FRα) have shown robust antitumor activity against epithelial cancers in vitro but not in the clinic because of their inability to persist and home to tumor in vivo. In this study, CARs were constructed containing a FRα-specific scFv (MOv19) coupled to the T-cell receptor CD3ζ chain signaling module alone (MOv19-ζ) or in combination with the CD137 (4-1BB) costimulatory motif in tandem (MOv19-BBζ). Primary human T cells transduced to express conventional MOv19-ζ or costimulated MOv19-BBζ CARs secreted various proinflammatory cytokines, and exerted cytotoxic function when cocultured with FRα(+) tumor cells in vitro. However, only transfer of human T cells expressing the costimulated MOv19-BBζ CAR mediated tumor regression in immunodeficient mice bearing large, established FRα(+) human cancer. MOv19-BBζ CAR T-cell infusion mediated tumor regression in models of metastatic intraperitoneal, subcutaneous, and lung-involved human ovarian cancer. Importantly, tumor response was associated with the selective survival and tumor localization of human T cells in vivo and was only observed in mice receiving costimulated MOv19-BBζ CAR T cells. T-cell persistence and antitumor activity were primarily antigen-driven; however, antigen-independent CD137 signaling by CAR improved T-cell persistence but not antitumor activity in vivo. Our results show that anti-FRα CAR outfitted with CD137 costimulatory signaling in tandem overcome issues of T-cell persistence and tumor localization that limit the conventional FRα T-cell targeting strategy to provide potent antitumor activity in vivo.
Keywords
Animals, Antigens, CD137/biosynthesis, Antigens, CD137/genetics, Female, Folate Receptor 1/immunology, Humans, Immunoglobulin Fragments/genetics, Immunoglobulin Fragments/immunology, Immunotherapy, Adoptive/methods, Mice, Ovarian Neoplasms/immunology, Ovarian Neoplasms/therapy, Protein Engineering, Receptors, Antigen, T-Cell/genetics, Receptors, Antigen, T-Cell/immunology, T-Lymphocytes/immunology, Xenograft Model Antitumor Assays
Pubmed
Web of science
Open Access
Yes
Create date
14/10/2014 12:42
Last modification date
09/05/2019 1:17
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