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Cytotherapy. 2016 Feb;18(2):278-90. doi: 10.1016/j.jcyt.2015.10.014. Epub 2015 Dec 17.

T lymphocytes engineered to express a CD16-chimeric antigen receptor redirect T-cell immune responses against immunoglobulin G-opsonized target cells.

Author information

1
Department of Clinical and Molecular Medicine, Sapienza University of Rome, Rome, Italy.
2
Department of Biomedicine, Institute of Translational Pharmacology, CNR, Rome, Italy; Laboratory of Molecular Medicine, Department of Systems Medicine, Tor Vergata University, Rome, Italy.
3
Department of Clinical Sciences and Translational Medicine, Tor Vergata University, Rome, Italy.
4
Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.
5
Laboratory of Molecular Medicine, Department of Systems Medicine, Tor Vergata University, Rome, Italy.
6
Department of Biomedicine, Institute of Translational Pharmacology, CNR, Rome, Italy. Electronic address: giuseppe.sconocchia@cnr.it.

Abstract

BACKGROUND AIMS:

Chimeric antigen receptors (CARs) designed for adoptive immunotherapy need to achieve two functions: antigen recognition and triggering of the lytic machinery of reprogrammed effector cells. Cytotoxic T cells have been engineered with FcγRIII (CD16) chimeric molecules to be redirected against malignant cells by monoclonal antibodies (mAbs). These cells have been proven to mediate granule-dependent cellular cytotoxicity, but it is not clear whether they can also kill malignant cells by a granule-independent mechanism of cell cytotoxicity.

METHODS:

We engineered a CD16A-CAR equipped with the extracellular CD16A, the hinge spacer and the transmembrane region of CD8, and the ζ-chain of the T-cell receptor/CD3 complex in tandem with the CD28 co-stimulatory signal transducer module. The CD16A-CAR was expressed and functionally tested in the MD45 cell line, a murine T-cell hybridoma with a defective granular exocytosis pathway but capable of killing target cells by a Fas ligand-mediated lysis.

RESULTS:

Our results indicate that in vitro cross-linking of CD16A-CAR on MD45 cells by the Fc fragment of mAb opsonized tumor cells induced interleukin-2 release and granule-independent cellular cytotoxicity.

CONCLUSIONS:

We conclude that strategies aimed to implement the therapeutic functions of mAbs used in the clinic with T-dependent immune responses driven by engineered T cells expressing FcγR-CAR can boost the antitumor efficacy of mAbs used in the clinic.

KEYWORDS:

CD16; CD28; Fas ligand; FcγR; MD45 cells; TCR; chimeric antigen receptors; ζ-chain

PMID:
26705740
DOI:
10.1016/j.jcyt.2015.10.014
[Indexed for MEDLINE]

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