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.

T lymphocytes engineered to express a CD16-chimeric antigen receptor redirect T-cell immune responses against immunoglobulin G-opsonized target cells / D'Aloia, MARIA MICHELA; Caratelli, Sara; Palumbo, Camilla; Battella, Simone; Arriga, Roberto; Lauro, Davide; Palmieri, Gabriella; Sconocchia, Giuseppe; Alimandi, Maurizio. - In: CYTOTHERAPY. - ISSN 1465-3249. - STAMPA. - 18:2(2016), pp. 278-290. [10.1016/j.jcyt.2015.10.014]

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

D'ALOIA, MARIA MICHELA;BATTELLA, SIMONE;PALMIERI, Gabriella;ALIMANDI, MAURIZIO
2016

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.
2016
CD16; CD28; fas ligand; FcγR; MD45 cells; TCR; chimeric antigen receptors; ζ-chain
01 Pubblicazione su rivista::01a Articolo in rivista
T lymphocytes engineered to express a CD16-chimeric antigen receptor redirect T-cell immune responses against immunoglobulin G-opsonized target cells / D'Aloia, MARIA MICHELA; Caratelli, Sara; Palumbo, Camilla; Battella, Simone; Arriga, Roberto; Lauro, Davide; Palmieri, Gabriella; Sconocchia, Giuseppe; Alimandi, Maurizio. - In: CYTOTHERAPY. - ISSN 1465-3249. - STAMPA. - 18:2(2016), pp. 278-290. [10.1016/j.jcyt.2015.10.014]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/842934
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