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

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• 作者：Maria Michela D'Aloia¹ ; ^* ; Sara Caratelli² ; ⁵ ; ^* ; Camilla Palumbo³ ; Simone Battella⁴ ; Roberto Arriga⁵ ; Davide Lauro⁵ ; Gabriella Palmieri⁴ ; Giuseppe Sconocchia² ; ^{giuseppe.sconocchia@cnr.it" class="auth_mail" title="E-mail the corresponding author} ; Maurizio Alimandi¹ ; ^*
• 关键词：CD16 ; CD28 ; chimeric antigen receptors ; FcγR ; Fas ligand ; MD45 cells ; TCR ; ζ-chain
• 刊名：Cytotherapy
• 出版年：2016
• 出版时间：February 2016
• 年：2016
• 卷：18
• 期：2
• 页码：278-290
• 全文大小：1663 K

文摘

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.