Universität zu Köln

Krug, Christian, Birkholz, Katrin, Paulus, Alexander, Schwenkert, Michael, Schmidt, Patrick ORCID: 0000-0002-1917-1446, Hoffmann, Nicole, Hombach, Andreas, Fey, Georg, Abken, Hinrich, Schuler, Gerold, Schuler-Thurner, Beatrice, Doerrie, Jan and Schaft, Niels ORCID: 0000-0001-8236-9298 (2015). Stability and activity of MCSP-specific chimeric antigen receptors (CARs) depend on the scFv antigen-binding domain and the protein backbone. Cancer Immunol. Immunother., 64 (12). S. 1623 - 1636. NEW YORK: SPRINGER. ISSN 1432-0851

Full text not available from this repository.

Abstract

Chimeric antigen receptor (CAR)-modified T cells emerged as effective tools in the immunotherapy of cancer but can produce severe on-target off-tissue toxicities. This risk can conceivably be overcome, at least partially, by transient transfection. The design of CARs, however, has so far not been optimized for use in non-permanent T cell modification. Here we compared the performance of T cells modified with three different first- and second-generation CARs, each specific for MCSP (HMW-MAA) which is commonly expressed by melanoma cells. Upon RNA transfer, the expression of all receptors was limited in time. The second-generation CARs, which combined CD28-CD3 zeta signaling, were expressed at higher levels and more prolonged than first-generation CARs with CD3 zeta only. The CD28 domain increased the cytokine production, but had only an indirect effect on the lytic capacity, by prolonging the CAR expression. Especially for the second-generation CARs, the scFv clearly impacted the level and duration of CAR expression and the T cell performance. Thus, we identified a CAR high in both expression and anti-tumor cell reactivity. T cells transfected with this CAR increased the mean survival time of mice after challenge with melanoma cells. To facilitate clinical application, this CAR was used to redirect T cells from late-stage melanoma patients by RNA transfection. These T cells mediated effective antigen-specific tumor cell lysis and release of pro-inflammatory cytokines, even after cryoconservation of the transfected T cells. Taken together, the analysis identified a CAR with superior anti-melanoma performance after RNA transfer which is a promising candidate for clinical exploration.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Krug, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Birkholz, Katrin UNSPECIFIED UNSPECIFIED UNSPECIFIED Paulus, Alexander UNSPECIFIED UNSPECIFIED UNSPECIFIED Schwenkert, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Schmidt, Patrick UNSPECIFIED orcid.org/0000-0002-1917-1446 UNSPECIFIED Hoffmann, Nicole UNSPECIFIED UNSPECIFIED UNSPECIFIED Hombach, Andreas UNSPECIFIED UNSPECIFIED UNSPECIFIED Fey, Georg UNSPECIFIED UNSPECIFIED UNSPECIFIED Abken, Hinrich UNSPECIFIED UNSPECIFIED UNSPECIFIED Schuler, Gerold UNSPECIFIED UNSPECIFIED UNSPECIFIED Schuler-Thurner, Beatrice UNSPECIFIED UNSPECIFIED UNSPECIFIED Doerrie, Jan UNSPECIFIED UNSPECIFIED UNSPECIFIED Schaft, Niels UNSPECIFIED orcid.org/0000-0001-8236-9298 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-385552
DOI:	10.1007/s00262-015-1767-4
Journal or Publication Title:	Cancer Immunol. Immunother.
Volume:	64
Number:	12
Page Range:	S. 1623 - 1636
Date:	2015
Publisher:	SPRINGER
Place of Publication:	NEW YORK
ISSN:	1432-0851
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CHONDROITIN SULFATE PROTEOGLYCAN; MELANOMA-ASSOCIATED ANTIGEN; HIGH-MOLECULAR-WEIGHT; T-CELL-ACTIVATION; PERICYTES DIMINISHES NEOVASCULARIZATION; MESSENGER-RNA; MONOCLONAL-ANTIBODY; ADOPTIVE IMMUNOTHERAPY; RECOMBINANT IMMUNORECEPTORS; CD28 COSTIMULATION Multiple languages Oncology; Immunology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/38555