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Oncoimmunology. 2017 Jun 20;6(10):e1342909. doi: 10.1080/2162402X.2017.1342909. eCollection 2017.

Characterization of a switchable chimeric antigen receptor platform in a pre-clinical solid tumor model.

Pishali Bejestani E1,2, Cartellieri M3, Bergmann R4,5, Ehninger A6, Loff S6, Kramer M7, Spehr J3, Dietrich A1,2,5, Feldmann A4, Albert S8, Wermke M7,8, Baumann M1,2,4,9,5,10, Krause M1,2,4,9,5,10, Bornhäuser M1,7,8,10, Ehninger G1,2,3,6,7,8,10, Bachmann M1,2,3,4,6,8,10, von Bonin M1,2,7.

Author information

1
German Cancer Consortium (DKTK), Dresden, Germany.
2
German Cancer Research Center (DKFZ), Heidelberg, Germany.
3
Cellex Patient Treatment GmbH, Dresden, Germany.
4
Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany.
5
OncoRay, National Center for Radiation Research in Oncology, University Hospital and Faculty of Medicine Carl Gustav Carus, Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany.
6
GEMoaB Monoclonals GmbH, Dresden, Germany.
7
Medical Department I, University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany.
8
UniversityCancerCenter (UCC), University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany.
9
Department of Radiation Oncology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany.
10
National Center for Tumor Diseases (NCT), Dresden, Germany.

Abstract

The universal modular chimeric antigen receptor (UniCAR) platform redirects CAR-T cells using a separated, soluble targeting module with a short half-life. This segregation allows precise controllability and flexibility. Herein we show that the UniCAR platform can be used to efficiently target solid cancers in vitro and in vivo using a pre-clinical prostate cancer model which overexpresses prostate stem cell antigen (PSCA). Short-term administration of the targeting module to tumor bearing immunocompromised mice engrafted with human UniCAR-T cells significantly delayed tumor growth and prolonged survival of recipient mice both in a low and high tumor burden model. In addition, we analyzed phenotypic and functional changes of cancer cells and UniCAR-T cells in association with the administration of the targeting module to reveal potential immunoevasive mechanisms. Most notably, UniCAR-T cell activation induced upregulation of immune-inhibitory molecules such as programmed death ligands. In conclusion, this work illustrates that the UniCAR platform mediates potent anti-tumor activity in a relevant in vitro and in vivo solid tumor model.

KEYWORDS:

Chimeric antigen receptors; immune checkpoints; immunoevasion; prostate stem cell antigen; solid tumors; targeting module

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