Arming T Cells with a gp100-Specific TCR and a CSPG4-Specific CAR Using Combined DNA- and RNA-Based Receptor Transfer

Tumor cells can develop immune escape mechanisms to bypass T cell recognition, e.g., antigen loss or downregulation of the antigen presenting machinery, which represents a major challenge in adoptive T cell therapy. To counteract these mechanisms, we transferred not only one, but two receptors into...

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Bibliographic Details
Published in:Cancers 2019-05, Vol.11 (5), p.696
Main Authors: Simon, Bianca, Harrer, Dennis C, Schuler-Thurner, Beatrice, Schuler, Gerold, Uslu, Ugur
Format: Article
Language:English
Subjects:
Animal models
Antigens
Cancer immunotherapy
Cell recognition
Cell surface
Cell therapy
Chimeric antigen receptors
Chondroitin sulfate
Clinical trials
Cytokines
Cytotoxicity
Deoxyribonucleic acid
DNA
Electroporation
Glycoprotein gp100
Immunotherapy
Lymphocytes
Lymphocytes T
Melanoma
mRNA
T cell receptors
Transfection
Tumor cells
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Summary:Tumor cells can develop immune escape mechanisms to bypass T cell recognition, e.g., antigen loss or downregulation of the antigen presenting machinery, which represents a major challenge in adoptive T cell therapy. To counteract these mechanisms, we transferred not only one, but two receptors into the same T cell to generate T cells expressing two additional receptors (TETARs). We generated these TETARs by lentiviral transduction of a gp100-specific T cell receptor (TCR) and subsequent electroporation of mRNA encoding a second-generation CSPG4-specific chimeric antigen receptor (CAR). Following pilot experiments to optimize the combined DNA- and RNA-based receptor transfer, the functionality of TETARs was compared to T cells either transfected with the TCR only or the CAR only. After transfection, TETARs clearly expressed both introduced receptors on their cell surface. When stimulated with tumor cells expressing either one of the antigens or both, TETARs were able to secrete cytokines and showed cytotoxicity. The confirmation that two antigen-specific receptors can be functionally combined using two different methods to introduce each receptor into the same T cell opens new possibilities and opportunities in cancer immunotherapy. For further evaluation, the use of these TETARs in appropriate animal models will be the next step towards a potential clinical use in cancer patients.
ISSN:2072-6694
2072-6694
DOI:10.3390/cancers11050696