A Chemical Switch System to Modulate Chimeric Antigen Receptor T Cell Activity through Proteolysis-Targeting Chimaera Technology
| Autor: | Yeongrin Kim, Jong Yeon Hwang, Hye Gwang Jeong, Chi Hoon Park, Sang Un Choi, So Myoung Lee, Chung Hyo Kang |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0106 biological sciences
T cell medicine.medical_treatment T-Lymphocytes Ubiquitin-Protein Ligases Cell Population Biomedical Engineering 01 natural sciences Biochemistry Genetics and Molecular Biology (miscellaneous) Immunotherapy Adoptive Cell Line Cell therapy 03 medical and health sciences Protein Domains 010608 biotechnology medicine Humans education 030304 developmental biology Histone Acetyltransferases 0303 health sciences education.field_of_study Receptors Chimeric Antigen Chemistry General Medicine Immunotherapy Azepines Chimeric antigen receptor Cell biology Thalidomide medicine.anatomical_structure Cell culture Proteolysis Interleukin-2 Cytokine secretion human activities Transcription Factors |
| Zdroj: | ACS synthetic biology. 9(5) |
| ISSN: | 2161-5063 |
| Popis: | Despite the excellent efficacy of chimeric antigen receptor (CAR T) cell therapy, concerns about its safety have been constantly raised. The side effects of CAR T cells result from an aberrantly upregulation of CAR T cell activity. Therefore, it is crucial to control the CAR T cell activity whenever the patient is at risk. For this purpose, the iCas9 system, which induces apoptosis in CAR T cell through caspase-9 dimerization by compound, has been invented and is currently going under clinical trial. However, the iCas9 system is irreversible, as the entire CAR T cell population is removed from the patient. Thus, CAR T cells, which are very expensive, should be reinfused to the patients after they recovered from the side-effect. Here, we propose a new CAR T cell safety strategy, which targets CAR "protein", not CAR "T cell". In this system, the CAR construct is modified to bear a bromodomain (BD). The addition of a BD in the CAR protein did not interfere with the original CAR functions, such as cytokine secretion and target cell lysis. Our data showed that the use of a proteolysis-targeting chimaera (PROTAC) compound against BD successfully degraded the BD-containing CAR protein. Moreover, the CAR expression is recovered when the PROTAC compound is removed from the cell, demonstrating that our system is reversible. In a target cell lysis assay, the PROTAC compound successfully suppressed the lytic activity of CAR T cells by degrading the CAR protein. In conclusion, we developed a new safety system in which CAR T cells can be "reversibly" controlled by a compound. |
| Databáze: | OpenAIRE |
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