Two-Dimensional Regulation of CAR-T Cell Therapy with Orthogonal Switches
| Autor: | An Lu, Kelly L. Sharp, Wei-Chun Chang, Kevin M. Slawin, Slawomir P. Szymanski, Steven M. Toler, Ming Zhang, Eva Morschl, David M. Spencer, Matthew R. Collinson-Pautz, My Linh T. Duong, J. Henri Bayle, Mary E. Brandt, Aaron E. Foster |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Cancer Research rimiducid Cell dimerizer lcsh:RC254-282 Article Cell therapy 03 medical and health sciences 0302 clinical medicine medicine Pharmacology (medical) CD40 biology rapamycin Cell growth Chemistry apoptosis costimulation switch iRC9 lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Chimeric antigen receptor CAR-T safety switch 030104 developmental biology medicine.anatomical_structure iMC Oncology Apoptosis 030220 oncology & carcinogenesis Toxicity biology.protein Cancer research Molecular Medicine Cytokine secretion cell therapy human activities |
| Zdroj: | Molecular Therapy: Oncolytics, Vol 12, Iss, Pp 124-137 (2019) Molecular Therapy Oncolytics |
| ISSN: | 2372-7705 |
| Popis: | Use of chimeric antigen receptors (CARs) as the basis of targeted adoptive T cell therapies has enabled dramatic efficacy against multiple hematopoietic malignancies, but potency against bulky and solid tumors has lagged, potentially due to insufficient CAR-T cell expansion and persistence. To improve CAR-T cell efficacy, we utilized a potent activation switch based on rimiducid-inducible MyD88 and CD40 (iMC)-signaling elements. To offset potential toxicity risks by this enhanced CAR, an orthogonally regulated, rapamycin-induced, caspase-9-based safety switch (iRC9) was developed to allow in vivo elimination of CAR-T cells. iMC costimulation induced by systemic rimiducid administration enhanced CAR-T cell proliferation, cytokine secretion, and antitumor efficacy in both in vitro assays and xenograft tumor models. Conversely, rapamycin-mediated iRC9 dimerization rapidly induced apoptosis in a dose-dependent fashion as an approach to mitigate therapy-related toxicity. This novel, regulatable dual-switch system may promote greater CAR-T cell expansion and prolonged persistence in a drug-dependent manner while providing a safety switch to mitigate toxicity concerns. Keywords: CAR-T, dimerizer, cell therapy, costimulation switch, apoptosis, rapamycin, rimiducid, iMC, iRC9, safety switch |
| Databáze: | OpenAIRE |
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