Sensitive manipulation of CAR T cell activity using a chimeric endocytosing receptor
Background Most adoptive cell therapies (ACTs) suffer from an inability to control the therapeutic cell’s behavior following its transplantation into a patient. Thus, efforts to inhibit, activate, differentiate or terminate an ACT after patient reinfusion can be futile, because the required drug adv...
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| Language: | English |
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BMJ Publishing Group
2020-10-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/8/2/e000756.full |
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| author | Xin Liu Boning Zhang John Victor Napoleon Qian Luo Madduri Srinivasarao Philip S Low |
| author_facet | Xin Liu Boning Zhang John Victor Napoleon Qian Luo Madduri Srinivasarao Philip S Low |
| author_sort | Xin Liu |
| collection | DOAJ |
| description | Background Most adoptive cell therapies (ACTs) suffer from an inability to control the therapeutic cell’s behavior following its transplantation into a patient. Thus, efforts to inhibit, activate, differentiate or terminate an ACT after patient reinfusion can be futile, because the required drug adversely affects other cells in the patient.Methods We describe here a two domain fusion receptor composed of a ligand-binding domain linked to a recycling domain that allows constitutive internalization and trafficking of the fusion receptor back to the cell surface. Because the ligand-binding domain is designed to bind a ligand not normally present in humans, any drug conjugated to this ligand will bind and endocytose selectively into the ACT.Results In two embodiments of our strategy, we fuse the chronically endocytosing domain of human folate receptor alpha to either a murine scFv that binds fluorescein or human FK506 binding protein that binds FK506, thereby creating a fusion receptor composed of largely human components. We then create the ligand-targeted drug by conjugating any desired drug to either fluorescein or FK506, thereby generating a ligand-drug conjugate with ~10-9 M affinity for its fusion receptor. Using these tools, we demonstrate that CAR T cell activities can be sensitively tuned down or turned off in vitro as well as tightly controlled following their reinfusion into tumor-bearing mice.Conclusions We suggest this ‘chimeric endocytosing receptor’ can be exploited to manipulate not only CAR T cells but other ACTs following their reinfusion into patients. With efforts to develop ACTs to treat diseases including diabetes, heart failure, osteoarthritis, cancer and sickle cell anemia accelerating, we argue an ability to manipulate ACT activities postinfusion will be important. |
| format | Article |
| id | doaj-art-35e17b7bcb1f4210902a49355db252f7 |
| institution | OA Journals |
| issn | 2051-1426 |
| language | English |
| publishDate | 2020-10-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-35e17b7bcb1f4210902a49355db252f72025-08-20T02:13:22ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262020-10-018210.1136/jitc-2020-000756Sensitive manipulation of CAR T cell activity using a chimeric endocytosing receptorXin Liu0Boning Zhang1John Victor Napoleon2Qian Luo3Madduri Srinivasarao4Philip S Low5Department of Nephrology, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People`s Republic of ChinaChemistry, Purdue University System, West Lafayette, Indiana, USAChemistry, Purdue University System, West Lafayette, Indiana, USAChemistry, Purdue University System, West Lafayette, Indiana, USAChemistry, Purdue University System, West Lafayette, Indiana, USAChemistry, Purdue University System, West Lafayette, Indiana, USABackground Most adoptive cell therapies (ACTs) suffer from an inability to control the therapeutic cell’s behavior following its transplantation into a patient. Thus, efforts to inhibit, activate, differentiate or terminate an ACT after patient reinfusion can be futile, because the required drug adversely affects other cells in the patient.Methods We describe here a two domain fusion receptor composed of a ligand-binding domain linked to a recycling domain that allows constitutive internalization and trafficking of the fusion receptor back to the cell surface. Because the ligand-binding domain is designed to bind a ligand not normally present in humans, any drug conjugated to this ligand will bind and endocytose selectively into the ACT.Results In two embodiments of our strategy, we fuse the chronically endocytosing domain of human folate receptor alpha to either a murine scFv that binds fluorescein or human FK506 binding protein that binds FK506, thereby creating a fusion receptor composed of largely human components. We then create the ligand-targeted drug by conjugating any desired drug to either fluorescein or FK506, thereby generating a ligand-drug conjugate with ~10-9 M affinity for its fusion receptor. Using these tools, we demonstrate that CAR T cell activities can be sensitively tuned down or turned off in vitro as well as tightly controlled following their reinfusion into tumor-bearing mice.Conclusions We suggest this ‘chimeric endocytosing receptor’ can be exploited to manipulate not only CAR T cells but other ACTs following their reinfusion into patients. With efforts to develop ACTs to treat diseases including diabetes, heart failure, osteoarthritis, cancer and sickle cell anemia accelerating, we argue an ability to manipulate ACT activities postinfusion will be important.https://jitc.bmj.com/content/8/2/e000756.full |
| spellingShingle | Xin Liu Boning Zhang John Victor Napoleon Qian Luo Madduri Srinivasarao Philip S Low Sensitive manipulation of CAR T cell activity using a chimeric endocytosing receptor Journal for ImmunoTherapy of Cancer |
| title | Sensitive manipulation of CAR T cell activity using a chimeric endocytosing receptor |
| title_full | Sensitive manipulation of CAR T cell activity using a chimeric endocytosing receptor |
| title_fullStr | Sensitive manipulation of CAR T cell activity using a chimeric endocytosing receptor |
| title_full_unstemmed | Sensitive manipulation of CAR T cell activity using a chimeric endocytosing receptor |
| title_short | Sensitive manipulation of CAR T cell activity using a chimeric endocytosing receptor |
| title_sort | sensitive manipulation of car t cell activity using a chimeric endocytosing receptor |
| url | https://jitc.bmj.com/content/8/2/e000756.full |
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