Artikel ; Online: Drug-regulated CD33-targeted CAR T cells control AML using clinically optimized rapamycin dosing.
The Journal of clinical investigation
2024 Band 134, Heft 9
Abstract: Chimeric antigen receptor (CAR) designs that incorporate pharmacologic control are desirable; however, designs suitable for clinical translation are needed. We designed a fully human, rapamycin-regulated drug product for targeting CD33+ tumors called ... ...
Abstract | Chimeric antigen receptor (CAR) designs that incorporate pharmacologic control are desirable; however, designs suitable for clinical translation are needed. We designed a fully human, rapamycin-regulated drug product for targeting CD33+ tumors called dimerizaing agent-regulated immunoreceptor complex (DARIC33). T cell products demonstrated target-specific and rapamycin-dependent cytokine release, transcriptional responses, cytotoxicity, and in vivo antileukemic activity in the presence of as little as 1 nM rapamycin. Rapamycin withdrawal paused DARIC33-stimulated T cell effector functions, which were restored following reexposure to rapamycin, demonstrating reversible effector function control. While rapamycin-regulated DARIC33 T cells were highly sensitive to target antigen, CD34+ stem cell colony-forming capacity was not impacted. We benchmarked DARIC33 potency relative to CD19 CAR T cells to estimate a T cell dose for clinical testing. In addition, we integrated in vitro and preclinical in vivo drug concentration thresholds for off-on state transitions, as well as murine and human rapamycin pharmacokinetics, to estimate a clinically applicable rapamycin dosing schedule. A phase I DARIC33 trial has been initiated (PLAT-08, NCT05105152), with initial evidence of rapamycin-regulated T cell activation and antitumor impact. Our findings provide evidence that the DARIC platform exhibits sensitive regulation and potency needed for clinical application to other important immunotherapy targets. |
|||||
---|---|---|---|---|---|---|
Mesh-Begriff(e) | Humans ; Sirolimus/pharmacology ; Sirolimus/administration & dosage ; Mice ; Animals ; Leukemia, Myeloid, Acute/immunology ; Leukemia, Myeloid, Acute/therapy ; Leukemia, Myeloid, Acute/drug therapy ; Leukemia, Myeloid, Acute/pathology ; Sialic Acid Binding Ig-like Lectin 3/immunology ; Sialic Acid Binding Ig-like Lectin 3/metabolism ; T-Lymphocytes/immunology ; T-Lymphocytes/drug effects ; Receptors, Chimeric Antigen/immunology ; Immunotherapy, Adoptive ; Female ; Xenograft Model Antitumor Assays ; Male | |||||
Chemische Substanzen | Sirolimus (W36ZG6FT64) ; Sialic Acid Binding Ig-like Lectin 3 ; CD33 protein, human ; Receptors, Chimeric Antigen | |||||
Sprache | Englisch | |||||
Erscheinungsdatum | 2024-03-19 | |||||
Erscheinungsland | United States | |||||
Dokumenttyp | Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Clinical Trial, Phase I | |||||
ZDB-ID | 3067-3 | |||||
ISSN | 1558-8238 ; 0021-9738 | |||||
ISSN (online) | 1558-8238 | |||||
ISSN | 0021-9738 | |||||
DOI | 10.1172/JCI162593 | |||||
Signatur |
|
|||||
Datenquelle | MEDical Literature Analysis and Retrieval System OnLINE |
Zusatzmaterialien
Kategorien
Verfügbar in ZB MED Köln/Königswinter
Ua VI Zs.184: Hefte anzeigen | Standort: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG) |
Über subito bestellen
Dieser Service ist kostenpflichtig (siehe Lieferbedingungen von subito). Bestellungen, die einen Artikel nebst Supplementary Material umfassen, werden grundsätzlich wie mehrfache Bestellungen bearbeitet. Gebühren fallen in diesen Fällen für jede einzelne Bestellung an.