Article ; Online: Drug-regulated CD33-targeted CAR T cells control AML using clinically optimized rapamycin dosing.
The Journal of clinical investigation
2024 Volume 134, Issue 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. |
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| MeSH term(s) | 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 | |||||
| Chemical Substances | Sirolimus (W36ZG6FT64) ; Sialic Acid Binding Ig-like Lectin 3 ; CD33 protein, human ; Receptors, Chimeric Antigen | |||||
| Language | English | |||||
| Publishing date | 2024-03-19 | |||||
| Publishing country | United States | |||||
| Document type | 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 | |||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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