Article
作者: Gregory, Philip D ; Martin, Unja ; Ngwenyama, Njabulo ; Hollands, Andrew ; Franke-Welch, Secil ; Zhang, Joy ; Zak, Daniel E ; Timmer, John ; Fitzgerald, Michael ; Lamble, Adam ; Appelbaum, Jacob ; Tulberg, Niklas ; Eckelman, Brendan ; Tampella, Giacomo ; Evandy, Claudya ; Sanabria, Angelica ; So, Pauline Pl ; Jones, Kyle ; Leung, Wai-Hang ; Hilton, Sarah K ; Jarjour, Jordan ; Sarkar, Semanti ; Jensen, Michael C ; Bilic, Sanela ; Rawlings-Rhea, Stephanie ; Gardner, Rebecca A ; Pogson, Mark ; Xia, Dong ; Krostag, Anne-Rachel ; Lewis, Paula ; Oda, Kaori ; Price, April E ; Gustafson, Joshua A ; Astrakhan, Alexander ; Woodworth, Jim ; Leonardi, Marissa ; Crago, William ; Logan, Rachael
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.