Drug-regulated CD33-targeted CAR T cells control AML using clinically optimized rapamycin dosing.

Area of Science:

• Immunotherapy
• Cancer Biology
• Pharmacology

Background:

• Chimeric antigen receptor (CAR) T-cell therapy offers promise but lacks precise control over T-cell activity.
• Developing clinically translatable CAR designs with pharmacologic regulation is a critical need for enhancing safety and efficacy.

Purpose of the Study:

• To design and evaluate a novel, fully human, rapamycin-regulated CAR T-cell product, DARIC33, for targeting CD33+ malignancies.
• To demonstrate the reversible control of T-cell effector functions and in vivo antileukemic activity mediated by DARIC33 in response to rapamycin.

Main Methods:

• Development of the dimerizing agent-regulated immunoreceptor complex (DARIC33) targeting CD33.
• Assessment of target-specific and rapamycin-dependent cytokine release, cytotoxicity, and transcriptional responses in vitro.
• Evaluation of in vivo antileukemic activity in preclinical models and assessment of CD34+ stem cell function.
• Integration of pharmacokinetic data to establish a clinically applicable rapamycin dosing schedule.

Main Results:

• DARIC33 exhibited target-specific and rapamycin-dependent T-cell activation, cytokine release, and cytotoxicity at low rapamycin concentrations (1 nM).
• T-cell effector functions were reversibly controlled by rapamycin withdrawal and re-exposure.
• DARIC33 demonstrated potent in vivo antileukemic activity without impacting CD34+ stem cell function.
• A clinically applicable rapamycin dosing schedule was estimated, and a Phase I trial (PLAT-08) is underway with promising initial results.

Conclusions:

• The DARIC33 platform provides sensitive and reversible pharmacologic control over CAR T-cell activity.
• DARIC33 exhibits the potency and safety profile required for clinical translation in CD33+ malignancies.
• The DARIC platform holds potential for application to other immunotherapy targets requiring precise regulation.