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

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

PROVIDER: PRJNA1073004 | ENA |

REPOSITORIES: ENA

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

Project description:Chimeric antigen receptor 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 dimerization 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 1nM rapamycin. Rapamycin withdrawal paused DARIC33-stimulated T cell effector functions, which were restored following re-exposure 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 1 DARIC33 trial has been initiated (PLAT-08, NCT05105152), with initial evidence of rapamycin-regulated T cell activation and anti-tumor impact. Our findings provide evidence that the DARIC platform exhibits sensitive regulation and potency needed for clinical application to other important immunotherapy targets.

2024-04-18 | GSE255002 | GEO

Full geroprotection from brief rapamycin treatment by persistently increased intestinal autophagy

Project description:The licensed drug rapamycin has potential to be repurposed for geroprotection. A key challenge is to avoid the adverse side-effects of clinical dosing regimes. Here we show a profound memory effect of brief rapamycin treatment. Brief, early adult treatment extended lifespan in Drosophila to the same degree as lifelong dosing. Lasting memory of earlier rapamycin treatment was mediated by elevated autophagy in enterocytes of the gut, accompanied by increased intestinal spermidine levels and improved structure and function of the ageing intestine. Brief elevation of autophagy itself induced a long-term increase in autophagy. In mice, short-term, 3-month treatment also induced a full memory effect, with enhanced autophagy in Paneth cells, improved Paneth cell architecture and gut barrier function at levels induced by chronic treatment, even 6 months after rapamycin was withdrawn. Past rapamycin treatment also enhanced the regenerative potential of aged intestine in intestinal organoids. Full geroprotective effects of chronic rapamycin treatment can thus be obtained with a brief pulse of the drug.

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RNA expression profiling of CD13/CD33-positive and CD13/CD33-negative B-ALL patients [miRNA expression]

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RNA expression profiling of CD13/CD33-positive and CD13/CD33-negative B-ALL patients [mRNA expression]

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RNA-seq of CD33 KO and control HSPCs

Project description:Gene expression profile of in vitro differentiated control and CD33 KO CD34+ cells (with 70-85% CD33 KO) were analyzed by RNA-seq to exclude any major impact of CD33 loss on downstream gene expression

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TREM2 Acts Downstream of CD33 in Modulating Microglial Pathology in Alzheimer's Disease

Project description:CD33-/- and/or TREM2-/- mice were crossed with the 5xFAD mouse model of Alzheimer’s disease to generate single and double CD33/TREM2 knock-out mice on 5xFAD background. Transcriptome and gene expression analyses were performed to analyze the impact of CD33 and/or TREM2 knock-out on the transcriptome of microglia in the context of amyloid pathology. The results revealed that CD33 and/or TREM2 knock-out reprogrammed microglial gene expression signatures in 5xFAD mice in an age-dependent manner. Differential gene expression in 5xFAD;CD33-/- microglia depended on the presence of TREM2. These data suggest that TREM2 acts downstream of CD33.

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RNA expression profiling of CD13/CD33-positive and CD13/CD33-negative B-ALL patients

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| PRJNA809330 | ENA