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The enhanced functionality of low-affinity CD19 CAR T cells is associated with activation priming and a polyfunctional cytokine phenotype

ABSTRACT: The enhanced functionality of low-affinity CD19 CAR T cells is associated with activation priming and a polyfunctional cytokine phenotype

PROVIDER: PRJNA662071 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12604044_1.fastq.gz	Fastqsanger.gz
	SRR12604044_2.fastq.gz	Fastqsanger.gz
	SRR12604045_1.fastq.gz	Fastqsanger.gz
	SRR12604045_2.fastq.gz	Fastqsanger.gz
	SRR12604046_1.fastq.gz	Fastqsanger.gz

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The enhanced functionality of low-affinity CD19 CAR T cells is associated with activation priming and a polyfunctional cytokine phenotype

Project description:We have compared a low-affinity second-generation anti-CD19 CAR (CAT) with the high-affinity FMC63 CAR used in tisagenlecleucel to understand the unknown molecular mechanisms that drive different CAR T cell treatment outcomes. CAT cells are characterized by a faster antigen dissociation rate and present an enhanced in vivo expansion and anti-tumor efficacy, showing lower toxicity to patients and a long-term persistence in a Phase I clinical study. To understand this improved CAT cells behaviour, we performed a systematic in vitro characterization of the transcriptomic (RNA-seq) and protein (CyTOF) changes between the two groups. The analysis focused on T cells expressing low-affinity vs high-affinity anti-CD19 CARs following stimulation with CD19-expressing cells. Our results show that CAT potent and long-term anti-tumour responses may be sustained by the establishment of a CAR T cells self-reinforcing circuit activated through cytokines polyfunctional crosstalk. This study may inform the design of versatile CAR T cells, capable of balancing safety and efficacy.

2022-11-22 | GSE157584 | GEO

Activation priming and cytokine polyfunctionality modulate the enhanced functionality of low-affinity CD19 CAR T cells.

Project description:We recently described a low-affinity second-generation CD19 chimeric antigen receptor (CAR) CAT that showed enhanced expansion, cytotoxicity, and antitumor efficacy compared with the high-affinity (FMC63-based) CAR used in tisagenlecleucel, in preclinical models. Furthermore, CAT demonstrated an excellent toxicity profile, enhanced in vivo expansion, and long-term persistence in a phase 1 clinical study. To understand the molecular mechanisms behind these properties of CAT CAR T cells, we performed a systematic in vitro characterization of the transcriptomic (RNA sequencing) and protein (cytometry by time of flight) changes occurring in T cells expressing low-affinity vs high-affinity CD19 CARs following stimulation with CD19-expressing cells. Our results show that CAT CAR T cells exhibit enhanced activation to CD19 stimulation and a distinct transcriptomic and protein profile, with increased activation and cytokine polyfunctionality compared with FMC63 CAR T cells. We demonstrate that the enhanced functionality of low-affinity CAT CAR T cells is a consequence of an antigen-dependent priming induced by residual CD19-expressing B cells present in the manufacture.

| S-EPMC10182295 | biostudies-literature

Transcriptional profiling of OT-1 cells during in vitro memory formation after high- or low-affinity priming

Project description:To understand the impact of TCR affinity during priming on memory formation, we performed transcriptional profiling of OT-1 cells at different time points after stimulation with high- or low-affinity ligands. Our findings indicate that low-affinity stimulaation is associated with earlier memory formation.

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Zfp36l1 establishes the high affinity CD8 T cell response by directly linking TCR affinity to cytokine sensing

Project description:The T cell effector phase is dominated by few T cells with high affinity TCR for the respective immunodominant antigen. During priming T cells have to process multiple cues in form of antigen, costimulation and cytokines, thus a plethora of T cells with different specificities and affinities has to compete for these cues. IL2 has been suggested to be a pivotal pleiotropic molecule which organizes the quantity, quality and clonal composition of T cells contributing to the effector response. How individual T cells compete for and respond to IL2 and other key cytokines at the molecular level and as a consequence, how this competition shapes population dynamics is still poorly understood. Here we describe how the RNA binding protein ZFP36L1 acts as a sensor of antigen affinity and establishes dominance of high affinity T cells by promoting the response to IL2.

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Transcription profiling by array of human CD19+CD127+ and CD19+CD127- B cell populations derived from neonatal cord blood CD34+ cells

Project description:We derived B-lineage cells by in vitro culture of neonatal cord blood CD34+ cells on MS-5 stromal cells with recombinant IL-7. These cultures yielded CD19+CD127+ and CD19+CD127- cell populations. We performed gene expression profiling on these populations and compared these with each other and with published expression profiles of freshly isolated BM precursor B-cell subsets (E-MEXP-384). These analyses yielded new insights into their different functionality and developmental stage.<br><br>A file containing statistical analysis of the normalized data is included in the file named E-MEXP-2878.additional.zip on the FTP site for this experiment.

2011-01-01 | E-MEXP-2878 | biostudies-arrayexpress

Expression data from allo-stimulated human CD19+ cells

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2023-09-24 | PXD042938 | Pride

Analysis of mechanisms of CD19- relapse following novel low affinity CD19 Chimeric Antigen Receptor (CAR) T-cells (CD19 CAR T-cells) in a Phase I clinical study in paediatric ALL: CARPALL

Project description:Phase I clinical study (CARPALL, NCT02443831) utilizing a novel low affinity CD19CAR CAR in patients age <25 with high risk CD19+ ALL. Seventeen patients were enrolled and 14 received an infusion of CAR T cells. Among those achieving complete remission, 6 subsequently relapsed, 5 with CD19- disease, 1 with CD19+ disease. Whole exome sequencing of bone marrow DNA from patients with CD19- relapse showed mutations in the CD19 gene predicted to result in loss of surface expression in 4/5 patients. These mutations were not detectable prior to CAR T cell therapy. With a median follow-up of 14 months, 5/14 patients (36%) are alive and disease-free. Overall survival was 84% at 6 months and 63% at 12 months and by the criteria used in the ELIANA study, event-free survival was 67% and 46%. Using more stringent criteria where an event is defined as molecular relapse, molecular EFS was 55% and 29 %. The median duration of remission in responding patients was 7.4 months.

| EGAS00001003733 | EGA

Priming

Project description:Priming

| OEX00014296 | NODE

Persistent changes in nociceptor translatomes govern hyperalgesic priming in mouse models

Project description:Hyperalgesic priming is a model system that has been widely used to understand plasticity in painful stimulus-detecting sensory neurons, called nociceptors. A key feature of this model system is that following priming, stimuli that do not normally cause hyperalgesia now readily provoke this state. We hypothesized that hyperalgesic priming occurs due to reorganization of translation of mRNA in nociceptors. To test this hypothesis we used paclitaxel treatment as the priming stimulus and translating ribosome affinity purification (TRAP) to measure persistent changes in mRNA translation in Nav1.8+ nociceptors. TRAP sequencing revealed 161 genes with persistently altered mRNA translation in the primed state. We identified Gpr88as upregulated, and Metrn as downregulated. We confirmed a functional role for these genes wherein a GPR88 agonist causes pain only in primed mice, and established hyperalgesic priming is reversed by Meteorin. Our work demonstrates that altered nociceptor translatomes are causative in producing hyperalgesic priming.

2024-08-06 | GSE274093 | GEO

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