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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.

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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.

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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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