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Abatacept/Ruxolitinib and Screening for Concomitant Respiratory Muscle Failure to Mitigate Fatality of Immune-Checkpoint Inhibitor Myocarditis

ABSTRACT: Abatacept/Ruxolitinib and Screening for Concomitant Respiratory Muscle Failure to Mitigate Fatality of Immune-Checkpoint Inhibitor Myocarditis

PROVIDER: PRJNA933920 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR23421567_1.fastq.gz	Fastqsanger.gz
	SRR23421567_2.fastq.gz	Fastqsanger.gz
	SRR23421568_1.fastq.gz	Fastqsanger.gz
	SRR23421568_2.fastq.gz	Fastqsanger.gz
	SRR23421569_1.fastq.gz	Fastqsanger.gz

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Abatacept/Ruxolitinib and Screening for Concomitant Respiratory Muscle Failure to Mitigate Fatality of Immune-Checkpoint Inhibitor Myocarditis

Project description:we performed bulk RNA sequencing assessing transcriptomics and pathways affected in our mouse model. In ICI-myocarditis mice (ctla4+/-pd1-/-), bulk RNA sequencing showed very distinct affected pathways in ICI-myocarditis mice compared to unaffected control mice (ctla4+/+ pd1-/-).

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Project description:Immune-checkpoint inhibitors (ICI) have revolutionized cancer therapy but are associated with infrequent but lethal myocarditis, for which management remains uncertain. Abatacept, a CTLA-4 fusion protein targeting CD86 on antigen presenting cells and leading to global T-cell anergy, has been described as a potential treatment in individual reports. Yet, abatacept treatment dosage, schedule and optimal combination with other immunosuppressive therapies are unclear. We describe a 25-year-old man who developed pembrolizumab (anti-PD1)-induced myocarditis 14 days after first injection for thymoma treatment, which deteriorated into cardiogenic shock, with sustained ventricular arrhythmia, requiring urgent extracorporeal life support implantation, despite prompt initiation of corticosteroids and mycophenolate-mofetil. Using a strategy of serial measurement ensuring with a target of >80% CD86 receptor occupancy on circulating monocytes, abatacept dose was adjusted and combined with ruxolitinib and methylprednisolone. This strategy resulted in high-dose of abatacept: 60 mg/kg in three doses (20 mg/kg each) within the first 10 days, followed by two doses. Clinical improvement occurred within 7 days, with resolution of systolic cardiac dysfunction, and ventricular arrhythmias resulting in successful discharge from hospital. We reversed a case of nearly lethal ICI-myocarditis, using specific patient-dose adjusted abatacept, which may serve as basis for personalized treatment of patients with severe ICI-adverse events. Trial registration number: NCT04294771.

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Project description:Background and methods: Ruxolitinib (RUX), a Jak1/2 inhibitor, has been reported to attenuate murine bone marrow failure recently. Its potential toxocicty of anemia and thrombocytopenia in human remains a concern. We tested the toxicity of ruxolitinib on hematopoiesis in normal mice by feeding the mice with RUX chow for 3 months. Bone marrow Lin-CD117+ cells were sorted from treated or untreated mice. RNA-Seq and analysis was performed using SMART-Seq mRNA LP Kit (Takara) and the Illumina Novaseq6000, according to the Institute's protocols. Results: Ruxolitinib reduced RBC and lymphocytes, but did not affect NEU and PLT in normal mice. RNA sequencing demonstrated that HSPCs from RUX-treated and untreated mice had overlapped transcriptome distribution in multiple dimentional scalling plot, indicating overall similarity at molecular level. Conclusion: Our results demonstrate that ruxolitinib has minimal toxicity on hematopoiesis in normal mice.

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