阅读说明：本技术 雷公藤内酯醇在制备用于治疗car-t诱发的细胞因子释放综合征的药物上的用途 (Application of triptolide in preparing medicine for treating CAR-T induced cytokine release syndrome ) 是由 朱学军 田芳 陈碧清 代兴斌 孔祥图 徐祖琼 姜鹏君 于 2020-08-05 设计创作，主要内容包括：本发明公开了雷公藤内酯醇在制备用于治疗CAR-T诱发的细胞因子释放综合征的药物上的用途。本发明研究发现雷公藤内酯醇可以选择性清除外周血活化的单核细胞,快速遏制CAR-T治疗后发生的CRS,对体内CAR-T细胞不影响,可能为CRS提供一种起效快速、有效、安全、方便的治疗方法,同时也具有良好的成本效益比,能够大大降低患者的临床治疗费用。此外,对新型冠状病毒(COVID-19)感染后的重症患者发生的CRS,也有望起到积极的治疗作用。(The invention discloses application of triptolide in preparing a medicament for treating CAR-T induced cytokine release syndrome. The research of the invention finds that triptolide can selectively remove mononuclear cells activated by peripheral blood, quickly suppress CRS generated after CAR-T treatment, has no influence on CAR-T cells in vivo, possibly provides a treatment method for CRS with quick, effective, safe and convenient effect, has good cost-benefit ratio and can greatly reduce the clinical treatment cost of patients. In addition, CRS, which occurs in severe patients after infection with the novel coronavirus (COVID-19), is expected to have a positive therapeutic effect.)

1. Use of triptolide in the manufacture of a medicament for treating CAR-T induced cytokine release syndrome.

2. The use of claim 1, wherein the medicament comprises a safe and effective amount of triptolide.

3. The use of claim 1, wherein triptolide selectively eliminates monocytes in peripheral blood of a patient with cytokine release syndrome.

4. The use of claim 1, wherein triptolide ameliorates high fever, hypoxia, hypotension and cytokine storm associated with cytokine release syndrome that occurs after CAR-T treatment and suppresses IL-6, IL-8, IL-5, IL-10, IL-17, IL-1 β, TNF α, IFN γ.

Technical Field

The invention belongs to the field of medicines, and particularly relates to a new medical application of triptolide, more particularly to an application of triptolide in preparing a medicine for treating CAR-T-induced cytokine release syndrome.

Background

Transgenic T cells expressing chimeric antigen receptors open up a new field of cancer immunotherapy, but often complicated by Cytokine Release Syndrome (CRS), have high incidence, show transient and significant increase of a large amount of cytokines and a series of clinical symptoms, seriously endanger the life of patients, and are main adverse events limiting the wide application of CAR-T cell therapy.

Treatment of CRS is usually preceded by steroids, which may be combined with trastuzumab infusion therapy for CRS characterized by hyperthermia, hypotension and hypoxia. In recent years, a series of improved strategies have been proposed, including modification of CAR-T to reduce the occurrence of CRS, neutralization to remove GM-CSF in vivo, inhibition of CAR-T cells using dasatinib, etc., but these strategies are still difficult to control CRS well at present. Current methods of treating CRS are primarily using tocilizumab (tocilizumab) and hormones. The efficacy of treatment of CRS with tuzumab is not ideal and may be associated with its ability to only clear IL-6; the hormone can effectively inhibit CRS, but when the hormone is used for treating CRS, most CAR-T cells can be subjected to apoptosis, the long-term curative effect of CAR-T is influenced, and the infection is easy to be complicated or aggravated.

Two recent independent model systems prove that monocytes/macrophages in mice are the main source of CRS cytokines, and the application of the clodronate liposome to remove the macrophages and monocytes in the mice can prevent the generation and death of CRS, but the clodronate liposome cannot be used for human bodies due to great toxic and side effects; etoposide is thought to be more capable of removing activated monocytes than other chemotherapeutic agents, but is less effective and has the potential to exacerbate hematopoietic suppression. Therefore, effective drugs capable of selectively removing monocytes in the human body are still lacking at present.

Previous studies have shown that triptolide has immunosuppressive effects, mainly focusing on immune regulation of T cells and B cells, while less research has been done on myeloid cells. In 2011 Titov and the like prove that the triptolide has an XPB action target spot and realizes the biological effect by inhibiting RNA enzyme transcription; in 2013, Lu et al report that TAB1 is an action target of triptolide, and 30nM triptolide can inhibit the activity of mouse macrophage TAK1 kinase after being treated in vitro for 12h, which suggests that TAB1 may be a potential therapeutic target of inflammatory diseases. However, it is not clear whether triptolide can clear monocytes in the human body and suppress CRS.

Disclosure of Invention

The purpose of the invention is as follows: the invention unexpectedly discovers the application of triptolide in preparing a medicine for treating CAR-T induced cytokine release syndrome.

Specifically, according to animal experiments, the 10 mug/kg dose of triptolide is continuously injected for 3 days, so that mouse abdominal cavity mononuclear/macrophage can be effectively reduced, the 20 mug/kg dose of triptolide is continuously injected for 3 days, so that mouse abdominal cavity mononuclear/macrophage can be remarkably reduced, and in addition, when the triptolide is applied to a human body, the recommended dosage range of the triptolide is 0.5 mug/kg-5 mug/kg body weight, preferably 1 mug/kg-2 mug/kg body weight.

Triptolide is found to selectively clear monocytes in peripheral blood of patients with cytokine release syndrome. In vitro experiments show that along with the increase of the concentration of triptolide, the proportion of mononuclear cells in peripheral blood of a patient is gradually reduced, 100ng/ml of triptolide can remove most of the mononuclear cells, and the influence on T cells is small.

Has the advantages that:

the invention discovers that triptolide, one of main components of the triptolide tablet, can quickly inhibit IL-6, IL-8, IL-5, IL-10, IL-17, IL-1 beta, TNF alpha and IFN gamma, can selectively remove mononuclear cells activated by peripheral blood by low-dose triptolide, quickly inhibit CRS generated after CAR-T treatment, has no influence on CAR-T cells in vivo, and possibly provides a treatment method with quick, effective, safe and convenient effect for CRS. It is further noted that patients infected with the novel coronavirus (COVID-19) have similar clinical manifestations as CRS that occurs after CAR-T treatment, with high fever, hypoxia and hypotension, and with cytokine storm, our findings are suggestive of treatment of COVID-19 infection.

Drawings

FIG. 1 is a diagram showing the results of the in vitro detection of the inhibitory activity of triptolide against different tumor cell lines;

FIG. 2 and FIG. 3 are graphs showing the effect of intraperitoneal injection of triptolide on mouse peritoneal mononuclear/macrophages;

FIG. 4 is a graph of the results of the effect of triptolide on monocytes and T cells in peripheral blood of CRS patients in vitro.

FIG. 5 is a graph of the results of the in vitro effect of triptolide on peripheral blood cytokine production in CRS patients.

Detailed Description

The present invention will be described in further detail with reference to specific examples. The examples will help to understand the present invention given the detailed embodiments and the specific operation procedures, but the scope of the present invention is not limited to the examples described below.