CN111789834A - Application of small octreone compounds in preventing and treating cytokine release syndrome caused by CAR-T therapy - Google Patents

Application of small octreone compounds in preventing and treating cytokine release syndrome caused by CAR-T therapy Download PDF

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CN111789834A
CN111789834A CN201910277549.8A CN201910277549A CN111789834A CN 111789834 A CN111789834 A CN 111789834A CN 201910277549 A CN201910277549 A CN 201910277549A CN 111789834 A CN111789834 A CN 111789834A
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chimeric antigen
cancer
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许晨光
刘茂玄
张宏玲
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Shenzhen Bindebio Technology Co ltd
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Abstract

The invention provides application of small octreone compounds in preparation of preparations for preventing and treating cytokine release syndrome caused by CAR-T therapy. Also provided is a pharmaceutical composition for treating malignant tumor, autoimmune disease or AIDS, comprising chimeric antigen receptor T cells and small octreone compounds. According to the invention, the chimeric antigen receptor T cell and the small octreone compound are combined, so that CRS side effects caused by CAR-T cell therapy can be prevented and/or treated at a low economic cost, and a good treatment effect of the CAR-T cell therapy is further exerted.

Description

Application of small octreone compounds in preventing and treating cytokine release syndrome caused by CAR-T therapy
Technical Field
The invention relates to the technical field of medicines, in particular to application of small octreone compounds in preventing and treating cytokine release syndrome caused by CAR-T therapy.
Background
Malignant diseases such as cancer are diseases which seriously harm human health in the global scope and seriously affect life. Currently, the treatment methods for cancer and the like include nonspecific immunotherapy, active immunotherapy, adoptive cellular immunotherapy, and the like. Among them, adoptive cellular immunotherapy is considered as a method in which it is possible to completely eliminate cancer cells in the existing technologies. The chimeric antigen receptor T cell (CAR-T) technology, one of the latest immune cell technologies in current adoptive cell-based therapeutic technologies, is to transfuse genetically modified T lymphocytes (which can express specific chimeric antigen receptors) back into the human body, and activate the T lymphocytes in a manner independent of major histocompatibility complexes, thereby specifically killing malignant target cells such as cancer cells. The CAR-T technology has strong targeting, killing activity and persistence on malignant cells, thereby showing great application prospect in the aspect of treating malignant diseases such as cancer and the like.
Although CAR-T cell therapy has achieved good results in some clinical trials, it has also been associated with serious side effects, such as the most common Cytokine Release Syndrome (CRS) at present, resulting in significant increases in the levels of certain cytokines in the patient's blood, fever, tachycardia, hypotension, etc., and, in severe cases, multiple organ failure and death. Therefore, there is a need to inhibit cytokine release during CAR-T cell immunotherapy and alleviate/eliminate CRS side effects to improve the therapeutic efficacy of CAR-T cells.
Disclosure of Invention
In view of the above, the present invention provides a technical solution for preventing or treating CRS caused by CAR-T cell immunotherapy.
In a first aspect, the invention provides the use of a small octreone compound in the preparation of an agent for the prevention and/or treatment of Cytokine Release Syndrome (CRS) caused by chimeric antigen receptor T (CAR-T) cell therapy.
Wherein, the small octreone compounds comprise small octreone, tautomers thereof, pharmaceutically acceptable salts or prodrugs thereof, and small octreone derivatives.
Wherein the structural formula of the small oxo ketone is shown as the following formula (I):
Figure BDA0002020541090000021
wherein the CAR-T cell therapy comprises use in the treatment of a malignancy, an autoimmune disease or AIDS.
Further, the malignant tumor includes one or more of leukemia, lymphoma, multiple myeloma, brain glioma, liver cancer, lung cancer, stomach cancer, esophageal cancer, colon cancer, pancreatic cancer, breast cancer, ovarian cancer, cervical cancer and prostate cancer, but is not limited thereto.
Further, the autoimmune disease includes one or more of systemic lupus erythematosus, rheumatoid arthritis, chronic active hepatitis, scleroderma, pemphigus, dermatomyositis, ulcerative colitis, and hashimoto's thyroiditis, but is not limited thereto.
The small octreone compound is a small molecular drug, the price of the small octreone compound is much lower than that of an antibody drug for inhibiting cell factors after CRS side effect occurs, and the purpose of reducing CRS side effect caused by CAR-T cell therapy can be achieved with lower economic cost; meanwhile, the small octreone can inhibit the activity of various cytokines by inhibiting the release of catecholamine substances, compared with the antibody drug which can only inhibit the activity of one cytokine, so that the prevention and/or treatment effect on CRS is better.
In a second aspect, the invention also provides a pharmaceutical composition comprising a chimeric antigen receptor T (CAR-T) cell and a small oderone.
Optionally, the CAR-T cells comprise CAR-T cells that target one or more of CD19, CD20, CD22, CD33, CD38, CD317, BCMA, EGFR, Mesothelin, DR5, c-met, OX40, HER 2.
Wherein the T cells in the CAR-T cells are from autologous T cells, allogeneic T cells, or iPSC-induced T cells.
In the pharmaceutical composition, the CAR-T cells and the small oderone compounds can exist independently or can exist in a mixed mode. When used as a pharmaceutical combination, the two may be administered simultaneously, sequentially or in different modes of administration.
In one embodiment of the invention, the CAR-T cells are administered intravenously and the small octodelins are administered intraperitoneally.
In a third aspect, the invention also provides an application of the pharmaceutical composition in preparing a preparation for treating malignant tumor, autoimmune disease or AIDS.
According to the invention, the CAR-T cell and the small octodes compound are combined, so that CRS side effects (not only inhibiting the level of a cytokine) caused by CAR-T cell therapy can be prevented and/or treated, and a better treatment effect of CAR-T cell therapy is further exerted.
Detailed Description
While the following is a description of the preferred embodiments of the present invention, it will be understood by those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the invention.
The embodiment of the invention provides application of small octreone compounds in preparing a preparation for preventing and/or treating Cytokine Release Syndrome (CRS) caused by chimeric antigen receptor T (CAR-T) cell therapy.
Wherein the structural formula of the small oxo ketone is shown as the following formula (I):
Figure BDA0002020541090000041
the "small ondone compound" of the present invention may include tautomers, pharmaceutically acceptable salts or prodrugs thereof, in addition to small ondone, and include various derivatives that can be modified by simple chemical methods (such as reduction, substitution, etc.) on the small ondone skeleton by those skilled in the art, and still remain for preventing and/or treating CRS caused by CAR-T cell therapy, and the synthesis method of the derivatives can refer to textbooks in the prior art.
Wherein, "pharmaceutically acceptable salt" refers to a salt of a compound prepared from a pharmaceutically acceptable non-toxic acid (including inorganic acids, organic acids), non-toxic base (including inorganic bases, organic bases), solvate, hydrate or clathrate. The "prodrugs" may be prepared in situ during isolation and purification of the compounds, or by separately reacting the purified compounds with suitable derivatizing agents.
The research of the applicant of the invention finds that the small ondansetron compound can prevent and/or treat CRS caused by CAR-T cell therapy by inhibiting the release of fine factors.
The small octreone compound is a small molecular drug, the price of the small octreone compound is much lower than that of an antibody drug for inhibiting cell factors after CRS side effect occurs, and the purpose of reducing CRS side effect caused by CAR-T cell therapy can be achieved with lower economic cost; meanwhile, the small octreone can inhibit the activity of various cytokines by inhibiting the release of catecholamine substances, compared with the antibody drug which can only inhibit the activity of one cytokine, so that the prevention and/or treatment effect on CRS is better.
CAR-T cells of the invention include CAR-T cells that target a variety of different malignant disease targets, such as: targeting one or more of CD19, CD20, CD22, CD33, CD38, CD317, BCMA, EGFR, Mesothelin, DR5, c-met, OX40, HER2, and the like.
Wherein the T cells in the CAR-T cells are from autologous T cells, allogeneic T cells, or iPSC-induced T cells.
Wherein the CAR-T cell therapy comprises use in the treatment of a malignancy, an autoimmune disease or AIDS.
Further, the malignant tumor includes one or more of leukemia, lymphoma, multiple myeloma, brain glioma, liver cancer, lung cancer, stomach cancer, esophageal cancer, colon cancer, pancreatic cancer, breast cancer, ovarian cancer, cervical cancer and prostate cancer, but is not limited thereto.
Further, the autoimmune disease includes one or more of systemic lupus erythematosus, rheumatoid arthritis, chronic active hepatitis, scleroderma, pemphigus, dermatomyositis, ulcerative colitis, and hashimoto's thyroiditis, but is not limited thereto.
Embodiments of the invention also provide a pharmaceutical composition comprising a chimeric antigen receptor T (CAR-T) cell and a small oddnone compound. The pharmaceutical composition is used for treating malignant tumor, autoimmune disease or AIDS, and can also be used for preventing and/or treating Cytokine Release Syndrome (CRS) caused by chimeric antigen receptor T (CAR-T) cell therapy.
Optionally, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier is preferably chemically inert to the small octreone compounds of the present invention and has no deleterious side effects or toxicity under the conditions of use.
Such pharmaceutically acceptable carriers, e.g., excipients, stabilizers, suspending agents or diluents, and the like, are well known to those skilled in the art and are publicly available. Exemplary carriers can include water, physiological saline, aqueous dextrose and related sugar solutions, monohydric alcohols (such as ethanol, isopropanol or cetyl alcohol), glycols (such as propylene glycol or polyethylene glycol), glycerol, ketals (such as 2, 2-dimethyl-1, 3-dioxolane-4-methanol), ethers (such as poly (ethylene glycol) 400), oils, fatty acids, fatty acid esters or glycerides, acetylated fatty acid glycerides with or without pharmaceutically acceptable surfactants, such as soaps or detergents, suspending agents (such as pectin, carbomer, methyl cellulose, hydroxypropyl methyl cellulose or carboxymethyl cellulose), or emulsifying agents and other pharmaceutical adjuvants. The choice of the carrier will depend in part on the particular small octode compound selected, as well as the particular method used to administer the composition.
In the pharmaceutical composition, the CAR-T cells and the small oderone compounds can exist independently or can exist in a mixed mode. When used as a pharmaceutical combination, the two may be administered simultaneously, sequentially or in different modes of administration.
For example, the CAR-T cells are administered parenterally, e.g., intravenously, intraarterially, subcutaneously, intradermally, intrathecally, or intramuscularly. The CAR-T cells can be dissolved or suspended in a solution suitable for parenteral administration in an acceptable carrier, including isotonic sterile injectable aqueous and non-aqueous solutions. The administration modes of the small octodone compound comprise oral administration, intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal administration, sublingual administration, spray nasal administration and the like. When the small octreone compound is administered by intravenous injection, subcutaneous injection, intramuscular injection, etc., it can be prepared into injection preparations.
In one embodiment of the invention, the CAR-T cells are administered intravenously and the small octodelins are administered intraperitoneally.
Where the small octreotide compounds are used in conjunction with CAR-T cells, various concentrations of the small octreotide compounds can be used in conjunction with various concentrations (or amounts) of CAR-T cells. For example, the CAR-T cells used have a density of 0.5X 106～5×106Individual cells/mL. For example, 1X 106、2×106Or 0.5X 106Individual cells/mL.
In addition, the embodiment of the present invention also provides a method for treating malignant tumor, autoimmune disease or AIDS, which comprises administering the pharmaceutical composition of the present invention to a test subject with malignant target cells.
The concentration of the small octreotide compound, the concentration (or number) of CAR-T cells may be adjusted depending on the particular subject. Wherein the malignant target cell is a cell targeted by the CAR-T cell. Such as cells corresponding to the above-mentioned malignant tumor, autoimmune disease or AIDS.
Optionally, the CAR-T cell to malignant target cell number ratio is (2-10): 1. for example 2.5:1, 5:1 or 10: 1.
The treatment of CRS induced in tumor therapy by CAR-T cell immunotherapy with small octreones is illustrated below as a specific example. The reagents used in the present invention are all common commercial products, and are all commercially available.
The method comprises the following specific steps:
1. mixing newborn (0-2 days) SGM3(NSG Tg)CMV-IL3,CSF2,KITLG1Eav/MloySzJ) mice were irradiated with sublethal doses (150 cGy) and immediately injected intrahepatically with 1X 105Individual human cord blood CD34+ cells, a nhsgm 3 humanized mouse was prepared. Humanized mouse T cells of nhsgm 3 were used to generate CAR-T cells targeted to CD 19.
2. Adult (6-8 weeks) SGM3(NSG Tg)CMV-IL3,CSF2,KITLG1Eav/MloySzJ) mice were irradiated with a sublethal dose (200 cGy) and injected immediately via tail vein with 1X 105Individual human cord blood CD34+ cells, HuSGM3 humanized adult mice were prepared.
After 3.4 weeks, the adult mice in step 2 were injected 2X 10 by tail vein injection6CD 19-targeted CAR-T cells prepared from nHuSGM3 humanized mice in step 1.
4. Immediately after CAR-T cell injection, either 20mg/kg of small octreone or an equal volume of PBS was i.p. daily for 3 consecutive days.
5. Weighing the body weight of the mice each day after the injection of the CAR-T cells, and measuring the body temperature of the mice; blood was taken every two days and the serum levels of human IL-6, IL-10, TNF- α and mouse serum amyloid A were measured. The CRS-related indexes are continuously detected for 21 days.
As a result, compared with the CAR-T cell therapy only targeting CD19, the CAR-T cell therapy targeting CD19 and the hydrochloride salt of small octreone are carried out on the adult mice with tumors at the same time, the body temperature is lower, and the content of cytokines such as human IL-6, IL-10 and TNF-alpha in serum is lower. This suggests that the use of small octreones has significant therapeutic effects on CRS caused by CAR-T cell immunotherapy in tumor treatment.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the present invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.

Claims (10)

1. The application of the small octreone compound in preparing a preparation for preventing and/or treating cytokine release syndrome caused by chimeric antigen receptor T cell therapy.
2. The use according to claim 1, wherein the small odeinone-like compound comprises small odeinone, a tautomer thereof, a pharmaceutically acceptable salt or prodrug thereof, and a small odeinone derivative.
3. The use of claim 1, wherein said chimeric antigen receptor T cell therapy comprises treatment of a malignancy, an autoimmune disease, or aids.
4. The use of claim 3, wherein the malignancy comprises one or more of leukemia, lymphoma, multiple myeloma, brain glioma, liver cancer, lung cancer, stomach cancer, esophageal cancer, colon cancer, pancreatic cancer, breast cancer, ovarian cancer, cervical cancer and prostate cancer;
the autoimmune disease comprises one or more of systemic lupus erythematosus, rheumatoid arthritis, chronic active hepatitis, scleroderma, pemphigus, dermatomyositis, ulcerative colitis, and hashimoto's thyroiditis.
5. A pharmaceutical composition comprising a chimeric antigen receptor T cell and a small oddnone compound.
6. The pharmaceutical composition of claim 5, wherein the chimeric antigen receptor T cell is a chimeric antigen receptor T cell that targets one or more of CD19, CD20, CD22, CD33, CD38, CD317, BCMA, EGFR, Mesothelin, DR5, c-met, OX40, HER 2.
7. The pharmaceutical composition of claim 5, wherein the T cells used in the chimeric antigen receptor T cells are derived from autologous T cells, allogeneic T cells, or iPSC-induced T cells.
8. The pharmaceutical composition of any one of claims 5-7, wherein the chimeric antigen receptor T cells and the small octreone compound are present alone or in a mixed state; the administration mode of the chimeric antigen receptor T cells and the small octodeline compound comprises simultaneous administration, sequential administration or administration in different administration modes.
9. The pharmaceutical composition of claim 8, wherein the chimeric antigen receptor T cells are administered intravenously and the small octreotide compounds are administered intraperitoneally.
10. Use of a pharmaceutical composition according to any one of claims 5-9 for the preparation of a formulation for the treatment of malignant tumors, autoimmune diseases or aids.
CN201910277549.8A 2019-04-08 2019-04-08 Application of small octreone compounds in preventing and treating cytokine release syndrome caused by CAR-T therapy Pending CN111789834A (en)

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