CN117045777A - Application of liraglutide as immune cell treatment synergist - Google Patents
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Abstract
The invention discloses application of liraglutide as an immune cell treatment synergist. The inventors have found that liraglutide can enhance the ability of unexpectedly enhancing the killing of immune cells, particularly NK cells, against tumors. In addition, compared with a control group without using liraglutide, pretreatment of tumors with liraglutide can significantly improve the tumor killing effect without toxic or side effects. Is especially suitable for patients suffering from diabetes (or obesity) and cancer at the same time. Since liraglutide has proven to be safe and effective, it is likely to be a new approach to provide more effective cancer treatment for obese and diabetic patients. The treatment methods of the present invention may thus have profound effects on existing cancer treatment strategies.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to application of liraglutide as an immune cell treatment synergist.
Background
Liraglutide (LIR) is a glucagon-like peptide-1 (GLP-1) analogue, which acts by mimicking the activity of glucagon-like peptide-1 (GLP-1). It binds to the GLP-1 receptor, activating it, thereby increasing insulin secretion, inhibiting glucagon secretion, thereby reducing the amount of glucose released by the liver, and helping to lower blood glucose levels. And thus are widely used for the treatment of type 2 diabetes (Drucker DJ., mol meta, 2022). Liraglutide can inhibit appetite through central nervous system, reduce food intake, thereby slowing postprandial blood glucose rise speed, increasing insulin sensitivity and suppressing appetite, and is helpful for controlling blood glucose level and managing diabetes. These effects help to lower blood glucose levels, improve insulin resistance, and promote weight loss (Drucker DJ., cell meta, 2018). Thus liraglutide is also approved for the treatment of obesity. Liraglutide can be used as a monotherapy or in combination with other antidiabetic agents (e.g., metformin).
The tumor immune cell treatment is adoptive immune cell treatment, including T cell modified by engineering T cell receptor, killer cell induced by cytokine, natural killer cell, tumor infiltrating lymphocyte, chimeric antigen receptor T cell treatment, etc., and is prepared by culturing special tumor immune cells in vitro and actively infusing the special tumor immune cells into tumor patients, thereby achieving the anti-tumor effect and having better application prospect in blood tumor and solid tumor. Taking NK cells as an example, NK (natural killer) cells are an important class of immune cells that are mainly responsible for recognizing and killing abnormal cells in the body, including infected cells, cancer cells, and other damaged or abnormal cells. NK cells are able to directly recognize and kill diseased cells by activating and inhibiting receptors on their surface. Under normal conditions, the inhibitory receptor is able to maintain tolerance to healthy cells, whereas activation of the receptor causes NK cells to kill abnormal cells. NK cells also produce a variety of cytokines such as interferon (IFN-. Gamma.) and tumor necrosis factor (TNF-. Alpha.) which play an important role in regulating immune responses and anti-tumor responses. NK (natural killer) cells are an emerging tumor treatment method with many of the following advantages:
target specificity: NK cells have natural killer action and can directly recognize and attack cancer cells. NK cell therapy is matched with radiotherapy and chemotherapy, so that tumor cells which cannot be completely resected in operation can be effectively cleared;
enhancement of immune response: NK cell therapy can enhance the immune response of the body, activate and enhance the ability of other immune cells (e.g. T cells, macrophages, etc.) to attack tumors. This helps to increase the efficiency of the immune system in combating cancer.
Low toxic and side effects: compared with other tumor treatment methods, such as chemotherapy and radiotherapy, NK cell treatment refers to in vitro amplification of NK cells separated from peripheral blood and other sources, and then the NK cells are adoptive to a patient, so that activation and proliferation of damaged NK cells of a tumor patient can be induced, the number of the NK cells is increased, and the NK cell is used as adoptive immunotherapy of malignant tumors of a blood system and solid cancers. NK cell therapy generally has low toxic side effects, no MHC restriction, no dependence on antibodies, killing tumor cells by post-release perforin and granzyme or by death receptors.
Is not easy to generate drug resistance: traditional chemotherapeutics may cause tumor cells to develop drug resistance, thereby weakening the therapeutic effect. But NK cell treatment is not easy to generate drug resistance, and can continuously and effectively attack tumors.
Individual suitability: NK cell therapy can be tailored to the individual condition of the patient, making the therapy more personalized and accurate.
NK cell therapy is combined with radiotherapy and chemotherapy, so that the curative effect of radiotherapy and chemotherapy can be improved, and side effects can be reduced. NK cell therapy is a good choice for patients with advanced cancer who are not suitable for surgery or radiotherapy and chemotherapy. NK cell therapy is adopted regularly after operation, so that the recurrence and metastasis of cancers can be prevented. Relieving cancer pain, improving sleep, improving life quality of patients, and prolonging life cycle of patients.
Sub-healthy people can be treated by NK cells to reduce the risk of cancer. Studies have shown that the number of peripheral blood NK cells in obese patients is relatively low and that the activity and function of these cells is significantly reduced compared to normal weight individuals. This means that Obesity can lead to NK cells being impaired in immune surveillance and anti-tumor effects (De barrea c., obosity, 2023). Some studies indicate that NK cell function may be impaired in diabetics, possibly manifested by reduced recognition and killing of tumors and infections. Some studies have also found that NK cell function in diabetics may be improved with good glycemic control (Berrou j., PLoS One, 2013).
Tumor immune cell therapy, particularly NK cell therapy, is increasingly becoming a promising area of clinical research, but there are still many challenges to be addressed, such as immunosuppression in TME, increased NK cell proliferation and cytotoxicity, etc. Future therapeutic approaches must not only target NK cells to tumor cells, but also maximize the effectiveness of therapeutic immune cell products by increasing the persistence and killing of these lymphocytes in the body.
Reference is made to:
Kim DS,Scherer PE.Obesity,Diabetes,and Increased Cancer Progression.Diabetes Metab J.2021；45(6):799-812.doi:10.4093/dmj.2021.0077.
Drucker DJ.Mechanisms of Action and Therapeutic Application of Glucagon-like Peptide-1.Cell Metab.2018；27(4):740-756.doi:10.1016/j.cmet.2018.03.001.
Drucker DJ.GLP-1physiology informs the pharmacotherapy of obesity.Mol Metab.2022；57:101351.doi:10.1016/j.molmet.2021.101351.
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disclosure of Invention
The invention aims to overcome at least one defect of the prior art and provide application of liraglutide as an immune cell treatment synergist.
The technical scheme adopted by the invention is as follows:
application of liraglutide in preparing immune cell treating synergist.
In some examples of use, the immune cells are selected from NK cells, NKT cells.
In some examples of use, the subject to immune cell therapy is a tumor patient.
In some examples of use, the patient is associated with obesity and/or diabetes.
In some examples of use, the tumor is selected from STAT3 activated tumors.
In some examples of use, the tumor is selected from mature B-cell non-hodgkin's lymphoma, acute myeloid leukemia, myelodysplastic syndrome, chronic myelogenous leukemia, neuroblastoma, renal cell carcinoma, melanoma, liver cancer, breast cancer, or ovarian cancer.
In some examples of use, the tumor is selected from STAT3 activated tumors selected from mature B cell non-hodgkin lymphoma, acute myeloid leukemia, myelodysplastic syndrome, chronic myelogenous leukemia, neuroblastoma, renal cell carcinoma, melanoma, liver cancer, breast cancer, or ovarian cancer.
In some examples of use, the amount of liraglutide is 0.6 to 1.8 mg/day.
In some examples of application, the immune cell therapy is performed within 0 to 13 hours after the administration of liraglutide.
In some examples of use, the amount of liraglutide is 0.6-1.8 mg/day and the immune cell therapy is performed within 0-13 hours after application of the liraglutide.
In some examples of application, the dose ratio of liraglutide to immune cells is 0.6-1.8 mg/(1-5) E10.
In some examples of application, the dose ratio of liraglutide to immune cells selected from NK cells, NKT cells is 0.6-1.8 mg/(1-5) E10.
In some examples of use, the immune cells are derived from at least one of peripheral blood, umbilical cord blood, and induced pluripotent stem cells.
In some examples of use, the immune cells are selected from at least one of NK cells, NKT cells, derived from peripheral blood, umbilical cord blood, and induced pluripotent stem cells.
The beneficial effects of the invention are as follows:
1. the inventors have found that liraglutide can enhance the ability of unexpectedly enhancing the killing of immune cells, particularly NK cells, against tumors.
2. And no obvious effect of the concentration dependence of the liraglutide is generated, and the toxicity of NK to tumor cells can be obviously improved by co-incubation of the liraglutide with low concentration.
3. In addition, compared with a control group without using liraglutide, after the use of the liraglutide for pretreatment of tumors, NK cell treatment can be combined with the liraglutide simultaneously to obviously improve the tumor killing effect, and the compound preparation has no toxic and side effects. For tumor patients who need liraglutide to treat diabetes (or obesity) at ordinary times, the liraglutide with a certain concentration in the body can achieve better tumor treatment effect by carrying out NK cell treatment at the moment, so the compound is particularly suitable for patients suffering from diabetes (or obesity) and cancer at the same time.
4. Since liraglutide has proven to be safe and effective, it is likely to be a new approach to provide more effective cancer treatment for obese and diabetic patients. The treatment methods of the present invention may thus have profound effects on existing cancer treatment strategies.
Drawings
FIG. 1 is the effect of different concentrations of liraglutide on the antitumor effect of NK cells pretreatment.
FIG. 2 is the results of liraglutide in promoting NK cell killing of tumor cells (target ratio 1:5).
FIG. 3 is the results of liraglutide in promoting NK cell killing of tumor cells (target ratio 1:10).
Detailed Description
The technical scheme of the invention is further described below in conjunction with experiments.
Acquisition of NK cells:
1. plasma extraction
The peripheral blood is split into 50mL centrifuge tubes on average, centrifuged at 700g for 15min at room temperature, the upper plasma layer is sucked into a new 50mL centrifuge tube and a 15mL centrifuge tube (the lower red liquid is used for extracting PBMC), the 50mL centrifuge tube is inactivated at 56 ℃ for 30min, -20 ℃ for 15min, centrifuged at 900g for 10min in a water bath, and the supernatant is sucked by a pipette and placed at 4 ℃ for standby.
Isolation of PBMC (mononuclear cells)
2.1 the lower red liquid obtained after the plasma extraction in the previous step is diluted with D-PBS1:1 and mixed well for standby.
2.2 according to the volume of diluted blood, 2-4 50ml centrifuge tubes are taken and added with 25ml lymphocyte separating liquid respectively.
2.3 the diluted blood is slowly added to the upper layer of lymphocyte separation liquid (e.g. 25mL of lymphocyte separation liquid, 25mL of diluted blood is needed) in a ratio of 1:1 to form a distinct layer between the blood and lymphocyte separation liquid, taking care not to mix the diluted blood into the lymphocyte separation liquid, and centrifuging at 700g for 30min at room temperature.
2.4 after centrifugation, three layers were visible in the tube, the upper layer being plasma and D-PBS, the lower layer being mainly erythrocytes and granulocytes, the middle layer being lymphocyte separation fluid. The interface between the upper and middle layers has a white cloud layer narrow band mainly containing mononuclear cells, which is mononuclear cells including lymphocyte and monocyte and contains blood platelet. The PBMC layer is taken out to a new 50ml centrifuge tube; normal saline was added to 45ml, and 700g was centrifuged for 5min.
2.5 removing supernatant, adding D-PBS to 40mL, mixing well, centrifuging at 700g for 10min, re-suspending to 40mL with D-PBS, and sampling and counting.
2.6 PBMC were collected by centrifugation at 700g for 10 min.
Culture of nk cells:
the NK cells are amplified and cultured for 14-16 days by using a serum-free culture kit of the NK cells of the YOUKANG, and the NK cells are harvested.
Example 1
Effect of different concentrations of liraglutide on the antitumor effect of cells after pretreatment of K562 cells, the experimental results are shown in fig. 1 (p <0.05; p <0.01; p <0.001; n.s. no statistical difference; data are expressed as mean ± standard deviation of three independent experiments), and the specific experimental steps are as follows:
s1) washing K562 cells with serum-free medium once before experiment, and adjusting the cell density to 4×10 with serum-free medium 5 Per mL, NK cells were washed once with serum-free medium and cell density was adjusted to 2X 10 with serum-free medium 6 /mL. The K562 cells with slightly more than the required cell number of each experimental group were taken and diluted 1×10 with serum-free medium 6 Adding liraglutide (0, 10, 20, 40, 80 uM) at 37deg.C and 5% CO 2 Incubating the incubator for 2 hours;
s2) centrifuging the liraglutide for 2 hours, pretreating the K562 cells and NK cells, and adjusting the density of the K562 cells to 4×10 with a serum-free medium 5 Per mL, NK cell density was adjusted to 2 x 10 with serum-free medium 6 /mL. Taking 96-well cell culture plates, and repeating each sample for 3 times according to the target ratio of 5:1 NK cells and K562 cells were added, followed by the corresponding concentrations of liraglutide, in a total volume of 150. Mu.l per well. The same number of effector cells as the experimental wells were set to naturally release the control wells, and medium was added to give a final volume of 150 μl per well. Setting the maximum release control holes of target cells with the same number as the experimental holes, addingThe medium was made to have a final volume of 135. Mu.l per well (followed by 15. Mu.l of lysate (step S3 addition)). The same number of target cells as the experimental wells were set to naturally release the control wells, and medium was added to give a final volume of 150 μl per well. Background (150. Mu.l serum-free cell culture medium per well) and volume correction wells (135. Mu.l serum-free cell culture medium per well+15. Mu.l lysate (step S5 addition)) were set;
s3) adding 15 microliters of D-PBS into the spontaneous release wells of effector cells and target cells;
s4) placing the culture plate at 37℃and 5% CO 2 Incubating in an incubator for 4 hours;
s5) adding 15 microlitres of lysate into the maximum release hole and the volume correction hole one hour before the incubation is finished, and incubating for 1 hour;
s6) 300g is centrifuged for 5 minutes, 120 microliter of supernatant is sucked out of each well and added to a new 96-well culture plate in a dark place, and 60 microliters of supernatant is added
Lifting an LDH detection working solution, uniformly mixing, shading, and incubating for 30 minutes at room temperature;
s7) puncturing large bubbles in the hole by using a syringe needle, and placing the 96-well plate in an enzyme-labeling instrument to detect the light absorption value at 490 nm;
s8) calculating cytotoxicity for each set of experiments: cytotoxicity (%) = (experimental OD value-effector cell natural release pore OD value-target cell natural release pore OD value)/(target cell lysis release pore OD value-target cell natural release pore OD value) ×100%.
Example 2
The results of experiments on NK cell killing tumor cells by different liraglutide pretreatment modes (the effective target ratio is 5:1) are shown in FIG. 2 (p <0.05; p <0.01; p <0.001; n.s. no statistical difference. Data are expressed as mean value.+ -. Standard deviation of three independent experiments), and the specific experimental steps are as follows:
s1) washing K562 cells with serum-free medium once before experiment, and adjusting the cell density to 4×10 with serum-free medium 5 Per mL, NK cells were washed once with serum-free medium and cell density was adjusted to 2X 10 with serum-free medium 6 /mL. The K562 cells and NK cells were taken slightly more than the number of cells required for each experimental group, and both cells were diluted 1X 10 with serum-free medium 6 20uM liraglutide is added to each of the above two solutions at 37deg.C and 5% CO 2 Incubating the incubator for 2 hours;
s2) centrifuging the K562 cells and NK cells after 2 hours of pretreatment with liraglutide, and adjusting the K562 cells density to 4 x 10 with serum-free medium 5 Per mL, NK cell density 2 x 10 6 /mL. Taking 96-well cell culture plates, and repeating each sample for 3 times according to the target ratio of 5:1 NK cells and K562 cells were added, followed by 20uM of liraglutide, in a total volume of 150. Mu.l per well. The same number of effector cell-treated liraglutide wells and target cell-treated liraglutide wells as the experimental wells were set, and medium was added to give a final volume of 150 μl per well. The same number of effector cells as the experimental wells were set to naturally release the control wells, and medium was added to give a final volume of 150 μl per well. The same number of target cell maximum release control wells as the experimental wells were set, and medium was added to give a final volume of 135. Mu.l per well (followed by 15. Mu.l of lysate (step S3 addition)). The same number of target cells as the experimental wells were set to naturally release the control wells, and medium was added to give a final volume of 150 μl per well. Background (150. Mu.l serum-free cell culture medium per well) and volume correction wells (135. Mu.l serum-free cell culture medium per well+15. Mu.l lysate (step S5 addition)) were set;
s3) adding 15 microliters of D-PBS into the spontaneous release wells of effector cells and target cells;
s4) placing the culture plate at 37℃and 5% CO 2 Incubating in an incubator for 4 hours;
s5) adding 15 microlitres of lysate into the maximum release hole and the volume correction hole one hour before the incubation is finished, and incubating for 1 hour;
s6) 300g is centrifuged for 5 minutes, 120 microliter of supernatant is sucked out from each hole and placed in a new 96-hole culture plate, 60 microliter of LDH detection working solution is added in a dark place, and the mixture is uniformly mixed and incubated for 30 minutes at room temperature in a dark place;
s7) puncturing large bubbles in the hole by using a syringe needle, and placing the 96-well plate in an enzyme-labeling instrument to detect the light absorption value at 490 nm;
s8) calculating cytotoxicity for each set of experiments: cytotoxicity (%) = (experimental OD value-effector cell natural release pore OD value-target cell natural release pore OD value)/(target cell lysis release pore OD value-target cell natural release pore OD value) ×100%.
Example 3
The effect of different liraglutide pretreatment modes on NK cell killing tumor cells (the effective target ratio is 10:1) is shown in fig. 3 (p <0.05; p <0.01; p <0.001; n.s. no statistical difference. Data are expressed as mean ± standard deviation of three independent experiments), and the specific experimental steps are as follows:
s1) washing K562 cells with serum-free medium once before experiment, and adjusting the cell density to 4×10 with serum-free medium 5 Per mL, NK cells were washed once with serum-free medium and cell density was adjusted to 4X 10 with serum-free medium 6 /mL. The K562 cells and NK cells were taken slightly more than the number of cells required for each experimental group, and both cells were diluted 1X 10 with serum-free medium 6 20uM liraglutide is added to each of the above two solutions at 37deg.C and 5% CO 2 Incubating the incubator for 2 hours;
s2) centrifuging the K562 cells and NK cells after 2 hours of pretreatment with liraglutide, and adjusting the K562 cells density to 4 x 10 with serum-free medium 5 Per mL, NK cell density 2 x 10 6 /mL. Taking 96-well cell culture plates, and repeating each sample for 3 times according to the target ratio of 10:1 NK cells and K562 cells were added, followed by 20uM of liraglutide, in a total volume of 150. Mu.l per well. The same number of effector cell-treated liraglutide wells and target cell-treated liraglutide wells as the experimental wells were set, and medium was added to give a final volume of 150 μl per well. The same number of effector cells as the experimental wells were set to naturally release the control wells, and medium was added to give a final volume of 150 μl per well. The same number of target cell maximum release control wells as the experimental wells were set, and medium was added to give a final volume of 135. Mu.l per well (followed by 15. Mu.l of lysate (step S5 addition)). The same number of target cells as the experimental wells were set to naturally release the control wells, and medium was added to give a final volume of 150 μl per well. Background (150. Mu.l serum-free cell culture medium per well) and volume correction wells (135. Mu.l serum-free cells per well) were setMedium+15 microliters of lysate (added in step S5));
s3) adding 15 microliters of D-PBS into the spontaneous release wells of effector cells and target cells;
s4) placing the culture plate in a 5% CO2 incubator at 37 ℃ for 4 hours;
s5) adding 15 microlitres of lysate into the maximum release hole and the volume correction hole one hour before the incubation is finished, and incubating for 1 hour;
s6) 300g is centrifuged for 5 minutes, 120 microliter of supernatant is sucked out from each hole and placed in a new 96-hole culture plate, 60 microliter of LDH detection working solution is added in a dark place, and the mixture is uniformly mixed and incubated for 30 minutes at room temperature in a dark place;
s7) puncturing large bubbles in the hole by using a syringe needle, and placing the 96-well plate in an enzyme-labeling instrument to detect the light absorption value at 490 nm;
s8) calculating cytotoxicity for each set of experiments: cytotoxicity (%) = (experimental OD value-effector cell natural release pore OD value-target cell natural release pore OD value)/(target cell lysis release pore OD value-target cell natural release pore OD value) ×100%.
Experimental summary:
the results of example 1 show that:
compared with untreated liraglutide groups, NK cell tumor killing was significantly increased, demonstrating that liraglutide can enhance NK cell tumor killing. The inventors further compared the tumor killing ability of NK cells with different concentrations of liraglutide. The results show that the toxic effect of NK cells has no obvious liraglutide concentration dependent effect, and the killing effect of NK cells on tumor cells can be obviously improved by co-incubation of the liraglutide with low concentration.
Studies have shown that liraglutide promotes the killing of immune cells mainly by inhibiting STAT3 signaling pathways in tumor cells, and that the effect of liraglutide in the tumor microenvironment is twofold, on the one hand, in tumors, NKG2D ligand (MICA/B, ULBP) and NK cell-attracting chemokine CCL5 are inhibited by STAT 3; upregulating surface expression of MHC I and PD-L1 molecules and secretion of immunosuppressive factor TGF-b; on the other hand, in NK cells, STAT3 reduces DNAM-1 expression in NK cells. Increased levels of DNAM-1 following Stat3 deficiency help to enhance killing of tumor cells expressing DNAM-1 ligand, increased expression of granzyme B and perforin following Stat3 deficiency. After the liraglutide is acted, NK cell recognition and killing cells are promoted.
To further explore how liraglutide enhances tumor killing of NK cells, an optimal treatment regimen was explored. The inventors designed different experimental groups: in order to verify whether liraglutide directly affects the tumor killing of NK cells, liraglutide was pre-treated with NK cells and tumor cells for 2 hours, respectively, before tumor cytotoxicity experiments; to verify whether a continuous treatment of liraglutide is required for the enhancement of NK cell tumor killing, the liraglutide treatment group was continued to be administered in the tumor cytotoxicity experiment after 2 hours of pretreatment of NK cells and tumor cells, respectively.
The results of example 2 show that:
1. compared with the control group without using the liraglutide, the direct treatment of NK cells or tumor cells by the liraglutide is the detection of cytotoxicity. The liraglutide has no toxic or side effect on cells.
2. Compared with the non-pretreated liraglutide group, the NK cell pretreatment group has no difference in the NK cell tumor killing effect; the NK cell tumor killing effect was also not different in the liraglutide pre-treated tumor cell group compared to the non-pre-treated liraglutide group. It is demonstrated that liraglutide does not directly promote its tumor killing ability by affecting NK, and also has no direct killing promoting effect on tumor cells.
3. After the tumor cells are pretreated by the liraglutide for 2 hours, and the liraglutide treatment is continued in the process of the common incubation of NK and tumor cells, the tumor killing property of the NK cells can be remarkably improved, and the cytotoxicity is improved by about 2 times compared with that of a group which is not treated by the liraglutide. Demonstrating that liraglutide plays a role in NK cell killing tumor; pretreatment of tumor groups, the strongest NK cytotoxicity also indicated that liraglutide was able to boost the sensitivity of tumor cells to NK cell killing.
Example 3 further demonstrates the role of liraglutide in tumor immune cell therapy, increasing the effective target ratio of NK cells to tumor cells to 10:1. the results showed agreement with the conclusions of example 2. After the tumor cells are pretreated by the liraglutide for 2 hours, and the liraglutide treatment is continued in the process of the common incubation of NK and tumor cells, the tumor killing property of the NK cells can be remarkably improved, the tumor cytotoxicity reaches 94%, and the tumor cells almost completely die. From this it follows that the effective target ratio 10:1, after the liraglutide is used for preprocessing tumor cells for 2 hours, the scheme of incubating NK and tumor cells and simultaneously maintaining low concentration of the liraglutide has the best tumor killing effect.
In conclusion, the experimental result of the inventor shows that the liraglutide enhances the killing capacity of NK cells on tumors by improving the sensitivity of the tumor cells to NK cell killing. In addition, compared with a control group without using liraglutide, the treatment with the liraglutide can obviously improve the tumor killing performance of NK cells without toxic and side effects.
The above description of the present invention is further illustrated in detail and should not be taken as limiting the practice of the present invention. It is within the scope of the present invention for those skilled in the art to make simple deductions or substitutions without departing from the concept of the present invention.
Claims (10)
1. Application of liraglutide in preparing immune cell treating synergist.
2. The use according to claim 1, wherein said immune cells are selected from NK cells, NKT cells.
3. The use according to claim 1 or 2, wherein the subject to immune cell therapy is a tumor patient.
4. The use according to claim 3, wherein the patient is associated with obesity and/or diabetes.
5. The use according to claim 3, wherein the tumour is selected from STAT3 activated tumours.
6. The use according to claim 5, wherein the tumour is selected from mature B-cell non-hodgkin's lymphoma, acute myeloid leukaemia, myelodysplastic syndrome, chronic myelogenous leukaemia, neuroblastoma, renal cell carcinoma, melanoma, liver cancer, breast cancer or ovarian cancer.
7. The use according to claim 1 or 2, characterized in that the amount of liraglutide is 0.6-1.8 mg/day.
8. Use according to claim 1 or 2, characterized in that the immune cell therapy is performed within 0-13 h after the administration of liraglutide.
9. The use according to claim 1 or 2, characterized in that the dose ratio of liraglutide to immune cells is 0.6-1.8 mg/(1-5) E10.
10. The use according to claim 1 or 2, wherein the immune cells are derived from at least one of peripheral blood, umbilical cord blood and induced pluripotent stem cells.
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| CN111789939A (en) * | 2019-04-09 | 2020-10-20 | 南京大学 | Application of liraglutide in preparation of tumor immunotherapy medicine |
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| CN111789939A (en) * | 2019-04-09 | 2020-10-20 | 南京大学 | Application of liraglutide in preparation of tumor immunotherapy medicine |
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