CN112516319A - Combination medicament for treating breast cancer - Google Patents
Combination medicament for treating breast cancer Download PDFInfo
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- CN112516319A CN112516319A CN202011446702.4A CN202011446702A CN112516319A CN 112516319 A CN112516319 A CN 112516319A CN 202011446702 A CN202011446702 A CN 202011446702A CN 112516319 A CN112516319 A CN 112516319A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/02—Bacterial antigens
- A61K39/04—Mycobacterium, e.g. Mycobacterium tuberculosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/14—Drugs for genital or sexual disorders; Contraceptives for lactation disorders, e.g. galactorrhoea
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
Abstract
The invention discloses a combined medicament for treating breast cancer, which consists of an effective amount of BCG preparation, an immunomodulator and pharmaceutically acceptable auxiliary materials. The combined medicament combines the BCG preparation and the immunomodulator, has good safety, can up-regulate the expression of related genes of chemotactic factors and anti-tumor effect genes, down-regulate the expression of related genes of immunosuppression, increase the number of tumor infiltrating lymphocytes and enhance the anti-tumor immunity; can well inhibit the growth of triple negative breast cancer tumors on animal tumor models, and is better than any single drug treatment method.
Description
Technical Field
The invention relates to the field of treatment of breast cancer, and in particular relates to a combined medicament for treating breast cancer.
Background
The breast cancer is a common female malignant tumor, the incidence rate of the breast cancer is increased year by year in China in recent years, and the breast cancer becomes the female malignant tumor with the highest incidence rate in China. Triple Negative Breast Cancer (TNBC) is a subtype of Breast Cancer, has the characteristics of high invasiveness, strong metastasis, poor prognosis and the like, is a recognized Breast disease difficult to treat, and is the lowest five-year survival rate in all types of Breast Cancer. TNBC refers specifically to breast cancer that lacks Estrogen Receptor (ER), Progestin Receptor (PR), and Human epidermal growth factor Receptor 2 (Her-2) expression. Trastuzumab and tamoxifen have good curative effects on Her-2 and ER over-expressed breast cancer patients, but have no curative effect on TNBC patients.
Currently, TNBC treatment is still based on surgical resection and chemotherapy, and effective methods for treating TNBC are urgently needed.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides a combined medicament for treating breast cancer, which combines a BCG preparation and an immunomodulator and can be used for treating the breast cancer, particularly triple negative breast cancer.
In order to achieve the purpose, the invention designs a combined medicament for treating breast cancer, which consists of an effective amount of BCG preparation, an immunomodulator and pharmaceutically acceptable auxiliary materials.
Further, the combined medicament comprises 1-3 parts of BCG preparation, 3-10 parts of immunomodulator and 3-10 parts of auxiliary material.
Still further, the bcg formulation is a phosphate buffered saline solution comprising bcg.
Still further, the immunomodulator is a Programmed cell Death receptor 1 (PD-1) molecular blocker or a Programmed cell Death Ligand 1 (PD-L1) molecular blocker or a PD-L1 antibody or a PD-1 antibody.
Still further, the immunomodulator is a PD-L1 molecular blocker.
Still further, the combined medicament consists of 1 part of BCG preparation, 7 parts of PD-L1 molecular blocking agent and 7 parts of auxiliary materials, wherein the BCG preparation is phosphate buffered saline solution containing BCG; in the BCG preparation, the content of BCG is 1.5 multiplied by 106CFU (colony forming unit).
Furthermore, the auxiliary materials are corn oil or olive oil or sesame oil (the auxiliary materials are all medical grade).
Still further, the breast cancer is triple negative breast cancer (which is a solid tumor).
The principle of the invention is as follows: in the combined medicament, Bacillus Calmette-guerin (BCG) is used for preventing tuberculosis, and has good safety. BCG has strong immune activation capability, is used for treating clinical bladder cancer, and can obviously reduce the recurrence rate of the bladder cancer after operation. Meanwhile, BCG can up-regulate the expression of Programmed Death Ligand 1 (PD-L1) in the tumor, while PD-L1 can inhibit the activity of T cells killing tumor cells to a certain extent, and the tumor treatment effect of BCG can be further improved by using an immunomodulator for blocking PD-L1; therefore, the BCG and immunomodulator combined therapy has good breast cancer tumor resisting effect, especially for triple negative breast cancer
The invention has the beneficial effects that:
the combined medicament combines the BCG preparation and the immunomodulator, has good safety, can up-regulate the expression of related genes of chemotactic factors and anti-tumor effect genes, down-regulate the expression of related genes of immunosuppression, increase the number of tumor infiltrating lymphocytes and enhance the anti-tumor immunity; the growth of triple negative breast cancer tumor can be well inhibited on an animal tumor model, and the method is better than any single drug treatment method; this indicates that the present invention has a good therapeutic effect on solid tumors.
Drawings
FIG. 1 is a graph of BCG treatment for TNBC increasing the number of tumor infiltrating lymphocytes;
FIG. 2 is a graph showing the increase in the number of CD3 positive T cells in frozen sections of BCG-treated TNBC tumors;
FIG. 3 is a graph of gene expression changes in BCG treatment TNBC tumors;
FIG. 4 is a graph of tumor volume reduction by BCG treatment with TNBC;
FIG. 5 is a graph of tumor size reduction and tumor progression for BCG treatment with TNBC;
FIG. 6 is a graph showing no significant lesions in spleen, lung and kidney of mice treated with BCG for TNBC;
FIG. 7 is a graph of BCG treatment TNBC mouse body weight;
FIG. 8 is a graph of in vivo imaging results of BCG and PD-L1 molecular blocking agent combined treatment of TNBC mice;
FIG. 9 is a graph of tumor volume reduction by TNBC treatment with BCG in combination with a molecular blocking agent PD-L1;
FIG. 10 is a graph of the body weight of TNBC mice treated with BCG in combination with a molecular blocking agent PD-L1;
FIG. 11 shows that TNBC treated with BCG in combination with a molecular blocking agent PD-L1 reduces tumor size and weight.
Detailed Description
The present invention is described in further detail below with reference to specific examples so as to be understood by those skilled in the art.
Example 1 BCG vaccine activates anti-tumor immunity
1. Construction of mouse model of in situ triple negative breast cancer
Injection of 1X 10 into the fourth pair of mammary fat pads in the right side of 8 week old female Balb/c mice64T1-luc cellsAnd constructing an in-situ breast cancer mouse model.
2. BCG vaccine for increasing tumor lymphocyte number
To analyze the effect of BCG treatment on tumor infiltrating lymphocytes, mice were intratumorally injected with 10 microliters of OD 5 days after tumor inoculation600BCG in PBS, 2, mice were anesthetized and sacrificed 9 days after BCG vaccination, and tumor masses were isolated. The tumor was separated from the surrounding fascia with sterile scissors and ground. The cell mass was removed through a 70 μm cell filter to obtain a single cell suspension. Lymphocytes were isolated using a mouse tumor-infiltrating tissue lymphocyte isolation kit (Solarbio). After 2 washes with 1% BSA in PBS (FACS solution) and 30min blocking with anti-mouse CD16/CD32, tumor infiltrating lymphocyte suspensions were incubated with the antibodies CD49b APC, CD3-PE, CD4-FITC and CD8 a-PacBlue. After 1h incubation, the FACS solution was washed once and then analyzed by flow cytometry using a Cytoflex-LX (Beckman-Coulter). Meanwhile, unground tumor sections were stained with anti-mouse CD3-PE antibody for 1h, Hoechst for 1min, and confocal images were collected on a 40-fold objective lens using an Olympus FV1000 microscope.
The results showed that BCG treated group CD3 compared to PBS treated group+、CD4+、CD8+The T cell and NK cell content increased (figure 1), indicating that BCG treatment increased the lymphocyte count of TME in TNBC mice. The results of the staining of frozen tumor sections with CD3 also showed CD3+ T cell proliferation in BCG-treated tumors (FIG. 2). These data indicate that bcg treatment can alter the immunosuppressive state of TME by recruiting more lymphocytes. BCG was suggested to be useful as a modification of TME for TNBC therapy.
3. Enhanced anti-tumor immunity of BCG vaccine at gene expression level
To analyze the effect of BCG treatment on TNBC mouse tumor gene expression, mice were anesthetized and sacrificed 9 days after BCG inoculation and tumor tissues were isolated. After total RNA was extracted from tumor mass, RNAseq library was constructed using the white RNA-seq Lib Prep Kit for Illumina Kit (ABclonal) and then sent to sequencing company (Genewiz) for high throughput sequencing. Upstream data analysis was performed using the nf-core rnaseq pipeline. The parameters are "-aligner hisat 2-skipbiotypqc-genome mm 10". The differential gene expression analysis was performed using DEseq2 and a normalized count matrix was derived. Differentially expressed genes were enriched by the GO-Immunesystems Process-EBI-Unit-GOA-ACAP-ARAP-08.05.2020 library using the Cytoscape/ClueGo software. The screening conditions are as follows: p is less than or equal to 0.05, the correction method is Bonferroni decompression, the minimum GO level is 3, the maximum GO level is 8, and the Kappa scoring threshold is 0.4.
The results show that BCG vaccine treatment can up-regulate the expression of chemokine related genes (Ccl5, Cxcl9, Cxcl10), lymphocyte activation genes (Cd69, Klrk1) and anti-tumor effect genes (Ifngr1, Gzma) and down-regulate the expression of immunosuppression related genes (Tigit, Vegfa) (figure 3), which shows that BCG has anti-tumor effect. Meanwhile, we found that genes associated with the PD1/PD-L1 immunoscreening site (Cd274 and Pdcd1) were up-regulated in breast tumors after bcg treatment (fig. 3). This means that the combined use of BCG and an immunoscreening site blocker (e.g. an anti-PD-L1 inhibitor) may have a better effect on tumor therapy.
EXAMPLE 2 triple dose BCG treatment of triple negative breast cancer
1. Construction of mouse model of in situ triple negative breast cancer
Injection of 1X 10 into the fourth pair of mammary fat pads in the right side of 8 week old female Balb/c mice64T1-luc cells, and constructing an orthotopic breast cancer mouse model.
2. Triple dose BCG vaccine for treating triple negative breast cancer
To verify the oncolytic effect of BCG, animals were randomized into three groups on day 5 post tumor vaccination. In the single-dose BCG treatment group, mice were intratumorally injected with one dose of BCG (1.5X 10) on day 5 after tumor inoculation6CFU). In the three-dose BCG treatment group, mice were intratumorally injected with one dose of BCG (1.5X 10) on days 5, 9 and 13 after tumor inoculation, respectively6CFU). In the PBS group, mice were injected with 10 μ l PBS on days 5, 9, and 13 after tumor inoculation. The long (L) and short (W) diameters of the tumor mass were measured with a vernier caliper every 2-3 days. According to the formula of ellipsoid volume calculation (i.e. 1/2 XLXW)2) Tumor volume was calculated. Recording every 2-3 daysOne body weight data, mice were killed by anesthesia 25 days after BCG injection. The tumor was separated from the surrounding fascia, weighed and photographed. The spleen, lung and kidney were analyzed histopathologically to identify side effects of BCG treatment.
The results showed that the tumor volume increase was slower in the single dose BCG group than in the PBS group, whereas the tumor volume increase was the slowest in the three dose BCG group (fig. 4). Tumor volume and weight were also minimal in the three-dose BCG group 25 days after inoculation (fig. 5). These data indicate that single dose bcg treatment can moderately slow the progression of TNBC, and that triple doses of bcg have a stronger inhibitory effect on TNBC. No pathological changes were observed in the liver, kidney and spleen between the three groups (fig. 6), indicating that neither single dose BCG nor triple dose BCG caused organic lesions in mice. However, the mice in the three-dose BCG group had a significant weight loss during treatment compared to the single-dose BCG group and PBS group (fig. 7), which may be associated with stronger immune stimulation induced by multiple BCG treatments.
EXAMPLE 3 combination of BCG formulations and immunomodulators for treatment of triple negative breast cancer
1. Construction of mouse model of in situ triple negative breast cancer
Injection of 1X 10 into the fourth pair of mammary fat pads in the right side of 8 week old female Balb/c mice64T1-luc cells, and constructing an orthotopic breast cancer mouse model.
2. BCG preparation and immunomodulator combined treatment of triple negative breast cancer
To verify the oncolytic effect of BCG and PD-L1 blocker (BMS202) combination therapy on TNBC mouse models, mice were randomized into four groups on day 5 post tumor vaccination. In the BCG vaccine combination anti-PD-L1 treatment group, mice were intratumorally given an intratumoral dose of BCG (1.5X 10) on day 5 after tumor inoculation6CFU), on day 9 after bcg injection, mice were injected intraperitoneally daily for 7 consecutive days with one dose (20 mg per kg mouse body weight) of BMS202 (7 parts in total) plus one dose (10 microliters) of corn oil (7 parts in total). In the three-dose BCG treatment group and PBS group, mice were treated according to the previous method. In the anti-PD-L1 treatment group, mice were injected intratumorally with 10. mu.l of PBS 5 days after tumor inoculation and 9 days after PBS injectionMice were dosed intraperitoneally (20 mg per kg mouse body weight) of BMS202 (7 parts total) plus one dose (10 microliters) of corn oil (7 parts total) for 7 days. The length (L) and short (W) diameter of each mouse tumor was recorded every 3-4 days with a vernier caliper. According to the formula of ellipsoid volume calculation (i.e. 1/2 XLXW)2) The total tumor volume was calculated for each animal. D-fluorescein (Promega) was injected intraperitoneally at a dose of 150mg/kg into 4 mice per group 21 days after tumor inoculation. Mice were imaged 15 minutes after injection using a small animal in vivo imager (PerkinElmer). Luciferase expression was quantitatively analyzed in the mouse model using imaging software (PerkinElmer). 30 days after tumor implantation, mice were killed by anesthesia and tumors were photographed and weighed.
The results show that real-time imaging of mice showed that, although three doses of BCG treatment were effective in alleviating the progression of TNBC compared to the PBS and anti-PD-L1 groups, none of the mice treated with a single dose of BCG in combination with anti-PD-L1 had detectable tumor luciferase signal (fig. 8), indicating that a single dose of BCG in combination with anti-PD-L1 treatment significantly inhibited the progression of TNBC.
Example 4
The combined medicament for treating breast cancer 1 consists of 1 part of BCG preparation, 7 parts of PD-L1 molecular blocking agent and 7 parts of medical corn oil, wherein the BCG preparation is phosphate buffered saline solution containing BCG; in the BCG preparation, the content of BCG is 1.5 multiplied by 106A CFU; the content of the PD-L1 molecular blocking agent is 0.4 mg per part; the corn oil content is 10 microliter per portion;
the results showed that the tumor volume was smaller in the group treated with combination agent 1 compared to the other groups treated with the combination agent (FIG. 9), indicating that the combination agent 1 treatment significantly inhibited the growth of breast cancer and that the combination agent 1 treatment had a better oncolytic effect. The mouse weight monitoring data show that combination 1 treatment was effective in reducing mouse weight loss induced by three doses of bcg treatment (figure 10), which may indicate that combination 1 treatment was more safe. The results for each group of tumor sizes and weights indicate that combination 1 treatment has significant therapeutic effect on TNBC mouse models (FIG. 11), eliminating most of the tumor mass.
Example 5
The combined medicament 2 for treating breast cancer consists of 3 parts of BCG preparation, 3 parts of PD-L1 molecular blocking agent and 3 parts of medical corn oil. Wherein the BCG preparation is phosphate buffered saline solution containing BCG; in the BCG preparation, the content of BCG is 1.5 multiplied by 106A CFU; the content of the PD-L1 molecular blocking agent is 0.4 mg per part; the corn oil content is 10 microliter per portion;
example 6
The combined medicament 3 for treating breast cancer consists of 2 parts of BCG preparation, 10 parts of PD-1 and 10 parts of medical corn oil. Wherein the BCG preparation is phosphate buffered saline solution containing BCG; in the BCG preparation, the content of BCG is 1.5 multiplied by 106A CFU; the content of the PD-L1 molecular blocking agent is 0.4 mg per part; the corn oil content is 10 microliters per serving.
Other parts not described in detail are prior art. Although the present invention has been described in detail with reference to the above embodiments, it is only a part of the embodiments of the present invention, not all of the embodiments, and other embodiments can be obtained without inventive step according to the embodiments, and the embodiments are within the scope of the present invention.
Claims (8)
1. A combination medicament for the treatment of breast cancer, characterized by: consists of an effective amount of BCG preparation, an immunomodulator and pharmaceutically acceptable auxiliary materials.
2. The combination pharmaceutical agent for use in the treatment of breast cancer according to claim 1, wherein: the combined medicament comprises 1-3 parts of BCG preparation, 3-10 parts of immunomodulator and 3-10 parts of auxiliary material.
3. The combination pharmaceutical agent for use in the treatment of breast cancer according to claim 1 or 2, wherein: the BCG preparation is phosphate buffered saline solution containing BCG.
4. The combination pharmaceutical agent for use in the treatment of breast cancer according to claim 1 or 2, wherein: the immunomodulator is a PD-1 molecular blocking agent or a PD-L1 molecular blocking agent or a PD-L1 antibody or a PD-1 antibody.
5. The combination pharmaceutical agent for use in the treatment of breast cancer according to claim 1 or 2, wherein: the immunomodulator is a PD-L1 molecular blocking agent.
6. The combination pharmaceutical agent for use in the treatment of breast cancer according to claim 5, wherein: the combined medicament consists of 1 part of BCG preparation, 7 parts of PD-L1 molecular blocking agent and 7 parts of auxiliary materials, wherein the BCG preparation is phosphate buffered saline solution containing BCG; in the BCG preparation, the content of BCG is 1.5 multiplied by 106CFU。
7. The combination pharmaceutical agent for use in the treatment of breast cancer according to claim 1 or 2, wherein: the auxiliary material is corn oil or olive oil or sesame oil.
8. The combination pharmaceutical agent for use in the treatment of breast cancer according to claim 1 or 2, wherein: the breast cancer is triple negative breast cancer.
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Citations (6)
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2020
- 2020-12-08 CN CN202011446702.4A patent/CN112516319A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105848680A (en) * | 2013-10-25 | 2016-08-10 | 药品循环有限责任公司 | Treatment using bruton's tyrosine kinase inhibitors and immunotherapy |
| WO2017070110A1 (en) * | 2015-10-19 | 2017-04-27 | Cold Genesys, Inc. | Methods of treating solid or lymphatic tumors by combination therapy |
| WO2018112360A1 (en) * | 2016-12-16 | 2018-06-21 | Evelo Biosciences, Inc. | Combination therapies for treating cancer |
| WO2018112364A1 (en) * | 2016-12-16 | 2018-06-21 | Evelo Biosciences, Inc. | Combination therapies for treating melanoma |
| CN111727197A (en) * | 2018-01-12 | 2020-09-29 | 美国安进公司 | anti-PD-1 antibodies and methods of treatment |
| WO2020180686A1 (en) * | 2019-03-01 | 2020-09-10 | Rampart Health, L.L.C. | Pharmaceutical composition combining immunologic and chemotherapeutic method for the treatment of cancer |
Non-Patent Citations (2)
| Title |
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| YONGHUA WANG等: "Bacillus Calmette–Guérin and anti-PD-L1 combination therapy boosts immune response against bladder cancer", 《ONCOTARGETS AND THERAPY》 * |
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