CN111375054A - Tumor vaccine composition, and preparation method and application thereof - Google Patents

Tumor vaccine composition, and preparation method and application thereof Download PDF

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CN111375054A
CN111375054A CN201811610725.7A CN201811610725A CN111375054A CN 111375054 A CN111375054 A CN 111375054A CN 201811610725 A CN201811610725 A CN 201811610725A CN 111375054 A CN111375054 A CN 111375054A
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vaccine composition
cells
cancer
tumor vaccine
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吴向华
张兰林
胡爱群
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Fudan University Shanghai Cancer Center
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    • A61K39/00—Medicinal preparations containing antigens or antibodies
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    • A61K39/0011—Cancer antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A61K2039/515—Animal cells
    • A61K2039/5154—Antigen presenting cells [APCs], e.g. dendritic cells or macrophages
    • 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
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration

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Abstract

The invention belongs to the technical field of tumor immunotherapy, and relates to a novel tumor vaccine composition, a preparation method thereof and application of the prepared tumor vaccine composition in preparation of products for treating solid tumors. The tumor vaccine composition prepared by the method comprises the steps of preparing an immunogenic cell death inducer with a certain concentration; immature human dendritic cells obtained by culturing autologous peripheral blood mononuclear cells; and co-incubating the obtained immunogenic cell death inducer with a certain concentration and the obtained autologous immature dendritic cells to form the personalized cancer vaccine composition. The vaccine composition has the advantages of overcoming tumor heterogeneity, high specificity, less adverse reaction, high efficiency and long-lasting anti-tumor effect. Can be used for immunotherapy of primary tumor and prevention of tumor recurrence and metastasis.

Description

Tumor vaccine composition, and preparation method and application thereof
Technical Field
The invention relates to the technical field of tumor immunotherapy, in particular to a novel tumor vaccine composition and a preparation method thereof. The invention also relates to the application of the prepared tumor vaccine composition in preparing a preparation for treating solid tumors.
Background
It is reported that malignant tumors are still a major cause of human death by endangering human health now and for a long time in the future. According to the world cancer report of the world health organization, it is expected that the number of new cases of malignant tumors reaches 1500 million and 1000 million people die every year in 2020 worldwide. Despite the great advances made in current surgery, chemotherapy, radiation therapy, molecular targeting and immunotherapy of tumors, the problems of tumor recurrence and metastasis still remain elusive. Research reports that tumor vaccine treatment can induce adaptive immune response aiming at tumor specific antigens and generate immune memory, can remove residual tumor focuses and effectively prevent tumor recurrence and metastasis. Tumor immunotherapy has now become a new tumor treatment modality following surgery, chemotherapy and radiotherapy, and has significant synergy with conventional therapies.
Tumor vaccines are one way of active specific immunotherapy. In the process of anti-tumor immune response, tumor specific antigen is taken up by Antigen Presenting Cells (APC), processed and presented to T cells for activation. Dendritic Cells (DCs) are the most powerful professional APC in human bodies, and HLA-I, HLA-II molecules are highly expressed on the membrane surface, can efficiently take, process and present antigens, and activate T cells to generate anti-tumor immune response, thereby becoming a key link of the anti-tumor immune response. The mature DC capable of effectively absorbing, processing and presenting the whole tumor neoantigen can activate in vivo T cells to become tumor antigen specific T cells, thereby effectively killing tumor cells and establishing a durable anti-tumor specific immune response.
Calreticulin (CRT) is a member of the DAMPs family of molecules and studies have shown that CRT is a characteristic marker of Immunogenic Cell Death (ICD) by translocation from the endoplasmic reticulum to the cell membrane early in tumor cell death. The calreticulin in the immunogenicity dead tumor cell translocates from cytoplasm to cell membrane, is recognized and phagocytized by a receptor on the surface of a dendritic cell, and then processes and presents tumor antigen to CD4+And CD8+T cells, thereby stimulating the body to generate a specific immune response against the tumor antigen.
The research discloses that the ICD inducer rose bengal is a natural pigment and has selective permeability on tumor cells to induce the ICD of the tumor cells. ICDs are important pathways for activating anti-tumor immunity, including the release of risk-associated molecular patterns (DAMPs) and tumor-associated antigens (TAAS), promoting phagocytosis of antigen-presenting cells, processing, and presentation of tumor antigens.
Studies have shown that, in tumor immunotherapy, tumor antigens are proteolytically degraded into polypeptides by proteasomes in Antigen Presenting Cells (APCs), and then transported to the endoplasmic reticulum lumen by peptide transporters to bind to newly synthesized HLA molecules (human leukocyte antigens, including HLA-class I molecules or HLA-class II molecules) and migrate to the surface of the APCs to form HLA-antigen peptide complexes, and after T cells recognize the HLA-antigen peptide complexes on the surface of the antigen presenting cells by TCRs (TCR) on their surface, the T cells are activated and proliferate under stimulation of a costimulatory signal (interaction of B7 molecules with CD28 molecules), and most of the T cells are further differentiated into cytotoxic effector cells. Cytotoxic T cells eliminate tumor cells, and a part of T lymphocytes become memory T cells to exert lasting specific anti-tumor immune function.
Based on the basis and the current situation of the prior art, the inventors of the present application intend to provide a novel tumor vaccine composition, a preparation method thereof, and an application of the prepared tumor vaccine composition in preparation of a preparation for treating solid tumors.
Disclosure of Invention
The invention aims to provide a novel tumor vaccine composition and a preparation method thereof based on the foundation and the current situation of the prior art, and application of the prepared tumor vaccine composition in preparation of a product for treating solid tumors.
Specifically, the invention provides a vaccine for immunotherapy of primary tumors and prevention of tumor recurrence and metastasis and a preparation method thereof. The multifunctional personalized cancer vaccine composition prepared by the method has the advantages of overcoming tumor heterogeneity, high specificity, less adverse reaction, high efficiency and long lasting anti-tumor effect.
More specifically, the present invention provides a tumor vaccine composition prepared by the following method comprising the steps of: (a) preparing an immunogenic cell death inducer with a certain concentration; (b) immature human dendritic cells obtained by culturing autologous peripheral blood mononuclear cells; (c) co-incubating the certain concentration of the immunogenic cell death inducer obtained in the step (a) and the autologous immature dendritic cells obtained in the step (b) to form a personalized cancer vaccine composition.
The immunogenic cell death inducer in the present invention refers to a characteristic substance such as a photosensitizer, e.g., rose bengal, which induces immunogenic death of tumor cells.
Photosensitizers for use in the present invention include, but are not limited to Rose Bengal (Rose Bengal).
The rose bengal in the invention is also called bengal, huhong sodium salt, acid red 94 and tetrachlorotetraiodofluorescein disodium.
The rose bengal concentration in the present invention is used at a corresponding appropriate concentration based on the different tumor cells.
In one aspect of the invention, a concentration of ICD inducer can be injected into tumor with rose bengal to induce immunogenic cell death in vivo, or can act on fresh tumor cells in vitro to obtain a characteristic tumor specific antigen peptide-MHC-I complex bound with molecular chaperone Calreticulin (CRT).
The immature dendritic cells of the present invention are obtained by culturing autologous peripheral blood mononuclear cells with cytokines.
The immunogenic cell death inducer of the present invention, such as rose bengal, a vaccine for inducing a prophylactic or therapeutic immune response can be administered in admixture or in combination with immature dendritic cells to more effectively establish an immune response.
The immunogenic cell death inducing agent which can be used may be considered a nanoparticle preparation, a microsphere preparation, a microcapsule preparation and the like.
The method for administering the above vaccine or pharmaceutical composition of the present invention includes intratumoral injection and the like.
The vaccines and pharmaceutical compositions of the present invention described above can also be used to treat tumor patients by in vitro methods, in other words, the immunogenic cell death inducing agents of the present invention can be contacted with primary tumor cells from patients in vitro, producing antigen presenting cells capable of recognizing the antigen or antigen complex of the present invention, thereby inducing specific T cells, particularly CD8+ T cells, and then returned to patients for the prevention or treatment of cancer.
In one aspect of the invention, methods are provided for producing antigen presenting cells, wherein one of the cells capable of antigen presentation is a dendritic cell.
The antigen-presenting cells of the present invention can be obtained by isolating lymphocytes from peripheral blood of a tumor patient, removing cells that cannot adhere to a culture dish, and culturing the adherent cells in the presence of GM-CSF and IL-4 to induce dendritic cells to prepare the antigen-presenting cells of the present invention.
The antigen-presenting cells of the present invention provided above can be used for the preparation of vaccine compositions for the treatment or prevention of cancer; the method used comprises intratumoral injection.
The vaccine composition of the invention can be used for treating malignant tumors. The malignant tumor includes solid tumor, more specifically, lung cancer, gastric cancer, gallbladder cancer, bile duct cancer, pancreatic cancer, liver cancer, colorectal cancer, breast cancer, ovarian cancer, soft tissue sarcoma, renal cancer, prostate cancer, etc., preferably liver cancer, colorectal cancer, malignant lymphoma, etc.
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FIG. 1a RB induces ICD in Lewis cells;
FIG. 1B RB induces ICD in B16 cells;
FIG. 2 markers of imDC cells and mDC maturation;
FIG. 3 impact of RB on imDC;
FIG. 4a RB treated tumor growth curves in combination with imDC in mice;
FIG. 4b RB treated tumor survival curves in combination with imDC in mice;
FIG. 5 the effect of the cells on killing tumor cells;
FIG. 6a solid map of inhibition of lung metastasis by RB in combination with imDC in mice;
FIG. 6b inhibition of lung metastasis rate in mice by RB in combination with imDC;
FIG. 7 intratumoral CD8+ T cell ratio following treatment of tumor-bearing mice.
Detailed Description
Example 1 tumor cells induced by ICD inducers exhibit ICD-characteristic CRT translocation
The invention adopts the tumor cells which are induced to generate immunogenic cell death by an ICD inducer as the source of the whole cell antigen, and comprises the following specific steps:
1.110 uM RB acts on Lewis cells for 30 min;
1.2 detecting translocation of ICD marker CRT by immunofluorescence method, the experimental result is shown in FIG. 1 a;
1.310 uM RB was applied to B16 cells for 30 min;
1.4 detection of translocation of ICD marker CRT by immunofluorescence, the experimental results are shown in FIG. 1 b.
Example 2 culture and characterization of DC cells
Dendritic Cells (DCs) are the most functional Antigen Presenting Cells found today (APC). It has been demonstrated that DCs are the only APC capable of significantly stimulating proliferation of Naive T cells (Naive Tcells), whereas other APCs (e.g. monocytes macrophages, B cells, etc.) can only stimulate activated or memory T cells. DCs are the initiators of adaptive T cell immune responses in the body and play an extremely important role in tumor immunity. If tumor antigen-loaded DCs are co-cultured with sorted CD8+ naive T lymphocytes, the body is stimulated to produce tumor antigen-specific Tsccm cells under the action of specific cytokines.
The culture and identification steps of the DC cells are as follows:
2.1 taking 1 mouse tibia and fibula bone marrow cells;
2.2 separating and purifying mononuclear cells (PBMC) by a lymphocyte separating liquid density gradient centrifugation method;
2.3 washing 2 times in serum-free culture medium to obtain PBMC with purity of over 90% and cell number of 1-3 × 108. Adherent cells (predominantly CD14 +'s monocytes), serum-free medium containing recombinant human GM-CSF (500U/ml) and recombinant human IL-4(500U/ml) were added at 37 deg.C with 5% CO2Culturing in an incubator, and inducing the monocyte to differentiate into DC cells;
2.4 half a dose of liquid is changed every 3d, and cell factors are complemented;
2.5 at day 6 of culture, the ratio according to tumor antigen: the imDC cells are added with 100uM RB (ethidium bromide) to treat the tumor antigen obtained after Lewis 24 according to the proportion of 1:10, and the DC is subjected to antigen loading;
2.669 h later, the DC cells are harvested;
2.7 flow cytometry detection of expression of molecules such as HLA-DR, CD8O, CD86 and CD14 on the surface of imDC and mDC cells. The results of the experiment are shown in FIGS. 2a and 2 b.
Example 3 Effect of RB on imDC
3.1 different concentrations of RB act on imDCs;
the viability of the imDCs was measured after 3.224 h using a cytometer and the results are shown in FIG. 3.
Example 4 tumor treatment Effect of RB in combination with imDC in mice
4.1 Male C57BL/6 mice of SPF grade 6-8 weeks old were inoculated subcutaneously in the right axilla with 1X106lewis cells, 6-8 mice per group, 4 groups in total;
4.2 when the tumor grows to about 4-5mM, 4 groups of mice are injected with PBS, 1mM RB and 1x10 intratumorally6RB in vitro Effect tumor cell induced mDC vaccine (RB-based mDC vacc), RB and iDC composition vaccine (RB-iDC vacc). RB-iDC vaccine: intratumoral 1mM RB, 10 min later, intratumoral 1X106imDC. The intratumoral injection volume was one-half of the mouse tumor volume, and the formula was calculated according to the formula (V ═ 0.5x (d)longx dshortx dshort))；
4.3 record the change in volume of the tumor each day, the results are shown in FIG. 4 a;
4.4 growth of the mice was observed and the results are shown in FIG. 4 b.
Example 5 Effect of cells on killing tumor cells
5.1 when the diameter of the tumor in the control group is about 10-15mm, taking spleens of 4-6 mice in each group;
5.2 separating and purifying mononuclear cells (PBMC) by lymphocyte separating liquid density gradient centrifugation, culturing in RPMI culture medium, and adding 5ng/ml IL-2;
5.3 acting Lewis cells with 100uM RB for 24h, then flushing PBMC in vitro for 5 days, and changing fresh culture medium containing 5ng/ml IL-2 every 2 days;
centrifuging at 1000rpm for 5min after 5.45 days to obtain lymphocytes, wherein the lymphocytes are used as effector cells, and the Lewis is used as target cellsAnd (4) cells. The number of target cells was 8X103lewis cells, effector cells mixed with target cells at E: T ratios of 25:1,12:1,6:1 and 3:1, effector cells (at each effector cell concentration) added to effector cell spontaneous LDH release control wells and experimental wells, target cells added to experimental wells, target cell spontaneous LDH release control wells and target cell maximum LDH release control wells, cell culture medium and lysis solution (10 ×) added to volume correction control wells, cell culture medium added to medium background control wells, and a final volume of 100 μ Ι. Centrifuging at 1110rpm for 4 min;
5.5 all effector and target cells were incubated in 96-well round bottom plates at 37 ℃ for 6 hours, 45min before centrifugation, 10ul 10 × lysis buffer was added to the target cell maximum LDH release control wells, centrifuged at 1110rpm for 4 min;
5.6 centrifugation, carefully transferring 50. mu.l of supernatant to a new 96-well round bottom plate, adding 50ul of substrate to each well, and incubating for 30 minutes at room temperature in the dark;
5.7 Add 50. mu.l stop solution to each well;
5.8 Absorbance was measured at 490nm and the percent cytotoxicity generated for each effective target ratio was calculated. Calculating the formula: the% cytotoxicity ═ (experiment-effector cell spontaneous-target cell spontaneous)/(target cell maximal-target cell spontaneous) x100, and the results are shown in fig. 5.
Example 6 RB in combination with imDC in mice inhibits pulmonary metastasis
6.1 PBS, RB-based mDC vaccine and RB-iDC vaccine after 21 days of treatment of mice in 4 experimental groups, mice were sacrificed and injected with India ink (15%) through the trachea;
6.2 both lungs of the mouse were collected and soaked in Fekete solution (100mL 70% ethanol, 5mL glacial acetic acid and 10mL formalin) at room temperature for 3 days;
after 6.33 days, the number of nodes on the surface of the lung for treatment is counted and photographed, and the experimental result is shown in figure 6 a;
6.4 calculate the lung metastasis rate of each group of mice, and the experimental results are shown in FIG. 6 b.
Example 7 intratumoral CD8+ T cell proportion following treatment of tumor-bearing mice
7.1 sterile removal of tumor tissue and cutting into 1-2mm3Then washed with RPMI-1640 medium;
7.2 tumor dissociation in PBS containing 1mg/mL collagenase D (Roche) and 30. mu.g/mL DNase I (Roche) with constant shaking at room temperature for 20 min;
7.3 the cell suspension was then filtered through a 40 μm nylon screen to remove any undigested tissue debris and washed twice with RPMI-1640 medium;
7.4 count cells and determine cell viability using trypan blue dye exclusion assay;
7.5 flow cytometry was used to measure the expression rate of CD8+ T cells, and the results are shown in FIG. 7.

Claims (10)

1. A tumor vaccine composition is characterized by comprising a certain concentration of immunogenic cell death inducer solution and autologous immature dendritic cells, and is prepared by the following method:
(1) preparing an immunogenic cell death inducer solution with a certain concentration, and filtering and sterilizing the solution;
(2) immature human dendritic cells obtained by culturing autologous peripheral blood mononuclear cells;
(3) mixing the immunogenic cell death inducer with a certain concentration obtained in the step (1) and the autologous immature dendritic cells with a certain quantity obtained in the step (2) to prepare the tumor vaccine composition.
2. The tumor vaccine composition according to claim 1, wherein the immunogenic cell death inducing agent is a photosensitizer, a characteristic substance, that induces immunogenic death of tumor cells.
3. The tumor vaccine composition of claim 2, wherein the photosensitizer is rose bengal.
4. The tumor vaccine composition of claim 3, wherein the rose bengal is formulated in a concentrated solution of rose bengal in saline.
5. The tumor vaccine composition according to claim 1, wherein the solution of the specific concentration of the immunogenic cell death inducing agent is 1mM rose bengal solution.
6. The tumor vaccine composition according to claim 1, wherein the immature dendritic cells are obtained from peripheral blood mononuclear cells.
7. The tumor vaccine composition according to claim 1, wherein the immature dendritic cells are induced by monocytes under the action of granulocyte-macrophage colony stimulating factor and interleukin-4.
8. Use of the tumor vaccine composition of claim 1 in the preparation of a preparation for the treatment of solid tumors.
9. The use according to claim 8, wherein the solid tumor is selected from the group consisting of lung cancer, gastric cancer, gallbladder cancer, cholangiocarcinoma, pancreatic cancer, liver cancer, colorectal cancer, breast cancer, ovarian cancer, soft tissue sarcoma, renal cancer, prostate cancer.
10. The use of claim 8, wherein said tumor vaccine composition is administered by intratumoral injection.
CN201811610725.7A 2018-12-27 2018-12-27 Tumor vaccine composition, and preparation method and application thereof Pending CN111375054A (en)

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Cited By (3)

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Publication number Priority date Publication date Assignee Title
CN113440607A (en) * 2021-06-30 2021-09-28 澳门大学 Full-target antigen presenting cell tumor vaccine and preparation method and application thereof
CN114748457A (en) * 2022-04-11 2022-07-15 中国医学科学院医学生物学研究所 Pharmaceutical composition for treating cervical cancer and application thereof
CN116763906A (en) * 2021-09-08 2023-09-19 周泽洋 Dendritic tumor vaccine cultivation technology

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CN114748457A (en) * 2022-04-11 2022-07-15 中国医学科学院医学生物学研究所 Pharmaceutical composition for treating cervical cancer and application thereof

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Application publication date: 20200707